Academic literature on the topic '19p13.3'

Microdeletions at 19p13.3 are rarely reported in the medical literature with significant phenotypic variability. Among the reported cases, common clinical manifestations have included developmental delay, facial dysmorphism, and hypotonia. Herein we described a child with a de novo 19p13.3 microdeletion, proximal to the reported cases of 19p13.3 microdeletion/duplication, with ocular manifestations of bilateral ocular colobomata complicated with microphthalmos and cataract, associated with short stature. This case highlights the phenotypic heterogeneity of deletions in the 19p13.3 region.

A female individual with concomitant deletions in 15q11.2 and 19p13.3 is reported. She presents facial dysmorphisms, motor delay, learning difficulties, and mild behavioral impairment. After chromosomal microarray analysis, the final karyotype was established as 46,XX.arr[GRCh37] 15q11.2 (22770421_23282798)×1,19p13.3(3793904_4816330)×1. The deletion in 15q11.2 is 507 kb in size involving 7 non-imprinted genes, 4 of which are registered in the OMIM database and are implicated in neuropsychiatric or neurodevelopmental disorders. The deletion in 19p13.3 is 1,022 kb in size and encompasses 47 genes, most of which do not have a well-known function. The genotype-phenotype correlation is discussed, and most of the features could be related to the 19p13.3 deletion, except for velopharyngeal insufficiency. Other genes encompassed in the deleted region, as well as unrecognized epistatic factors could also be involved. Nevertheless, the two-hit model related to the 15q11.2 deletion would be an important hypothesis to be considered.

<sec><title>Study Design</title><p>Prospective case-controlled study.</p></sec><sec><title>Purpose</title><p>This study aimed to assess genetic influence in Saudi Arabian children with adolescent idiopathic scoliosis (AIS).</p></sec><sec><title>Overview of Literature</title><p>The genetic locus linked to chromosome 19p for idiopathic scoliosis has been described. A pilot study conducted at King Fahd Hospital of the University, Al-Khobar showed that three microsatellite markers (D19S216, D19S894, and DS1034) of chromosome 19p13.3 were significant in Saudi Arabian females compared with healthy subjects.</p></sec><sec><title>Methods</title><p>A total of 100 unrelated Saudi Arabian girls treated for AIS, their parents, healthy siblings, and healthy subjects were recruited for genetic analysis of markers on chromosome 19p13.3. After informed consent was obtained from their parents, blood samples were collected and parametric and nonparametric linkage analyses were performed using GENEHUNTER ver. 2.1. Multipoint linkage analysis was used to specify an autosomal dominant trait with a gene frequency of 0.01 and an estimated penetrance of 80% at the genotypic and allelic levels.</p></sec><sec><title>Results</title><p>Five hundred blood samples were collected and analyzed for microsatellite markers (D19S216, D19S894, and DS1034) of chromosome 19p13.3. Comparison among patients, family members, and healthy subjects revealed no significant association between markers and scoliosis at the genotypic level: D19S216 (<italic>p</italic>=0.21), D19S894 (<italic>p</italic>=0.37), and DS1034 (<italic>p</italic>=0.25). However, at the allelic level, a statistically significant association was observed for marker DS1034 (<italic>p</italic>=0.008), and marker D19S216 showed significance between fathers and patients (<italic>p</italic>&lt;0.001) compared with patients and mothers. The other two markers, D19S216 (<italic>p</italic>=0.25) and D19S894 (<italic>p</italic>=0.17), showed no significant association between patients and mothers.</p></sec><sec><title>Conclusions</title><p>At the allelic level, marker DS1034 was significantly associated with AIS patients and their fathers. This allelic marker on chromosome 19p13.3 appears to be important in AIS etiology.</p></sec>

Abstract Introduction/Objective Microdeletion of a region of the short arm of chromosome 19 results in a very rare syndrome called 19p13.3 deletion syndrome, which manifest itself in developmental delay as well as structural abnormalities such as facial dysmorphism and macrocephaly. Methods/Case Report We present a case of 14-month-old patient, born at term and was large for her gestational age. She had dysmorphic facial features including posterior cleft palate for which, she required placement of G-tube. Post-delivery, she experienced respiratory distress as well as hypoglycemic episodes. Over the period of time, her mother also noticed occasional bleeding through her gums with teething. Genetic workup was performed, which revealed 2.4 Mb of microdeletion at chromosome 19 region p13.3, including deletion of PIAS4, MAP2K2, GNA11, TBXA2R, RAX2 genes. TBXA2R mutation is associated with bleeding disorder due to a defect in platelet aggregation. The mutation in TBXA2R can lead to platelet type 13 bleeding disorder. For this purpose, a platelet aggregation study was performed to evaluate platelet function disorders. However, the result of the platelet aggregation study was inconclusive as it showed decrease responses to all agonists including arachidonic acid, epinephrine, ADP, collagen and ristocetin. Further work-up by electron microscopy (EM) of platelets (PL) revealed a significant decrease of delta granules (DG) (0.89 DG/PL, normal 4-6 DG/PL), consistent with delta granule storage pool deficiency (δ-SPD). Other abnormalities observed by EM included occasional gray platelets, platelets with immature and/or decreased numbers of α-granules, and rare giant α-granules. Results (if a Case Study enter NA) NA Conclusion To the best of our knowledge, no other case of 19p13.3 microdeletion syndrome with δ-SPD and associated abnormalities in α-granules has previously been described in the literature. Although it is unclear if there is any relationship between δ-SPD and 19p13.3 deletion syndrome, further investigation is warranted.

Patients with childhood acute myeloid leukemia (AML) with complex karyotypes (CKs) have a dismal outcome. However, for patients with a KMT2A rearrangement (KMT2A-r), the prognosis appears to depend on the fusion partner gene rather than the karyotype structure. Thus, a precise characterization of KMT2A-r and the fusion partner genes, especially in CKs, is of interest for managing AML. We describe the clinical and molecular features of a child who presented with a large abdominal mass, AML, and a new CK, involving chromosomes 11, 16, and 19 leading to a KMT2A-MLLT1 fusion and 2 extra copies of the ELL gene, thus resulting in the concurrent overexpression of MLLT1 and ELL. Molecular cytogenetic studies defined the karyotype as 47,XY,der(11)t(11;16)(q23.3;p11.2),der(16)t(16;19)(p11.2;p13.3),der(19)t(11;19)(q23.3;p13.3),+der(19)t(16;19)(16pter→p11.2::19p13.3→19q11::19p11→19p13.3::16p11.2→16pter). Array CGH revealed a gain of 30.5 Mb in the 16p13.3p11.2 region and a gain of 18.1 Mb in the 19p13.3p12 region. LDI-PCR demonstrated the KMT2A-MLLT1 fusion. Reverse sequence analysis showed that the MLLT1 gene was fused to the 16p11.2 region. RT-qPCR quantification revealed that ELL and MLLT1 were overexpressed (4- and 10-fold, respectively). In summary, this is a pediatric case of AML presenting a novel complex t(11;16;19) variant with overexpression of ELL and MLLT1.

Migraine is a common, debilitating neurovascular disease charactensed by severe recurrent headache, nausea and vomiting, photophobia and phonophobia. It is clinically diagnosed based on criteria specified by the International Headache Society (IHS), defining two major classes of migraine: migraine with aura (MA) and migraine without aura (MO) MA sufferers experience neurovascular disturbances that precede the headache phase of an attack. Although migraine is partly influenced by environmental determinants, there is a significant genetic component, with disease heritability estimated to be up to 60% and mode of transmission multifactorial. The disorder is common with a large Dutch study reporting lifetime prevalence estimates of 33% in women and 13.3% in men, with an earlier study estimating 24% of women and 12% of men in the overall population. Mutations in various ion channel genes are responsible for neuromuscular and other neurological disorders. Inherited ion channel mutations or 'channelopathies' are increasingly found to be the cause of various neurological disorders in humans. In familial hemiplegic migraine (FHM), a rare subtype of migraine with aura, mutations in the CACNA1A gene (localised at C19p13) have been fbund (FHM1). This gene codes for the alphalA subunit of the neuronal voltage-dependent P/Q-type calcium channel. Recently a second gene, ATP1A2 (FHM2) (localised at C1q23), was implicated in some EHM families. The ATP1A2 ion channel gene, codes for the alpha2 subunit of the Na+, K+ ion ATPase pump. These findings of mutations in these genes have focused attention on central nervous system ionic channels and helped to better understand EHM pathophysiology, where the best genetic evidence providing molecular insight into migraine still comes flom the mutations detected in the rare form of migraine with aura; FHM. Migraine family studies, at the Genomic Research Centre (GRC), have utilised linkage analysis methods in providing results that have indicated suggestive linkage to the FHM1-CACNA1A region on l9p13, in a large multigenerational family (Migraine Family 1; MEl) affected with typical migraine. Also linkage studies conducted within the GRC have implicated an additional susceptibility region on chromosome 1q31, but still not ruling out a second susceptibility region on C1q23, with the possibility of there being two distinct loci, on the chromosome lq region. The focus of research in this thesis is on two main chromosomal regions, which were tested for migraine susceptibility on chromosome 1 and chromosome 19. The research involved a cross-disciplinary approach utilising association, linkage and mutation screening approaches. Allelic candidate gene studies can provide a suitable method for locating genes of small effect that contribute to complex genetic disorders, such as migraine. Family linkage studies are useful for detection of chromosomal susceptibility regions and association studies are powerful when a plausible candidate gene and a sequence variant with potential functional relevance is examined. Mutation screening studies can indicate a direct cause of disorders such as migraine, where possible sequence variants may alter the translation of proteins in genes, causing the disease. The first gene exanted on chromosome 19 was that of the Low Density Lipoprotein Receptor (LDLR) gene. The LDLR gene is a cell surface receptor that plays an important role in cholesterol homeostasis. We investigated the (TA)n polymorphism in exon 18 of the LDLR gene on chromosome l9pl3.2 performing an association analysis in 244 typical migraine affected patients, 151 suffering from migraine with aura, 96 with migraine without aura and 244 unaffected controls. The populations consisted of Caucasians only and controls were age and sex matched. The results showed no significant difference between groups for allele frequency distributions of the (TA)n polymorphism even after separation of the migraine affected individuals into subgroups of MA and MO affected patients. This is in contradiction to Mochi et al, 2003 who found a positive association of this variant with MO. Our study discusses possible differences between the two studies and extends this research by investigating circulating cholesterol levels in a migraine affected genetically-isolated population. Another gene examined on chromosome l9pl3 was the insulin receptor gene (1NSR). The aim of this study was to investigate through direct sequencing the INSR gene in DNA samples from a migraine affected family previously showing linkage to chromosome l9pl3 in an attempt to detect disease associated mutations. The insulin receptor gene (INSR) on chromosome 19pl3.3-13.2 is a gene of interest since a number of SNPs located within the gene have been implicated in migraine with (MA) and without aura (MO). Six DNA samples obtained from non-founding migraine affected members of migraine family one (MF 1) were used in this study. Genomic DNA was sequenced for the 1NSR gene in exons 1-22 and the promoter region. In the six migraine family member samples, previously reported single nucleotide polymorphisms (SNP5) were detected within two exonic DNA coding regions of the INSR gene. These SNPs, in exon 13 and 17, do not alter the normal INSR polypeptide sequence. In addition, intron 7 also revealed a DNA base sequence variation. For the 5' untranslated promoter region of the gene, no mutations were detected. In conclusion, this study detected no INSR mutations in affected members of a chromosome 19 linked migraine pedigree. Hence, migraine linkage to this chromosomal region may involve other candidate genes. The NOTCH3 gene on C19p13.2-p13.l has previously been shown to be a gene involved in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and may also be implicated in migraine as there are some symptom similarities between the two disorders. The TNFSF7 gene localised on Cl9pl3 is homologous to the ligands of the TNF receptor family, including TNF-alpha and TNF-beta, genes that have both been previously associated with migraine. This study investigated the migraine susceptibility locus at Cl9p13 studying two genes that may be involved in the disorder. The NOTCH3 gene was analysed by sequencing all exons with known CADASIL mutations in a family (MF1) that has previously been shown to be linked to Cl9pl3. The sequencing results for affected members of this pedigree proved to be negative for all known sequence variants giving rise to mutation causing amino acid changes for CADASIL. The direct sequencing results displayed that of a normal coding sequence for the NOTCH3 gene F or the TNFSF7 gene, this was investigated through SNP association analysis using a matched case-control migraine diagnosed population. Chi-square results showed non-significant P values across all populations tested against controls except for the MO subgroup which displayed a weak association with the TNFSF7 SNP (genotype, allele analysis P = 0.036, P = 0 017 respectively). Our results suggest that common migraine is not caused by any known CADASIL mutations in the NOTCH3 gene of interest however, the TNFSF7 gene displayed signs of involvement in a MO affected population, but, further studies are needed to confirm these results and to further explore a TNF receptor - migraine potential interaction. A final examination on chromosome 19 involved a case report of an extremely rare and severe form of migraine. As stated earlier Familial Hemiplegic Migraine (FHM) is a severe rare sub-type of migraine and gene mutations on chromosome 19 have been identified in the calcium channel gene CACNA1A (Cl9pl3) fOr FHM. Recently a gene mutation (S218L) for a dramatic syndrome originating from FHM, commonly named 'migraine coma', has implicated exon 5 of the CACNA1A gene. The occurrence of trivial head trauma, in FHM patients, may also be complicated by severe, sometimes even fatal, cerebral edema and coma occurring after a lucid interval. Hemiplegic migraine has also been found to be sporadic in which both forms share a similar spectrum of clinical presentations and genetic heterogeneity. The case report presented in this study enhances the involvement of the S218L CACNA1A mutation in the extremely rare disorder of minor head trauma induced migraine coma. It not only proves to be a powerful diagnostic tool in detecting cases of FHM head trauma induced coma but also for sporadic hemiplegic migraine (SHM) coma subjects. We conclude from this case study that the S218L mutation, in the CACNA1A calcium channel subunit gene, is involved in sporadic hemiplegic migraine (SHM), delayed cerebral edema and coma after minor head trauma. This thesis also involved analysis of chromosome 1 for migraine susceptibility, where FHM studies provided a foundation fOr common migraine research on chromosome 1. Studies have suggested that mutations in the CACNA1A gene on chromosome l9p cause FHM in only approximately 50% of affected pedigrees. The CACNAIA gene has previously been tested, within the Genomics Research Centre, in the common forms of migraine; however no new mutations or the FHM mutations were detected in these MA/MO affected samples. A second FHM susceptibility locus maps to chromosome 1q23 and mutations in the ATP1A2 gene have recently been implicated in two Cl-linked FHM pedigrees. As FHM is considered a rare and severe form of MA, it is possible that the chromosome 1q23 locus, and the ATP1A2 gene, may be involved in the common forms of migraine with (MA) and possibly without aura (MO). Also, we have previously reported evidence of linkage to microsatellite markers on chromosome 1q31 in a large pedigree affected predominately with MA, which suggests the possibility that there are two distinct loci for migraine susceptibility on chromosome 1. The objectives of this study were to extend our linkage analysis of chromosome lq microsatellite markers in predominantly migraine with aura pedigrees. Also, our aim was to test the novel FHM-2 ATP1A2 gene for involvement in these migraine affected pedigrees and a previous pedigree (Migraine Family 14; MF 14) showing evidence of linkage of markers to Clq31. This was performed by a chromosome 1 scan (31 markers) in 21 multiplex pedigrees affected mainly with MA. Also, the known FHM-2 ATP1A2 gene mutations were tested, by sequencing, fOr involvement in MA and MO in these pedigrees. Mutation screening by direct sequencing was also performed throughout the coding areas of the ATP1A2 gene in 3 MA individuals fiom MF14. The results of this study detected evidence for linkage in our migraine pedigrees at chromosome 1q23, to microsatellite markers spanning the ATP1A2 (FHM-2) gene. However testing of the known ATP1A2 gene mutations (for FHM) in migraine probands of pedigrees showing excess allele sharing was negative, with no mutations detected in these migraineurs. Sequencing of the entire coding areas of the gene through 3 MA affecteds from MF14, a pedigree showing significant linkage to this region, was also negative for mutations. In conclusion, this study reported that microsatellite markers on chromosome 1q23 show evidence of excess allele sharing in MA and some MO pedigrees, suggesting linkage to the common forms of migraine and the presence of a susceptibility gene in this region. The new FHM-2 (ATPIA2 gene) mutations reported by Fusco et al, 2003 do not cause migraine in probands of affected pedigrees showing excess allele sharing to markers in this genomic region. Also no mutations were detected in all exons of the ATP1A2 gene in 3 MA affected individuals from a large pedigree (MF14) showing linkage to this region. Investigation in this thesis continued on chromosome 1, with other genes being examined on C1q23, as well as the C1q31 region for a migraine susceptibility locus or gene. Previously in our laboratory, evidence for linkage was shown to migraine at C1q31 in one family predominantly affected with MA, with microsatellite markers in this region. The initial Cl study (above; ATP1A2 gene) has also provided evidence for linkage to the chromosome 1 locus 1q23, with evidence for excess allele sharing of markers in predominantly MA affected pedigrees. To further investigate both chromosome I loci, an investigation with six candidate genes that lie within the C1q23 and 1q31 regions through association analysis was undertaken. The results from this study reported non-significant chi-square results, showing P values greater than 0.05 across all SNPs (and a CA rpt) tested. An exception was the rs704326 SNP from exon 43 of the CACNA1E gene on C1q31. P values significantly less than 0.001 were obtained in the total migraine population and the MA subgroup, with similar frequency comparisons ascertained in both genotype and allele analysis. Examination through contingency table analysis of the CACNA1E flequency data indicated that the risk allele (A) was over-represented in the migraine group compared to the control group. Further comparison of the genotype data indicated a difference in frequency distributions (P less than 0 0001). Stratified analyses of migraine subtypes indicated that this association was specifically attributed to the MA subtype group. Odds ratios produced an OR of 4.14 with a 95% CI of 2.36 - 7.26 (P less than 0.0001). The positive association results obtained within the CACNA1E gene are interesting in the fact that FHM is considered to be a rare and severe form of migraine with aura (MA) and FHM-1 is caused by mutations contained within the calcium channel gene CACNA1A (localized at Cl9p13). The idea that FHM and specifically an FHM gene in the C1q31 genomic region may also contribute to susceptibility to the more common forms of migraine i e. migraine with aura, strongly supports and reinforces the idea that a common defective gene may be influencing both FHM and typical migraine. In conclusion, this thesis undertook a cross-disciplinary approach to genetic research of a complex disorder. The research involved linkage, association and mutation analysis strategies of migraine. This research implicated a specific variant on chromosome 1 and further supported the heterogeneic nature of migraine. Future directions into migraine research should involve further investigation of this specific variant and this genomic region. Such studies may aid in the development of more precise diagnosis and treatment methods for this complex disorder.

Migraine is a common, debilitating neurovascular disease charactensed by severe recurrent headache, nausea and vomiting, photophobia and phonophobia. It is clinically diagnosed based on criteria specified by the International Headache Society (IHS), defining two major classes of migraine: migraine with aura (MA) and migraine without aura (MO) MA sufferers experience neurovascular disturbances that precede the headache phase of an attack. Although migraine is partly influenced by environmental determinants, there is a significant genetic component, with disease heritability estimated to be up to 60% and mode of transmission multifactorial. The disorder is common with a large Dutch study reporting lifetime prevalence estimates of 33% in women and 13.3% in men, with an earlier study estimating 24% of women and 12% of men in the overall population. Mutations in various ion channel genes are responsible for neuromuscular and other neurological disorders. Inherited ion channel mutations or 'channelopathies' are increasingly found to be the cause of various neurological disorders in humans. In familial hemiplegic migraine (FHM), a rare subtype of migraine with aura, mutations in the CACNA1A gene (localised at C19p13) have been fbund (FHM1). This gene codes for the alphalA subunit of the neuronal voltage-dependent P/Q-type calcium channel. Recently a second gene, ATP1A2 (FHM2) (localised at C1q23), was implicated in some EHM families. The ATP1A2 ion channel gene, codes for the alpha2 subunit of the Na+, K+ ion ATPase pump. These findings of mutations in these genes have focused attention on central nervous system ionic channels and helped to better understand EHM pathophysiology, where the best genetic evidence providing molecular insight into migraine still comes flom the mutations detected in the rare form of migraine with aura; FHM. Migraine family studies, at the Genomic Research Centre (GRC), have utilised linkage analysis methods in providing results that have indicated suggestive linkage to the FHM1-CACNA1A region on l9p13, in a large multigenerational family (Migraine Family 1; MEl) affected with typical migraine. Also linkage studies conducted within the GRC have implicated an additional susceptibility region on chromosome 1q31, but still not ruling out a second susceptibility region on C1q23, with the possibility of there being two distinct loci, on the chromosome lq region. The focus of research in this thesis is on two main chromosomal regions, which were tested for migraine susceptibility on chromosome 1 and chromosome 19. The research involved a cross-disciplinary approach utilising association, linkage and mutation screening approaches. This research implicated a specific variant on chromosome 1 and further supported the heterogeneic nature of migraine. Future directions into migraine research should involve further investigation of this specific variant and this genomic region. Such studies may aid in the development of more precise diagnosis and treatment methods for this complex disorder.
Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Medical Science
Full Text

碩士
國立臺灣大學
流行病學研究所
90
Cancer is believed to arise from a series of genetic alterations, including activation of proto-oncogenes and/or inactivation of tumor suppressor genes. The two-hit hypothesis proposed by Knudson, indicating that two mutational events are necessary to inactivate both alleles of a tumor suppressor gene, and, more importantly, the same tumor suppressor genes are responsible for both inherited and sporadic forms of the same cancer. Because one of the two hits is commonly involved genetic loss of the locus harboring tumor suppressor gene, the identification of a high frequency of genomic deletion detected by allelic loss or loss of heterozygosity(LOH) in specific genomic regions is widely used to provide critical evidence about the location and importance of putative tumor suppressor genes. Germ-line mutations in the STK11/LKB1 gene on chromosome 19p13 are found to be the causes of the Peutz-Jeghers syndrome(PJS), in which intestinal hamartomas are associated with elevated risks of several cancer types, including breast cancer. However, subsequent studies failed to identify STK11/LKB1 mutation, which is seemingly inconsistent to the importance of this gene in breast cancer defined in PJS patients and high LOH frequency found in 19p13 in breast cancer. One common explanation for this inconsistent result suggests other breast cancer-associated genes may be located at the loci adjacent to STK11/LKB1, and are responsible for the high frequency of LOH observed at 19p. In order to know whether other genes are at the neighboring loci of STK11/LKB1, and to define the importance of STK11/LKB1, the present study performed high-resolution allelotyping for loss of heterozygosity (LOH) on 19p13.3-13.2, based on laser-capture-microdissected tumor tissues from 140 breast cancers patients. A total of 24 microsatellite markers at these loci were employed to define the contribution of 19p13.3-13.2 in breast cancer development. The results show that:(1)Five commonly deleted regions(CDRs) are identified on chromosome 19p13.3-13.2, including D19S814-D19S565 (the STK11/LKB1 gene locus), and D19S894-D19S884 (the SAFB gene locus). These suggest STK11/LKB1 gene and SAFB gene may play an important role in breast cancer development. (2)Frequent allele loss we found in other three CDRs of chromosome 19p13.3-13.2 may harbor unknown tumor suppressor genes. (3)High LOH frequency in these CDRs supports the importance of allelic loss on chromosome 19p13.3-13.2 during breast tumorigenesis. (4)The frequency of the fractional allele loss(FAL) of chromosome 19p13.3-13.2 is found to be significantly associated with increasing grade of breast cancer differentiation (p=0.01).(5) Multiple genes on 19p13.3-13.2 may synergitically contribute to breast cancer progression.

The calcium-sensing receptor (CaSR) plays a key role in maintaining calcium homeostasis. The CaSR regulates parathyroid hormone (PTH) secretion and calcium reabsorption by the kidney. Loss-of-function CASR mutations on chromosome 3q21.1 cause familial hypocalciuric hypercalcaemia type 1 (FHH1). FHH1 patients are usually asymptomatic. Biochemically, FHH1 is characterized by mild-to-moderate hypercalcaemia, inappropriately low urinary calcium excretion and a normal or mildly elevated circulating PTH level. Loss-of-function GNA11 mutations on chromosome 19p13.3 lead to FHH2. GNA11 gene encodes Gα‎-11 which mediates downstream CaSR signalling. Patients with FHH2 mutations display a mild FHH phenotype. Loss-of-function AP2S1 mutations on chromosome 19q.13.3 give rise to FHH3. AP2S1 gene encodes the adaptor-related protein complex 2 sigma (AP2σ‎) which is crucial for clathrin-mediated endocytosis, CaSR signalling, and trafficking. FHH3 may be a more severe form of FHH that may produce symptomatic hypercalcaemia, low bone mineral density, and cognitive dysfunction. Calcimimetic therapy may be considered for patients with FHH types 1–3.