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Author: Grafiati

Published: 11 March 2023

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1

Wang, C., R. Lu, X. Ouyang, M. W. L. Ho, W. Chia, F. Yu, and K. L. Lim. "Drosophila Overexpressing Parkin R275W Mutant Exhibits Dopaminergic Neuron Degeneration and Mitochondrial Abnormalities." Journal of Neuroscience 27, no. 32 (August 8, 2007): 8563–70. http://dx.doi.org/10.1523/jneurosci.0218-07.2007.

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2

Carr, Jonathan, Ilaria Guella, Chelsea Szu-Tu, Sihaam Boolay, Brigitte Glanzmann, Matthew J. Farrer, and Soraya Bardien. "Double homozygous mutations (R275W and M432V) in the ParkinGene associated with late-onset Parkinson's disease." Movement Disorders 31, no. 3 (February 10, 2016): 423–25. http://dx.doi.org/10.1002/mds.26524.

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3

Ruffmann, Claudio, Michela Zini, Stefano Goldwurm, Manuela Bramerio, Sonia Spinello, Damiana Rusconi, Marcello Gambacorta, Fabrizio Tagliavini, Gianni Pezzoli, and Giorgio Giaccone. "Lewy body pathology and typical Parkinson disease in a patient with a heterozygous (R275W) mutation in the Parkin gene (PARK2)." Acta Neuropathologica 123, no. 6 (May 4, 2012): 901–3. http://dx.doi.org/10.1007/s00401-012-0991-7.

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4

Novak, Gabriela, Steven Finkbeiner, Gaia Skibinski, Michela Bernini, Cristina Donato, and Alexander Skupin. "Generation of two human induced pluripotent stem cell lines from fibroblasts of Parkinson’s disease patients carrying the ILE368ASN mutation in PINK1 (LCSBi002) and the R275W mutation in Parkin (LCSBI004)." Stem Cell Research 61 (May 2022): 102765. http://dx.doi.org/10.1016/j.scr.2022.102765.

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5

Jennings, Juliet E., Marianthi Georgitsi, Ian Holdaway, Adrian F. Daly, Maria Tichomirowa, Albert Beckers, Lauri A. Aaltonen, Auli Karhu, and Fergus J. Cameron. "Aggressive pituitary adenomas occurring in young patients in a large Polynesian kindred with a germline R271W mutation in the AIP gene." European Journal of Endocrinology 161, no. 5 (November 2009): 799–804. http://dx.doi.org/10.1530/eje-09-0406.

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ObjectiveMutations in the aryl hydrocarbon receptor-interacting protein (AIP) were recently shown to confer a pituitary adenoma predisposition in patients with familial isolated pituitary adenomas (FIPA). We report a large Samoan FIPA kindred from Australia/New Zealand with an R271W mutation that was associated with aggressive pituitary tumors.Design and methodsCase series with germline screening of AIP and haplotype analyses among R271W families.ResultsThis previously unreported kindred consisted of three affected individuals that either presented with or had first symptoms of a pituitary macroadenoma in late childhood or adolescence. The index case, a 15-year-old male with incipient gigantism and his maternal aunt, had somatotropinomas, and the maternal uncle of the index case had a prolactinoma. All tumors were large (15, 40, and 60 mm maximum diameter) and two required transcranial surgery and radiotherapy. All three affected subjects and ten other unaffected relatives were found to be positive for a germline R271W AIP mutation. Comparison of the single nucleotide polymorphism patterns among this family and two previously reported European FIPA families with the same R271W mutation demonstrated no common ancestry.ConclusionsThis kindred exemplifies the aggressive features of pituitary adenomas associated with AIP mutations, while genetic analyses among three R271W FIPA families indicate that R271W represents a mutational hotspot that should be studied further in functional studies.

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6

Allen, Simon, Adel M. Abuzenadah, Joanna Hinks, Joanna L. Blagg, Turkiz Gursel, Jørgen Ingerslev, Anne C. Goodeve, Ian R. Peake, and Martina E. Daly. "A novel von Willebrand disease–causing mutation (Arg273Trp) in the von Willebrand factor propeptide that results in defective multimerization and secretion." Blood 96, no. 2 (July 15, 2000): 560–68. http://dx.doi.org/10.1182/blood.v96.2.560.

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Abstract In this report we describe the molecular defect underlying partial and severe quantitative von Willebrand factor (VWF) deficiencies in 3 families previously diagnosed with types 1 and 3 Von Willebrand-disease. Analysis of the VWF gene in affected family members revealed a novel C to T transition at nucleotide 1067 of the VWF complemetary DNA (cDNA), predicting substitution of arginine by tryptophan at amino acid position 273 (R273W) of pre–pro-VWF. Two patients, homozygous for the R273W mutation, had a partial VWF deficiency (VWF:Ag levels of 0.06 IU/mL and 0.09 IU/mL) and lacked high-molecular weight VWF multimers in plasma. A third patient, also homozygous for the R273W mutation, had a severe VWF deficiency (VWF:Ag level of less than 0.01 IU/mL) and undetectable VWF multimers in plasma. Recombinant VWF having the R273W mutation was expressed in COS-7 cells. Pulse-chase experiments showed that secretion of rVWFR273W was severely impaired compared with wild-type rVWF. However, the mutation did not affect the ability of VWF to form dimers in the endoplasmic reticulum (ER). Multimer analysis showed that rVWFR273W failed to form high-molecular-weight multimers present in wild-type rVWF. We concluded that the R273W mutation is responsible for the quantitative VWF deficiencies and aberrant multimer patterns observed in the affected family members. To identify factors that may function in the intracellular retention of rVWFR273W, we investigated the interactions of VWF expressed in COS-7 cells with molecular chaperones of the ER. The R273W mutation did not affect the ability of VWF to bind to BiP, Grp94, ERp72, calnexin, and calreticulin in COS-7 cells.

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7

Allen, Simon, Adel M. Abuzenadah, Joanna Hinks, Joanna L. Blagg, Turkiz Gursel, Jørgen Ingerslev, Anne C. Goodeve, Ian R. Peake, and Martina E. Daly. "A novel von Willebrand disease–causing mutation (Arg273Trp) in the von Willebrand factor propeptide that results in defective multimerization and secretion." Blood 96, no. 2 (July 15, 2000): 560–68. http://dx.doi.org/10.1182/blood.v96.2.560.014k01_560_568.

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In this report we describe the molecular defect underlying partial and severe quantitative von Willebrand factor (VWF) deficiencies in 3 families previously diagnosed with types 1 and 3 Von Willebrand-disease. Analysis of the VWF gene in affected family members revealed a novel C to T transition at nucleotide 1067 of the VWF complemetary DNA (cDNA), predicting substitution of arginine by tryptophan at amino acid position 273 (R273W) of pre–pro-VWF. Two patients, homozygous for the R273W mutation, had a partial VWF deficiency (VWF:Ag levels of 0.06 IU/mL and 0.09 IU/mL) and lacked high-molecular weight VWF multimers in plasma. A third patient, also homozygous for the R273W mutation, had a severe VWF deficiency (VWF:Ag level of less than 0.01 IU/mL) and undetectable VWF multimers in plasma. Recombinant VWF having the R273W mutation was expressed in COS-7 cells. Pulse-chase experiments showed that secretion of rVWFR273W was severely impaired compared with wild-type rVWF. However, the mutation did not affect the ability of VWF to form dimers in the endoplasmic reticulum (ER). Multimer analysis showed that rVWFR273W failed to form high-molecular-weight multimers present in wild-type rVWF. We concluded that the R273W mutation is responsible for the quantitative VWF deficiencies and aberrant multimer patterns observed in the affected family members. To identify factors that may function in the intracellular retention of rVWFR273W, we investigated the interactions of VWF expressed in COS-7 cells with molecular chaperones of the ER. The R273W mutation did not affect the ability of VWF to bind to BiP, Grp94, ERp72, calnexin, and calreticulin in COS-7 cells.

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8

Tan, Manuela M. X., Naveed Malek, Michael A. Lawton, Leon Hubbard, Alan M. Pittman, Theresita Joseph, Jason Hehir, et al. "Genetic analysis of Mendelian mutations in a large UK population-based Parkinson’s disease study." Brain 142, no. 9 (July 19, 2019): 2828–44. http://dx.doi.org/10.1093/brain/awz191.

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AbstractOur objective was to define the prevalence and clinical features of genetic Parkinson’s disease in a large UK population-based cohort, the largest multicentre prospective clinico-genetic incident study in the world. We collected demographic data, Movement Disorder Society Unified Parkinson’s Disease Rating Scale scores, and Montreal Cognitive Assessment scores. We analysed mutations in PRKN (parkin), PINK1, LRRK2 and SNCA in relation to age at symptom onset, family history and clinical features. Of the 2262 participants recruited to the Tracking Parkinson’s study, 424 had young-onset Parkinson’s disease (age at onset ≤ 50) and 1799 had late onset Parkinson’s disease. A range of methods were used to genotype 2005 patients: 302 young-onset patients were fully genotyped with multiplex ligation-dependent probe amplification and either Sanger and/or exome sequencing; and 1701 late-onset patients were genotyped with the LRRK2 ‘Kompetitive’ allele-specific polymerase chain reaction assay and/or exome sequencing (two patients had missing age at onset). We identified 29 (1.4%) patients carrying pathogenic mutations. Eighteen patients carried the G2019S or R1441C mutations in LRRK2, and one patient carried a heterozygous duplication in SNCA. In PRKN, we identified patients carrying deletions of exons 1, 4 and 5, and P113Xfs, R275W, G430D and R33X. In PINK1, two patients carried deletions in exon 1 and 5, and the W90Xfs point mutation. Eighteen per cent of patients with age at onset ≤30 and 7.4% of patients from large dominant families carried pathogenic Mendelian gene mutations. Of all young-onset patients, 10 (3.3%) carried biallelic mutations in PRKN or PINK1. Across the whole cohort, 18 patients (0.9%) carried pathogenic LRRK2 mutations and one (0.05%) carried an SNCA duplication. There is a significant burden of LRRK2 G2019S in patients with both apparently sporadic and familial disease. In young-onset patients, dominant and recessive mutations were equally common. There were no differences in clinical features between LRRK2 carriers and non-carriers. However, we did find that PRKN and PINK1 mutation carriers have distinctive clinical features compared to young-onset non-carriers, with more postural symptoms at diagnosis and less cognitive impairment, after adjusting for age and disease duration. This supports the idea that there is a distinct clinical profile of PRKN and PINK1-related Parkinson’s disease. We estimate that there are approaching 1000 patients with a known genetic aetiology in the UK Parkinson’s disease population. A small but significant number of patients carry causal variants in LRRK2, SNCA, PRKN and PINK1 that could potentially be targeted by new therapies, such as LRRK2 inhibitors.

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9

Moreau, Adrien, Pascal Gosselin-Badaroudine, Lucie Delemotte, Michael L. Klein, and Mohamed Chahine. "Gating pore currents are defects in common with two Nav1.5 mutations in patients with mixed arrhythmias and dilated cardiomyopathy." Journal of General Physiology 145, no. 2 (January 26, 2015): 93–106. http://dx.doi.org/10.1085/jgp.201411304.

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The gating pore current, also called omega current, consists of a cation leak through the typically nonconductive voltage-sensor domain (VSD) of voltage-gated ion channels. Although the study of gating pore currents has refined our knowledge of the structure and the function of voltage-gated ion channels, their implication in cardiac disorders has not been established. Two Nav1.5 mutations (R222Q and R225W) located in the VSD are associated with atypical clinical phenotypes involving complex arrhythmias and dilated cardiomyopathy. Using the patch-clamp technique, in silico mutagenesis, and molecular dynamic simulations, we tested the hypothesis that these two mutations may generate gating pore currents, potentially accounting for their clinical phenotypes. Our findings suggest that the gating pore current generated by the R222Q and R225W mutations could constitute the underlying pathological mechanism that links Nav1.5 VSD mutations with human cardiac arrhythmias and dilatation of cardiac chambers.

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10

Andolfo, Immacolata, Roberta Russo, Francesco Manna, Marica Lisa Salve, Alok K. Sharma, Seth L. Alper, Lucia De Franceschi, and Achille Iolascon. "Detection of Familial Pseudohyperkalemia Among Italian Blood Donors By Genetic Screening for the R276W Mutation in ABCB6." Blood 126, no. 23 (December 3, 2015): 2132. http://dx.doi.org/10.1182/blood.v126.23.2132.2132.

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Abstract Introduction Isolated Familial Pseudohyperkalemia (FP) is a dominant red cell trait characterized by cold-induced slow 'passive leak' of red cell K+ into plasma, first described in a large Scottish family from Edinburgh (Stewart GW, et al., 1979). Although in freshly obtained blood samples plasma [K+] was normal, it was increased when measured in blood stored at or below room temperature. This trait was accompanied by mild abnormalities of red cell shape. Functional gene mapping and sequencing analysis of the candidate genes within the 2q35-q36 critical interval in three multigenerational FP families with 20 affected individuals identified two novel heterozygous missense mutations in the ABCB6 gene that cosegregated with disease phenotype (Andolfo I. et al., 2013). The two genomic substitutions altered two adjacent nucleotides within codon 375 of ABCB6, a porphyrin transporter that in erythrocyte membranes bears the Langereis blood group antigen system (Krishnamurthy PC, et al., 2006; Helias V, et al., 2012). Recently, the ABCB6 mutation R723Q was found in two patients with FP (Bawazir W, et al.,2014). Of note, both patients presented as blood donors, and increased cold-induced potassium leak was demonstrated. The transfusion of pseudohyperkalemic blood has clinical implications especially for neonates and infants receiving large-volume RBC transfusions. In this study we analyzed one additional family and report the first functional characterization of an ABCB6 mutation, towards understanding the pathogenic mechanism of FP. Moreover, we screened an Italian blood donor population for the R276W variant of the ABCB6 gene. Methods DNA was obtained for genetic analysis from affected and unaffected family members, after signed informed consent, according to the Declaration of Helsinki. The search for mutations was performed by direct sequencing of the ABCB6 gene. cDNAs encoding full-length wildtype ABCB6 were cloned into pcDNA3.1. Our patients' novel point mutation (c.826C>T, p.R276W) was introduced into pcDNA3.1-ABCB6 by site-directed mutagenesis. WT and mutant constructs were transfected into HEK-293 cells and the cells were maintained at 30°C for 72 hrs to evaluate the effects of reduced temperature. After transfection, the cells were incubated in a medium containing 86rubidium (86Rb+) as a surrogate for K+. 86Rb+ was determined in cell lysate, and K content of extracellular medium was determined by atomic absorption spectrometry. Results We found the heterozygous mutation c.826G>T, p. R276W in an Irish family. This mutation is annotated in public databases as single nucleotide variants (SNVs), and is predicted by PolyPhen2 and SIFT to be damaging. Variant R276W showed a minor allele frequency (MAF) of 1.3:100 confirming that many patients with FP could be present in the blood donor population. R276W and previously identified ABCB6 variants R375Q and R375Wwere overexpressed in HEK-293 cells to characterize the functional properties of these variants. Expression of ABCB6 mutants showed no change in RNA or polypeptide levels. However, measurement of ouabain- and bumetanide-resistant net cation flux demonstrated a greater loss of cell K from mutant ABCB6-expressing cells than from WT ABCB6-expressing cells. The high allele frequency of ABCB6 variant R276W prompted a genetic screen of 327 blood donors. The variant was present in 0.3% (1/327) of the donor cohort, and this single subject with ABCB6 R276W exhibited slightly increased MCV and variably increased plasma K+ concentrations. Conclusions: Our findings demonstrate that missense mutations in ABCB6 lead to increased K+ efflux from RBCs in FP patients. Storage of FP blood can cause a significant increase in blood K+ levels, with especially serious clinical implications for neonates and infants receiving large-volume transfusions of whole blood. Furthermore, the prevalence of FP might be underestimated, since patients with FP can be asymptomatic and thus undetected in the donor population. Screening for the most frequent ABCB6 variation, R276W, confirmed that FP patients are present in the Italian blood donor population. In the future, genetic tests for FP could be added to blood donor prescreening to improve the quality and safety of donor units. Disclosures No relevant conflicts of interest to declare.

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11

Asa, Anie Day D. C., Rujira Wanotayan, Mukesh Kumar Sharma, Kaima Tsukada, Mikio Shimada, and Yoshihisa Matsumoto. "Functional analysis of XRCC4 mutations in reported microcephaly and growth defect patients in terms of radiosensitivity." Journal of Radiation Research 62, no. 3 (April 12, 2021): 380–89. http://dx.doi.org/10.1093/jrr/rrab016.

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Abstract Non-homologous end joining is one of the main pathways for DNA double-strand break (DSB) repair and is also implicated in V(D)J recombination in immune system. Therefore, mutations in non-homologous end-joining (NHEJ) proteins were found to be associated with immunodeficiency in human as well as in model animals. Several human patients with mutations in XRCC4 were reported to exhibit microcephaly and growth defects, but unexpectedly showed normal immune function. Here, to evaluate the functionality of these disease-associated mutations of XRCC4 in terms of radiosensitivity, we generated stable transfectants expressing these mutants in XRCC4-deficient murine M10 cells and measured their radiosensitivity by colony formation assay. V83_S105del, R225X and D254Mfs*68 were expressed at a similar level to wild-type XRCC4, while W43R, R161Q and R275X were expressed at even higher level than wild-type XRCC4. The expression levels of DNA ligase IV in the transfectants with these mutants were comparable to that in the wild-type XRCC4 transfectant. The V83S_S105del transfectant and, to a lesser extent, D254Mfs*68 transfectant, showed substantially increased radiosensitivity compared to the wild-type XRCC4 transfectant. The W43R, R161Q, R225X and R275X transfectants showed a slight but statistically significant increase in radiosensitivity compared to the wild-type XRCC4 transfectant. When expressed as fusion proteins with Green fluorescent protein (GFP), R225X, R275X and D254Mfs*68 localized to the cytoplasm, whereas other mutants localized to the nucleus. These results collectively indicated that the defects of XRCC4 in patients might be mainly due to insufficiency in protein quantity and impaired functionality, underscoring the importance of XRCC4’s DSB repair function in normal development.

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12

Aarskog, D., H. G. Eiken, R. Bjerknes, and O. L. Myking. "Pituitary dwarfism in the R271W Pit-1 gene mutation." European Journal of Pediatrics 156, no. 11 (October 1997): 829–34. http://dx.doi.org/10.1007/s004310050722.

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13

Strege, Peter R., Amelia Mazzone, Cheryl E. Bernard, Leila Neshatian, Simon J. Gibbons, Yuri A. Saito, David J. Tester, et al. "Irritable bowel syndrome patients have SCN5A channelopathies that lead to decreased NaV1.5 current and mechanosensitivity." American Journal of Physiology-Gastrointestinal and Liver Physiology 314, no. 4 (April 1, 2018): G494—G503. http://dx.doi.org/10.1152/ajpgi.00016.2017.

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The SCN5A-encoded voltage-gated mechanosensitive Na+ channel NaV1.5 is expressed in human gastrointestinal smooth muscle cells and interstitial cells of Cajal. NaV1.5 contributes to smooth muscle electrical slow waves and mechanical sensitivity. In predominantly Caucasian irritable bowel syndrome (IBS) patient cohorts, 2–3% of patients have SCN5A missense mutations that alter NaV1.5 function and may contribute to IBS pathophysiology. In this study we examined a racially and ethnically diverse cohort of IBS patients for SCN5A missense mutations, compared them with IBS-negative controls, and determined the resulting NaV1.5 voltage-dependent and mechanosensitive properties. All SCN5A exons were sequenced from somatic DNA of 252 Rome III IBS patients with diverse ethnic and racial backgrounds. Missense mutations were introduced into wild-type SCN5A by site-directed mutagenesis and cotransfected with green fluorescent protein into HEK-293 cells. NaV1.5 voltage-dependent and mechanosensitive functions were studied by whole cell electrophysiology with and without shear force. Five of 252 (2.0%) IBS patients had six rare SCN5A mutations that were absent in 377 IBS-negative controls. Six of six (100%) IBS-associated NaV1.5 mutations had voltage-dependent gating abnormalities [current density reduction (R225W, R433C, R986Q, and F1293S) and altered voltage dependence (R225W, R433C, R986Q, G1037V, and F1293S)], and at least one kinetic parameter was altered in all mutations. Four of six (67%) IBS-associated SCN5A mutations (R225W, R433C, R986Q, and F1293S) resulted in altered NaV1.5 mechanosensitivity. In this racially and ethnically diverse cohort of IBS patients, we show that 2% of IBS patients harbor SCN5A mutations that are absent in IBS-negative controls and result in NaV1.5 channels with abnormal voltage-dependent and mechanosensitive function. NEW & NOTEWORTHY The voltage-gated Na+ channel NaV1.5 contributes to smooth muscle physiology and electrical slow waves. In a racially and ethnically mixed irritable bowel syndrome cohort, 2% had mutations in the NaV1.5 gene SCN5A. These mutations were absent in irritable bowel syndrome-negative controls. Most mutant NaV1.5 channels were loss of function in voltage dependence or mechanosensitivity.

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MORIZONO, Hiroki, Mendel TUCHMAN, Basavapatna S. RAJAGOPAL, Mark T. McCANN, Chad D. LISTROM, Xiaoling YUAN, Divakaramenon VENUGOPAL, George BARANY, and Norma M. ALLEWELL. "Expression, purification and kinetic characterization of wild-type human ornithine transcarbamylase and a recurrent mutant that produces ‘late onset’ hyperammonaemia." Biochemical Journal 322, no. 2 (March 1, 1997): 625–31. http://dx.doi.org/10.1042/bj3220625.

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Ornithine Transcarbamylase Deficiency, an X-linked disorder, is the most common cause of inherited urea cycle disorders. Approx. 90 mutations that produce reduced levels of ornithine transcarbamylase (OTCase) activity have been identified in patients [Tuchman (1993) Hum. Mutat. 2, 174–178; Tuchman and Plante (1995) Hum. Mutat. 5, 293–295]. A model of the three-dimensional structure of OTCase, developed on the basis of its homology to the catalytic subunit of Escherichia coli aspartate transcarbamylase (ATCase) [Tuchman, Morizono, Reish, Yuan and Allewell (1995) J. Med. Genet. 32, 680–688], and in good agreement with the crystal structure of Pseudomonas aeruginosa OTCase [Villeret, Tricot, Stalon and Dideberg (1995) Proc. Natl. Acad. Sci. U.S.A. 92, 10762–10766], indicates that many mutations that produce severe clinical symptoms are at the active site or buried in the interior of the protein. However, one of the few recurrent mutations, R277W, an alteration that produces a milder phenotype of ornithine transcarbamylase deficiency, is located in the model in a loop remote from the active site that is analogous to a similar loop (the 240's loop, a flexible loop of the catalytic chain of Escherichia coliaspartate transcarbamylase, comprised of residues 230–250) of ATCase. Human wild-type OTCase and the R277W mutant have been cloned and overexpressed in E. coli and a rapid and efficient purification method utilizing the bisubstrate analogue, NΔ-(phosphonacetyl)-l-ornithine, has been developed and used to purify both proteins. Gel chromatography indicates both are trimeric. The pH dependence of the kinetic parameters of the wild-type enzyme is similar to that of E. coli OTCase [Kuo, Herzberg and Lipscomb (1985) Biochemistry 24, 4754–4761], suggesting that its catalytic mechanism is similar, although its maximal activity is approx. 10-fold less. Compared with the wild-type, the R277W mutant has nearly 70-fold lower affinity for l-ornithine, shows no substrate inhibition, and its thermal stability is reduced by 5 °C. Its reduced affinity for l-ornithine, which in turn results in lower activity at physiological concentrations of ornithine, as well as its reduced stability, may contribute to the clinical effects that it produces.

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DiOrio, J. P., M. W. Mosesson, K. R. Siebenlist, J. D. Olson, J. F. Hainfeld, and J. S. Wall. "The Basis for Fibrinogen Cedar Rapids (γ R275C) Fibrin Network Structure." Proceedings, annual meeting, Electron Microscopy Society of America 54 (August 11, 1996): 928–29. http://dx.doi.org/10.1017/s042482010016710x.

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Fibrinogen ‘Cedar Rapids’ is a heterozygous dysfibrinogenemia characterized by delayed and abnormal fibrin polymerization. The specific molecular defect (γ R275C) is relatively common, but in only one case, fibrinogen Tokyo II, has the ultrastructural basis for defective clot formation been determined. This report reflects similar structural studies on Cedar Rapids fibrinogen and fibrin. Crosslinked fibrinogen molecules and fibrils, were prepared at 1 mg/ml in the presence of factor XIIIa (100 u/ml). When γ chains had become ˜10 to 20% crosslinked to γ dimers, samples were diluted with Hepes buffered saline, pH 7, to a fibrinogen concentration of 5 to 10 μg/ml. Three μl was then injected into 3 μl buffer on a carbon-coated EM grid, the specimen allowed to attach for one minute, fluid-exchanged several times with 150 mM NH4 acetate solution, frozen in liquid nitrogen, freeze-dried, and imaged at the Brookhaven STEM facility using a 40 kv probe focused at 0.25 nm. Fibrin for scanning EM (SEM) was formed directly on carbon-formvar coated gold grids. Clots that had formed overnight were fixed with 2.5% glutaraldehyde in 0.1 M Hepes, pH 7 buffer containing 0.2% tannic acid, washed with buffer, dehydrated, CO2 critical point dried, coated with 7.5 nm platinum, and imaged in a JOEL Field Emission SEM operated at 5 kV.

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Masi, Alessandra di, Mara Viganotti, Fabio Polticelli, Paolo Ascenzi, Caterina Tanzarella, and Antonio Antoccia. "The R215W mutation in NBS1 impairs γ-H2AX binding and affects DNA repair: molecular bases for the severe phenotype of 657del5/R215W Nijmegen breakage syndrome patients." Biochemical and Biophysical Research Communications 369, no. 3 (May 2008): 835–40. http://dx.doi.org/10.1016/j.bbrc.2008.02.129.

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17

Maleva Kostovska, I., M. Jakimovska, K. Kubelka-Sabit, M. Karadjozov, A. Arsovski, L. Stojanovska, and Dijana Plaseska-Karanfilska. "Clinical Relevance of CHEK2 And NBN Mutations in the Macedonian Population." Balkan Journal of Medical Genetics 18, no. 1 (June 1, 2015): 47–54. http://dx.doi.org/10.1515/bjmg-2015-0005.

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AbstractClinical importance of the most common CHEK2 (IVS2+1 G>A, 1100delС, I157T and del5395) and NBN (R215W and 657del5) gene mutations for breast cancer development in Macedonian breast cancer patients is unknown. We performed a case-control study including 300 Macedonian breast cancer patients and 283 Macedonian healthy controls. Genotyping was done using a fast and highly accurate single-nucleotide primer extension method for the detection of five mutations in a single reaction. The detection of the del5395 was performed using an allele-specific duplex polymerase chain reaction (PCR) assay. We have found that mutations were more frequent in breast cancer patients (n = 13, 4.3%) than in controls (n = 5, 1.8%), although without statistical significance. Twelve patients were heterozygous for one of the analyzed mutations, while one patient had two mutations (NBN R215W and CHEK2 I157T). The most frequent variant was I157T, found in 10 patients and four controls (p = 0.176) and was found to be associated with familial breast cancer (p = 0.041). CHEK2 1100delC and NBN 657del5 were each found in one patient and not in the control group. CHEK2 IVS2+1G>A and del5395 were not found in our cohort. Frequencies of the studied mutations are low and they are not likely to represent alleles of clinical importance in the Macedonian population.

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Yorgan, Timur Alexander, Tim Rolvien, Julian Stürznickel, Nele Vollersen, Fabiola Lange, Anke Baranowsky, Irm Hermans-Borgmeyer, et al. "Mice carrying a ubiquitous R235W mutation of Wnt1 display a bone-specific phenotype." Bone Reports 13 (October 2020): 100645. http://dx.doi.org/10.1016/j.bonr.2020.100645.

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Yorgan, Timur Alexander, Tim Rolvien, Julian Stürznickel, Nele Vollersen, Fabiola Lange, Wenbo Zhao, Anke Baranowsky, et al. "Mice Carrying a Ubiquitous R235W Mutation of Wnt1 Display a Bone‐Specific Phenotype." Journal of Bone and Mineral Research 35, no. 9 (May 20, 2020): 1726–37. http://dx.doi.org/10.1002/jbmr.4043.

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20

Heneghan, John F., Arash Akhavein, Maria J. Salas, Boris E. Shmukler, Lawrence P. Karniski, David H. Vandorpe, and Seth L. Alper. "Regulated transport of sulfate and oxalate by SLC26A2/DTDST." American Journal of Physiology-Cell Physiology 298, no. 6 (June 2010): C1363—C1375. http://dx.doi.org/10.1152/ajpcell.00004.2010.

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Nephrolithiasis in the Slc26a6−/− mouse is accompanied by 50–75% reduction in intestinal oxalate secretion with unchanged intestinal oxalate absorption. The molecular identities of enterocyte pathways for oxalate absorption and for Slc26a6-independent oxalate secretion remain undefined. The reported intestinal expression of SO42− transporter SLC26A2 prompted us to characterize transport of oxalate and other anions by human SLC26A2 and mouse Slc26a2 expressed in Xenopus oocytes. We found that hSLC26A2-mediated [14C]oxalate uptake ( K1/2 of 0.65 ± 0.08 mM) was cis-inhibited by external SO42− ( K1/2 of 3.1 mM). hSLC26A2-mediated bidirectional oxalate/SO42− exchange exhibited extracellular SO42− K1/2 of 1.58 ± 0.44 mM for exchange with intracellular [14C]oxalate, and extracellular oxalate K1/2 of 0.14 ± 0.11 mM for exchange with intracellular 35SO42−. Influx rates and K1/2 values for mSlc26a2 were similar. hSLC26A2-mediated oxalate/Cl− exchange and bidirectional SO42−/Cl− exchange were not detectably electrogenic. Both SLC26A2 orthologs exhibited nonsaturable extracellular Cl− dependence for efflux of intracellular [14C]oxalate, 35SO42−, or 36Cl−. Rate constants for 36Cl− efflux into extracellular Cl−, SO42−, and oxalate were uniformly 10-fold lower than for oppositely directed exchange. Acidic extracellular pH (pHo) inhibited all modes of hSLC26A2-mediated anion exchange. In contrast, acidic intracellular pH (pHi) selectively activated exchange of extracellular Cl− for intracellular 35SO42− but not for intracellular 36Cl− or [14C]oxalate. Protein kinase C inhibited hSLC26A2 by reducing its surface abundance. Diastrophic dysplasia mutants R279W and A386V of hSLC26A2 exhibited similar reductions in uptake of both 35SO42− and [14C]oxalate. A386V surface abundance was reduced, but R279W surface abundance was at wild-type levels.

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21

Ward, Tarsha, Warren Tai, Sarah Morton, Francis Impens, Petra Van Damme, Delphi Van Haver, Evy Timmerman, et al. "Mechanisms of Congenital Heart Disease Caused by NAA15 Haploinsufficiency." Circulation Research 128, no. 8 (April 16, 2021): 1156–69. http://dx.doi.org/10.1161/circresaha.120.316966.

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Rationale: NAA15 (N-alpha-acetyltransferase 15) is a component of the NatA (N-terminal acetyltransferase complex). The mechanism by which NAA15 haploinsufficiency causes congenital heart disease remains unknown. To better understand molecular processes by which NAA15 haploinsufficiency perturbs cardiac development, we introduced NAA15 variants into human induced pluripotent stem cells (iPSCs) and assessed the consequences of these mutations on RNA and protein expression. Objective: We aim to understand the role of NAA15 haploinsufficiency in cardiac development by investigating proteomic effects on NatA complex activity and identifying proteins dependent upon a full amount of NAA15. Methods and Results: We introduced heterozygous loss of function, compound heterozygous, and missense residues (R276W) in iPSCs using CRISPR/Cas9. Haploinsufficient NAA15 iPSCs differentiate into cardiomyocytes, unlike NAA15 -null iPSCs, presumably due to altered composition of NatA. Mass spectrometry analyses reveal ≈80% of identified iPSC NatA targeted proteins displayed partial or complete N-terminal acetylation. Between null and haploinsufficient NAA15 cells, N-terminal acetylation levels of 32 and 9 NatA-specific targeted proteins were reduced, respectively. Similar acetylation loss in few proteins occurred in NAA15 R276W induced pluripotent stem cells. In addition, steady-state protein levels of 562 proteins were altered in both null and haploinsufficient NAA15 cells; 18 were ribosomal-associated proteins. At least 4 proteins were encoded by genes known to cause autosomal dominant congenital heart disease. Conclusions: These studies define a set of human proteins that requires a full NAA15 complement for normal synthesis and development. A 50% reduction in the amount of NAA15 alters levels of at least 562 proteins and N-terminal acetylation of only 9 proteins. One or more modulated proteins are likely responsible for NAA15-haploinsufficiency mediated congenital heart disease. Additionally, genetically engineered induced pluripotent stem cells provide a platform for evaluating the consequences of amino acid sequence variants of unknown significance on NAA15 function.

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22

Ballhausen, D. "Recessive multiple epiphyseal dysplasia (rMED): phenotype delineation in eighteen homozygotes for DTDST mutation R279W." Journal of Medical Genetics 40, no. 1 (January 1, 2003): 65–71. http://dx.doi.org/10.1136/jmg.40.1.65.

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23

Vreken, P., A. B. P. Van Kuilenburg, R. Meinsma, and A. H. van Gennip. "Dihydropyrimidine dehydrogenase (DPD) deficiency: identification and expression of missense mutations C29R, R886H and R235W." Human Genetics 101, no. 3 (December 11, 1997): 333–38. http://dx.doi.org/10.1007/s004390050637.

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24

Ahmad, I., S. M. Austin, B. B. Back, R. R. Betts, F. P. Calaprice, K. C. Chan, A. A. Chishti, et al. "Internal pair conversion in heavy nuclei." Physical Review C 55, no. 6 (June 1, 1997): R2755—R2759. http://dx.doi.org/10.1103/physrevc.55.r2755.

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Burkardt, Matthias. "Light-cone momentum distribution of heavy quarks." Physical Review D 46, no. 7 (October 1, 1992): R2751—R2755. http://dx.doi.org/10.1103/physrevd.46.r2751.

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Bernard, Véronique, Norbert Kaiser, Joachim Kambor, and Ulf-G. Meissner. "Hyperon polarizabilities." Physical Review D 46, no. 7 (October 1, 1992): R2756—R2758. http://dx.doi.org/10.1103/physrevd.46.r2756.

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Cvetič, Mirjam, and Paul Langacker. "Neutrino masses within the minimal supersymmetric standard model." Physical Review D 46, no. 7 (October 1, 1992): R2759—R2763. http://dx.doi.org/10.1103/physrevd.46.r2759.

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Bernard, Véronique, Norbert Kaiser, and Ulf-G. Meissner. "Threshold parameters ofπKscattering in QCD." Physical Review D 43, no. 9 (May 1, 1991): R2757—R2760. http://dx.doi.org/10.1103/physrevd.43.r2757.

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Kassner, K., C. Misbah, and R. Baumann. "Eutectic dynamics: A host of new states." Physical Review E 51, no. 4 (April 1, 1995): R2751—R2754. http://dx.doi.org/10.1103/physreve.51.r2751.

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30

Lontano, Maurizio, and Fabio Raimondi. "Stopping power of nonmonochromatic heavy-ion clusters with two-ion correlation effects." Physical Review E 51, no. 4 (April 1, 1995): R2755—R2758. http://dx.doi.org/10.1103/physreve.51.r2755.

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31

Fiorito, R. B., D. W. Rule, M. A. Piestrup, X. K. Maruyama, R. M. Silzer, D. M. Skopik, and A. V. Shchagin. "Polarized angular distributions of parametric x radiation and vacuum-ultraviolet transition radiation from relativistic electrons." Physical Review E 51, no. 4 (April 1, 1995): R2759—R2762. http://dx.doi.org/10.1103/physreve.51.r2759.

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32

Schachter-Tokarz, Esther, Bruno Cassinat, Charikleia Kelaidi, Christine Chomienne, Claude Gardin, Emmanuel Raffoux, Herve Dombret, Pierre Fenaux, and Robert Gallagher. "Uncommon Mutations in PML-RARα Associated with Poor Outcome after First Relapse in APL." Blood 110, no. 11 (November 16, 2007): 4248. http://dx.doi.org/10.1182/blood.v110.11.4248.4248.

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Abstract Background. Mutations in the RARα-region ligand binding domain (LBD) of PML-RARα were detected in 30 – 40% of patients (pts) tested after first relapse from ATRA-chemotherapy (CT) regimens in 2 North American Phase III trials. However, no follow-up data were reported to assess whether this affected subsequent outcome. Methods. In the current study, 8 relapse pts were tested by previously-published techniques for PML-RARα LBD mutations after relapse from ATRA-CT regimens of the EAG. Treatment was according to the APL2000 protocol: randomization to induction with ATRA+DNR with AraC (arm-A) or no AraC (arm-B) followed by 2 consolidation courses with DNR with (A) or without (B) AraC and then 2 years maintenance with ATRA for 15 days every 3 months, as well as, 6MP and MTX (Ades, et al, J Clin Oncology24, 5703, 2006); 1 off-protocol (OP) pt was treated according to APL-93, which is similar to APL2000-A (Fenaux, et al, Blood94, 1192, 1999). Results. Patient Treatment Days to Relapse Days ATRA Maintenance Days Off ATRA PML-RARα LBD Mutation Status Post-Relapse 1-Au APL2000-B 1037 120 173 No CR2 2-An OP like-A 1072 120 210 No CR2 3-Ho APL2000-A 1194 105 529 No CR2 4_Ge APL2000-B 557 90 0 del/ins & R276W Rel1→Dead 5-Lu OP like-93 1249 0 ~1200 No Dead in CR2 6-Ro OP like-A + VP16 992 0 ~950 No CR2 7-Ka APL2000-B 530 45 0 ΔK227→S229/ M227 Rel3→Dead 8-Ma APL2000-B + AraC 406 45 0 R272W & N298S Rel2→CR3 Mutations were observed in the reported incidence range: 3/8 pts (37.5%). However, the findings were unusual, since 2/3 mutations were deletion mutations, while only 2/30 reported mutations were deletions, and since 2/3 pts harbored 2 mutant subclones, while only 1/30 such cases has been reported. Also, the nature of the mutations was unusual. In pt 7, the ΔK227∅S229/M227 mutation was atypically located in the amino-region of the LBD. In pt 4, a very atypical deletion/insertion (del/ins) mutation began in the hinge RARα-region at S157, extending 630 nt to R367, and was associated with a 547 nt insertion from the beginning of intron 4 that changed the translational reading frame, encoding a truncated protein lacking the entire LBD. Most notably, the 3 pts harboring these uncommon mutations either failed to achieve a second complete remission (CR) or suffered subsequent relapses, leading to death in 2 pts from resistant disease (pts 4 & 7), while 0/5 non-mutant pts relapsed (pt 5, death in CR2 was treatment-related). Discussion. With such a small sample size, it is not possible to determine whether the uncommon mutations occurred by chance or related to some unrecognized element in the EAG pts. No readily apparent basis could be identified: the modest treatment dose-schedule differences from other Phase III studies using common therapeutic agents seems an improbable cause; one each of the mutant/non-mutant pts had an extra chromosome (trisomy 8); 2 of the non-mutant cases had treatment-related APL. Although further study is needed to determine whether the poor outcome in 3 pts was related to the uncommon nature of their mutations, these results suggest that testing for PML-RARα mutations at first relapse may be of prognostic and potential therapeutic value.

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Torisu, Hiroyuki, Ryutaro Kira, Naomi Kanazawa, Megumi Takemoto, Masafumi Sanefuji, Yasunari Sakai, Seiichi Tsujino, and Toshiro Hara. "A novel R275X mutation of the SLC25A15 gene in a Japanese patient with the HHH syndrome." Brain and Development 28, no. 5 (June 2006): 332–35. http://dx.doi.org/10.1016/j.braindev.2005.10.002.

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34

Kanosue, K., Y. H. Zhang, M. Yanase-Fujiwara, and T. Hosono. "Hypothalamic network for thermoregulatory shivering." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 267, no. 1 (July 1, 1994): R275—R282. http://dx.doi.org/10.1152/ajpregu.1994.267.1.r275.

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Warming one side of a rat's preoptic area and anterior hypothalamus (POAH) suppresses shivering on both sides of the body, and the present study evaluated the extent to which signals mediating this suppression cross the midline within and below the POAH. Hind paw shivering during unilateral POAH thermal stimulation was measured for rats in which the POAH had been midsagittally transected and for rats in which one side of the hypothalamus had been coronally transected just caudal to the POAH. In midsagittally transected rats, unilateral warming on either side of the POAH suppressed shivering equally on both sides of the body. In unilaterally transected rats, POAH warming on the transected side did not affect shivering, but warming the intact side suppressed shivering equally on both sides of the body. When a unilateral transection of only the lateral part of the hypothalamus included the medial forebrain bundle, the effect was the same as that of a unilateral transection of the whole hypothalamus. These results indicate that no information controlling shivering is exchanged between the left and right POAH and that efferent signals from the POAH, descending through the medial forebrain bundle, cross the midline somewhere below the hypothalamus to innervate both sides of the body equally.

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35

Burbach, J. A., E. H. Schlenker, and J. L. Johnson. "Morphometry, histochemistry, and contractility of dystrophic hamster diaphragm." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 253, no. 2 (August 1, 1987): R275—R284. http://dx.doi.org/10.1152/ajpregu.1987.253.2.r275.

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Differences in gross and microscopic morphology, fiber-size distribution, and fiber-type composition were present in the diaphragm of 35-, 130-, and 180-day-old dystrophic (Bio 14.6) compared with age-matched control (Bio F1B) hamsters. The dystrophic diaphragm was significantly thicker than the control at 130 and 180 days. Increases in wet-to-dry weight ratios, connective tissue per unit area, and muscle fiber number suggest that increased tissue hydration, fibrosis, and fiber hyperplasia contribute to diaphragm hypertrophy. Marked variations of fiber areas and diameters were evident in each fiber type at each age, but generalized atrophy predominated over hypertrophy, resulting in significant decreases in cross-sectional areas of each fiber type. Significant differences in fiber-type composition were noted in the dystrophic vs. control diaphragm at each age: at 35 days the percentage of slow-oxidative fibers was lower and in fast-oxidative fibers was higher; at 130 days the percentage of fast-oxidative fibers remained elevated; at 180 days the percentage of fast-glycolytic fibers was reduced. In vitro contractility studies of 130-day-old animals showed that twitch and peak tension development were significantly lower in the dystrophic compared with the control diaphragm, whereas optimal length, contraction time, and half-relaxation time were within control limits. Microscopic and physiological abnormalities were also present in the soleus of 130-day-old dystrophic animals. As in the diaphragm, fiber areas were reduced, connective tissue area increased, and peak and twitch tension decreased significantly compared with the control soleus. The histopathological and pathophysiological changes in the diaphragm correlated well with each other and are consistent with the slowly evolving inability of the dystrophic hamster to increase tidal volume and minute ventilation in response to a hypercapnic challenge.

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36

Summy-Long, J. Y., S. Gestl, M. L. Terrell, G. Wolz, and M. Kadekaro. "Osmoregulation of the magnocellular neuroendocrine system during lactation." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 272, no. 1 (January 1, 1997): R275—R288. http://dx.doi.org/10.1152/ajpregu.1997.272.1.r275.

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Glucose utilization and Fos expression were used to compare responses of cerebral structures involved in osmoregulation in virgin and lactating rats given 0.15, 0.85, or 1.5 M NaCl subcutaneously. In virgin animals, glucose utilization increased (P < 0.05) in the supraoptic nuclei (SON), paraventricular nuclei (PVN), and neural lobe (NL) proportionally to the osmotic stimulus (0.15 M NaCl < 0.85 M NaCl < 1.5 M NaCl), whereas metabolism in the median preoptic nucleus (MPO) and median eminence (ME) increased only after 1.5 M NaCl. In lactating rats, enhanced utilization of glucose in response to osmotic stimulation was absent in the PVN (0.85 M NaCl), MPO, and ME or significantly (P < 0.01) reduced (SON, PVN, NL) compared with virgin animals. Glucose utilization in each structure correlated linearly with plasma osmolality but with a lower slope (P < 0.05) in lactating animals. Magnocellular neurons expressing Fos in the SON increased linearly with plasma osmolality and were more numerous (P < 0.05) in control lactating animals but increased less (P < 0.05) than in virgin rats after 0.85 M NaCl. The attenuated magnocellular response during lactation results from reduced afferent activation from osmosensitive forebrain sites.

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37

Costford, Sheila R., Nihan Kavaslar, Nadav Ahituv, Shehla N. Chaudhry, Wendy S. Schackwitz, Robert Dent, Len A. Pennacchio, Ruth McPherson, and Mary-Ellen Harper. "Gain-of-Function R225W Mutation in Human AMPKγ3 Causing Increased Glycogen and Decreased Triglyceride in Skeletal Muscle." PLoS ONE 2, no. 9 (September 19, 2007): e903. http://dx.doi.org/10.1371/journal.pone.0000903.

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38

Slavov, V., N. M.A.ssou, I. Gabriel, G. Dhonneur, and P. Duvaldestin. "R275 Le niveau de curarisation affecte-T-il l'analyse bispectrale lors de l'induction de l'anesthesie ?" Annales Françaises d'Anesthésie et de Réanimation 17, no. 8 (1998): 949. http://dx.doi.org/10.1016/s0750-7658(98)80394-8.

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39

Dang, Xiawei, Emily K. Walton, Barbara Zablocka, Robert H. Baloh, Michael E. Shy, and Gerald W. Dorn. "Mitochondrial Phenotypes in Genetically Diverse Neurodegenerative Diseases and Their Response to Mitofusin Activation." Cells 11, no. 6 (March 21, 2022): 1053. http://dx.doi.org/10.3390/cells11061053.

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Mitochondrial fusion is essential to mitochondrial fitness and cellular health. Neurons of patients with genetic neurodegenerative diseases often exhibit mitochondrial fragmentation, reflecting an imbalance in mitochondrial fusion and fission (mitochondrial dysdynamism). Charcot–Marie–Tooth (CMT) disease type 2A is the prototypical disorder of impaired mitochondrial fusion caused by mutations in the fusion protein mitofusin (MFN)2. Yet, cultured CMT2A patient fibroblast mitochondria are often reported as morphologically normal. Metabolic stress might evoke pathological mitochondrial phenotypes in cultured patient fibroblasts, providing a platform for the pre-clinical individualized evaluation of investigational therapeutics. Here, substitution of galactose for glucose in culture media was used to redirect CMT2A patient fibroblasts (MFN2 T105M, R274W, H361Y, R364W) from glycolytic metabolism to mitochondrial oxidative phosphorylation, which provoked characteristic mitochondrial fragmentation and depolarization and induced a distinct transcriptional signature. Pharmacological MFN activation of metabolically reprogrammed fibroblasts partially reversed the mitochondrial abnormalities in CMT2A and CMT1 and a subset of Parkinson’s and Alzheimer’s disease patients, implicating addressable mitochondrial dysdynamism in these illnesses.

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40

Mosesson, M. W., K. R. Siebenlist, and J. D. Olson. "29. Thrombophilia associated with dysfibrinogenemia (fibrinogen Cedar Rapids (g R275C)) and a concurrent heterozygous factor V Leiden defect." Fibrinolysis 10 (August 1996): 11. http://dx.doi.org/10.1016/s0268-9499(96)80791-0.

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41

Linenberger, M. L., J. Kindelan, R. L. Bennett, A. P. Reiner, and H. C. F. C�t�. "Fibrinogen Bellingham: A ?-chain R275C substitution and a ?-promoter polymorphism in a thrombotic member of an asymptomatic family." American Journal of Hematology 64, no. 4 (2000): 242–50. http://dx.doi.org/10.1002/1096-8652(200008)64:4<242::aid-ajh2>3.0.co;2-o.

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42

Voskoboinik, Ilia, Marie-Claude Thia, Annette De Bono, Kylie Browne, Erika Cretney, Jacob T. Jackson, Phillip K. Darcy, Stephen M. Jane, Mark J. Smyth, and Joseph A. Trapani. "The Functional Basis for Hemophagocytic Lymphohistiocytosis in a Patient with Co-inherited Missense Mutations in the Perforin (PFN1) Gene." Journal of Experimental Medicine 200, no. 6 (September 13, 2004): 811–16. http://dx.doi.org/10.1084/jem.20040776.

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About 30% of cases of the autosomal recessive immunodeficiency disorder hemophagocytic lymphohistiocytosis are believed to be caused by inactivating mutations of the perforin gene. We expressed perforin in rat basophil leukemia cells to define the basis of perforin dysfunction associated with two mutations, R225W and G429E, inherited by a compound heterozygote patient. Whereas RBL cells expressing wild-type perforin (67 kD) efficiently killed Jurkat target cells to which they were conjugated, the substitution to tryptophan at position 225 resulted in expression of a truncated (∼45 kD) form of the protein, complete loss of cytotoxicity, and failure to traffic to rat basophil leukemia secretory granules. By contrast, G429E perforin was correctly processed, stored, and released, but the rat basophil leukemia cells possessed reduced cytotoxicity. The defective function of G429E perforin mapped downstream of exocytosis and was due to its reduced ability to bind lipid membranes in a calcium-dependent manner. This study elucidates the cellular basis for perforin dysfunctions in hemophagocytic lymphohistiocytosis and provides the means for studying structure–function relationships for lymphocyte perforin.

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Flood, Veronica H., Hamid A. Al-Mondhiry, Antony C. Bakke, and David H. Farrell. "Fibrinogen Hershey IV: A Novel Dysfibrinogen with a γ V411I Mutation in the Integrin αIibβ3 Binding Site." Blood 106, no. 11 (November 16, 2005): 2133. http://dx.doi.org/10.1182/blood.v106.11.2133.2133.

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Abstract The C-terminal segment of the fibrinogen γ chain plays a crucial role in platelet aggregation via its interaction with the platelet receptor αIIbβ3. It is well established that the last four amino acids of the γ chain (408 to 411) are critical for this function, as mutations or deletions of this region abrogate fibrinogen’s ability to bind αIIbβ3. We describe here the first naturally occurring fibrinogen mutation affecting the C-terminal region of the γ chain and investigate its effects on platelet interactions. The proband, a 49-year-old woman, was diagnosed with dysfibrinogenemia based on a prolonged thrombin time and low fibrinogen activity (55 mg/dL). Her bleeding history was significant for menorrhagia and one episode of post-operative hemorrhage. DNA sequencing of the fibrinogen genes demonstrated heterozygosity for two mutations, γ R275C and γ V411I. The latter γ V411I mutation represents a novel mutation affecting the C-terminal amino acid of the γ chain. We hypothesized that this mutation would decrease fibrinogen’s affinity for the platelet receptor αIIbβ3. In order to isolate the effects of this mutation on fibrinogen-platelet binding, γ 400-411 dodecapeptides were synthesized to mimic the C-terminal γ chain sequence. One peptide contained the wild-type sequence ending in valine (γ 400-V411), and the second peptide incorporated the isoleucine mutation (γ 400-I411). Previous studies have demonstrated that the wild type γ 400-V411 dodecapeptide inhibits platelet aggregation by competing for fibrinogen binding to αIIbβ3. We performed platelet aggregation studies comparing inhibition of aggregation with the wild-type γ 400-V411 and the mutant γ 400-I411 peptides. Washed platelets were obtained from a normal donor, and platelet aggregation monitored using the agonist ADP. The IC50 for the initial rate of aggregation with the γ 400-I411 peptide was 214 μM, compared to 133 μM with the wild-type peptide. We then examined the extent of aggregation in the presence of either wild-type or mutant peptide. Consistent with the previous results, total aggregation was lower with the wild-type peptide compared to the mutant peptide. The IC50 for the γ 400-I411 peptide was 450 μM compared to 250 μM with the γ 400-V411 peptide. Overall, these findings suggest that the γ I411 mutation results in a decreased ability to bind platelets. In the heterozygous state, however, the available amount of wild-type fibrinogen may be sufficient to support platelet aggregation. The bleeding diathesis observed for the proband could therefore reflect other factors, especially the γ R275C mutation.

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44

Negahdar, Maria, Ingvild Aukrust, Janne Molnes, Marie H. Solheim, Bente B. Johansson, Jørn V. Sagen, Knut Dahl-Jørgensen, et al. "GCK-MODY diabetes as a protein misfolding disease: The mutation R275C promotes protein misfolding, self-association and cellular degradation." Molecular and Cellular Endocrinology 382, no. 1 (January 2014): 55–65. http://dx.doi.org/10.1016/j.mce.2013.08.020.

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45

Bezzina, Connie R., Martin B. Rook, W. Antoinette Groenewegen, Lucas J. Herfst, Allard C. van der Wal, Jan Lam, Habo J. Jongsma, Arthur A. M. Wilde, and Marcel M. A. M. Mannens. "Compound Heterozygosity for Mutations (W156X and R225W) inSCN5AAssociated With Severe Cardiac Conduction Disturbances and Degenerative Changes in the Conduction System." Circulation Research 92, no. 2 (February 7, 2003): 159–68. http://dx.doi.org/10.1161/01.res.0000052672.97759.36.

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46

Tasca, Giorgio, Massimiliano Mirabella, Aldobrando Broccolini, Mauro Monforte, Mario Sabatelli, Gian Luca Biscione, Giulio Piluso, et al. "An Italian case of hereditary myopathy with early respiratory failure (HMERF) not associated with the titin kinase domain R279W mutation." Neuromuscular Disorders 20, no. 11 (November 2010): 730–34. http://dx.doi.org/10.1016/j.nmd.2010.07.269.

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47

Marsden, L., I. R. Peake, M. E. Daly, and S. A. Croft. "Can full-length wild-type von Willebrand factor (VWF) or the VWF propeptide rescue secretion of the R273W VWF variant associated with quantitative deficiency?" Journal of Thrombosis and Haemostasis 1 (July 2003): P1662. http://dx.doi.org/10.1111/j.1538-7836.2003.tb05757.x.

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48

Turton, James P. G., Rachel Reynaud, Ameeta Mehta, John Torpiano, Alexandru Saveanu, Kathryn S. Woods, Anatoly Tiulpakov, et al. "Novel Mutations within the POU1F1 Gene Associated with Variable Combined Pituitary Hormone Deficiency." Journal of Clinical Endocrinology & Metabolism 90, no. 8 (August 1, 2005): 4762–70. http://dx.doi.org/10.1210/jc.2005-0570.

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Context: Mutations within the gene encoding the pituitary-specific transcription factor POU1F1 are associated with combined pituitary hormone deficiency (CPHD). Most of the affected individuals manifest GH, prolactin, and TSH deficiency. Objective: We have now screened 129 individuals with CPHD and isolated GH deficiency for mutations within POU1F1. Results: Causative mutations were identified in 10 of 129 individuals (7.8%). Of these, five patients harbored the dominant negative R271W mutation, which is a well-recognized mutational hot spot. We have also identified a second frequently occurring mutation, E230K, which appears to be common in Maltese patients. Additionally, we describe two novel mutations within POU1F1, an insertion of a single base pair (ins778A) and a missense mutation (R172Q). Functional studies have revealed that POU1F1 (E230K) is associated with a reduction in transactivation, although DNA-binding affinity is similar to the wild-type protein. On the other hand, POU1F1 (R172Q) is associated with a reduction in DNA binding and transactivation, whereas POU1F1 (ins778A) is associated with loss of DNA binding and a reduction in transactivation. Conclusions: Our data suggest that the phenotype associated with POU1F1 mutations may be more variable, with the occasional preservation of TSH secretion. Additionally, our data revealed POU1F1 mutations in three patients who were diagnosed as having ACTH deficiency but who, on further evaluation, were found to have normal cortisol secretion. Hence, elucidation of the genotype led to further evaluation of the phenotype, with the cessation of cortisol replacement that had been commenced unnecessarily. These data reflect the importance of mutational analysis in patients with CPHD.

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Mateju, Martin, Petra Kleiblova, Zdenek Kleibl, Marketa Janatova, Jana Soukupova, Ivana Ticha, Jan Novotny, and Petr Pohlreich. "Germline mutations 657del5 and 643C>T (R215W) in NBN are not likely to be associated with increased risk of breast cancer in Czech women." Breast Cancer Research and Treatment 133, no. 2 (April 11, 2012): 809–11. http://dx.doi.org/10.1007/s10549-012-2049-x.

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50

Crawford, S. A., S. R. Costford, C. Aguer, S. C. Thomas, R. A. deKemp, J. N. DaSilva, D. Lafontaine, et al. "Naturally occurring R225W mutation of the gene encoding AMP-activated protein kinase (AMPK)γ3 results in increased oxidative capacity and glucose uptake in human primary myotubes." Diabetologia 53, no. 9 (May 15, 2010): 1986–97. http://dx.doi.org/10.1007/s00125-010-1788-7.

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