Literatura académica sobre el tema "Golgipathie"

The Golgi apparatus (GA) is involved in a whole spectrum of activities, from lipid biosynthesis and membrane secretion to the posttranslational processing and trafficking of most proteins, the control of mitosis, cell polarity, migration and morphogenesis, and diverse processes such as apoptosis, autophagy, and the stress response. In keeping with its versatility, mutations in GA proteins lead to a number of different disorders, including syndromes with multisystem involvement. Intriguingly, however, > 40% of the GA-related genes known to be associated with disease affect the central or peripheral nervous system, highlighting the critical importance of the GA for neural function. We have previously proposed the term “Golgipathies” in relation to a group of disorders in which mutations in GA proteins or their molecular partners lead to consequences for brain development, in particular postnatal-onset microcephaly (POM), white-matter defects, and intellectual disability (ID). Here, taking into account the broader role of the GA in the nervous system, we refine and enlarge this emerging concept to include other disorders whose symptoms may be indicative of altered neurodevelopmental processes, from neurogenesis to neuronal migration and the secretory function critical for the maturation of postmitotic neurons and myelination.

GRASP65 is a Golgi-associated peripheral protein encoded by theGORASP1gene and required for Golgi cisternal stacking in vitro. A key role of GRASP65 in the regulation of cell division has also been suggested. However, depletion of GRASP65 in mice has little effect on the Golgi structure and the gene has not been associated with any human phenotype to date. Here, we report the identification of the first human pathogenic variant ofGORASP1(c.1170_1171del; p.Asp390Glufs*18) in a patient combining a neurodevelopmental disorder with neurosensory, neuromuscular, and skeletal abnormalities. Functional analysis revealed that the variant leads to a total absence of GRASP65. The structure of the Golgi apparatus did not show fragmentation, but glycosylation anomalies such as hyposialylation were detected. Mitosis analyses revealed an excess of prometaphases and metaphases with polar chromosomes, suggesting a delay in the cell cycle. These phenotypes were recapitulated in RPE cells in which a similar mutation was introduced by CRISPR/Cas9. These results indicate that loss of GRASP65 in humans causes a novel Golgipathy associated with defects in glycosylation and mitotic progression.

Abstract Human post-natal neurodevelopmental delay is often associated with cerebral alterations that can lead, by themselves or associated with peripheral deficits, to premature death. Here, we report the clinical features of 10 patients from six independent families with mutations in the autosomal YIF1B gene encoding a ubiquitous protein involved in anterograde traffic from the endoplasmic reticulum to the cell membrane, and in Golgi apparatus morphology. The patients displayed global developmental delay, motor delay, visual deficits with brain MRI evidence of ventricle enlargement, myelination alterations and cerebellar atrophy. A similar profile was observed in the Yif1b knockout (KO) mouse model developed to identify the cellular alterations involved in the clinical defects. In the CNS, mice lacking Yif1b displayed neuronal reduction, altered myelination of the motor cortex, cerebellar atrophy, enlargement of the ventricles, and subcellular alterations of endoplasmic reticulum and Golgi apparatus compartments. Remarkably, although YIF1B was not detected in primary cilia, biallelic YIF1B mutations caused primary cilia abnormalities in skin fibroblasts from both patients and Yif1b-KO mice, and in ciliary architectural components in the Yif1b-KO brain. Consequently, our findings identify YIF1B as an essential gene in early post-natal development in human, and provide a new genetic target that should be tested in patients developing a neurodevelopmental delay during the first year of life. Thus, our work is the first description of a functional deficit linking Golgipathies and ciliopathies, diseases so far associated exclusively to mutations in genes coding for proteins expressed within the primary cilium or related ultrastructures. We therefore propose that these pathologies should be considered as belonging to a larger class of neurodevelopmental diseases depending on proteins involved in the trafficking of proteins towards specific cell membrane compartments.

AbstractDyggve–Melchior–Clausen dysplasia (DMC) and Smith–McCort dysplasia (SMC types 1 and 2) are rare spondylo‐epi‐metaphyseal dysplasias with identical radiological and clinical findings. DMC and SMC type 1 are allelic disorders caused by homozygous or compound heterozygous variants in DYM, while biallelic causative variants in RAB33B lead to SMC type 2. The terminology “skeletal golgipathies” has been recently used to describe these conditions, highlighting the pivotal role of these two genes in the organization and intracellular trafficking of the Golgi apparatus. In this study, we investigated 17 affected individuals (8 males, 9 females) from 10 unrelated consanguineous families, 10 diagnosed with DMC and seven with SMC type 2. The mean age at diagnosis was 9.61 ± 9.72 years, ranging from 20 months to 34 years, and the average height at diagnosis was 92.85 ± 15.50 cm. All patients exhibited variable degrees of short trunk with a barrel chest, protruding abdomen, hyperlordosis, and decreased joint mobility. A total of nine different biallelic variants were identified, with six being located in the DYM gene and the remaining three detected in RAB33B. Notably, five variants were classified as novel, four in the DYM gene and one in the RAB33B gene. This study aims to comprehensively assess clinical, radiological, and molecular findings along with the long‐term follow‐up findings in 17 patients with DMC and SMC type 2. Our results suggest that clinical symptoms of the disorder typically appear from infancy to early childhood. The central notches of the vertebral bodies were identified as early as 20 months and tended to become rectangular, particularly around 15 years of age. Pseudoepiphysis was observed in five patients; we believe this finding should be taken into consideration when evaluating hand radiographs in clinical assessments. Furthermore, our research contributes to an enhanced understanding of clinical and molecular aspects in these rare “skeletal golgipathies,” expanding the mutational spectrum and offering insights into long‐term disease outcomes.

AbstractWe present a case study of a patient exhibiting acquired microcephaly along with global developmental delay and drug‐resistant epilepsy. Brain magnetic resonance imaging revealed distinctive features, including a Z‐shaped morphology of the brainstem, volumetric reduction of white matter, diffuse thinning of the corpus callosum, and partial fusion of the cerebellar hemispheres at their most cranial portion. Whole‐exome sequencing uncovered a pathogenic variant in the ARF3 gene c.200A>T, p.(Asp67Val). The neurodevelopmental disorder associated with the ARF3 gene is exceptionally rare, with only two previously documented cases in the literature. This disorder is characterized by global developmental delay and brain malformations, particularly affecting the white matter, cerebellum, and brainstem. It can also manifest as acquired microcephaly and epilepsy. These phenotypic characteristics align with Golgipathies, underscoring the significance of considering this group of conditions in relevant clinical contexts. In cases where a Z‐shaped morphology of the brainstem is observed, ARF3‐associated disorder should be included in the list of differential diagnoses.

BackgroundLimb-girdle muscular dystrophies (LGMD) are a heterogeneous group of genetically determined muscle disorders. TRAPPC11-related LGMD is an autosomal-recessive condition characterised by muscle weakness and intellectual disability.MethodsA clinical and histopathological characterisation of 25 Roma individuals with LGMD R18 caused by the homozygousTRAPPC11c.1287+5G>A variant is reported. Functional effects of the variant on mitochondrial function were investigated.ResultsThe c.1287+5G>A variant leads to a phenotype characterised by early onset muscle weakness, movement disorder, intellectual disability and elevated serum creatine kinase, which is similar to other series. As novel clinical findings, we found that microcephaly is almost universal and that infections in the first years of life seem to act as triggers for a psychomotor regression and onset of seizures in several individuals withTRAPPC11variants, who showed pseudometabolic crises triggered by infections. Our functional studies expanded the role of TRAPPC11 deficiency in mitochondrial function, as a decreased mitochondrial ATP production capacity and alterations in the mitochondrial network architecture were detected.ConclusionWe provide a comprehensive phenotypic characterisation of the pathogenic variantTRAPPC11c.1287+5G>A, which is founder in the Roma population. Our observations indicate that some typical features of golgipathies, such as microcephaly and clinical decompensation associated with infections, are prevalent in individuals with LGMD R18.

BackgroundDyggve-Melchior-Clausen dysplasia (DMC) and Smith-McCort dysplasia (SMC types 1 and 2) are rare spondyloepimetaphyseal dysplasias with identical radiological findings. The presence of intellectual disability in DMC and normal intellect in SMC differentiates the two. DMC and SMC1 are allelic and caused by homozygous or compound heterozygous variants in DYM. SMC2 is caused by variations in RAB33B. Both DYM and RAB33B are important in intravesicular transport and function in the Golgi apparatus.MethodsDetailed clinical phenotyping and skeletal radiography followed by molecular testing were performed in all affected individuals. Next-generation sequencing and Sanger sequencing were used to confirm DYM and RAB33B variants. Sanger sequencing of familial variants was done in all parents.Results24 affected individuals from seven centres are described. 18 had DMC and 6 had SMC2. Parental consanguinity was present in 15 of 19 (79%). Height <3 SD and gait abnormalities were seen in 20 and 14 individuals, respectively. The characteristic radiological findings of lacy iliac crests and double-humped vertebral bodies were seen in 96% and 88% of the affected. Radiological findings became attenuated with age. 23 individuals harboured biallelic variants in either DYM or RAB33B. Fourteen different variants were identified, out of which 10 were novel. The most frequently occurring variants in this group were c.719 C>A (3), c.1488_1489del (2), c.1484dup (2) and c.1563+2T>C (2) in DYM and c.400C>T (2) and c.186del (2) in RAB33B. The majority of these have not been reported previously.ConclusionThis large cohort from India contributes to the increasing knowledge of clinical and molecular findings in these rare ‘Golgipathies’.

Mon doctorat porte sur l'étude de deux maladies génétiques récessives qui touchent le développement cérébral postnatal et résultent de variants dans des gènes impliquant l'appareil de Golgi. La première maladie étudiée, le syndrome de Dyggve-Melchior-Clausen (DMC) a conduit à impliquer en 2003 la première protéine golgienne, la DYMECLINE, dans une microcéphalie postnatale, et a ensuite mené au concept de Golgipathies neurodéveloppementales. Les atteintes neurodéveloppementales du DMC sont associées à une déficience intellectuelle et à des anomalies squelettiques spécifiques également postnatales (dysplasie spondylo-epi-métaphysaire) et résultent de la déficience du gène DYM codant pour la DYMECLINE dont l'absence induit un défaut de transport antérograde entre le réticulum endoplasmique et l'appareil de Golgi notamment dans les neurones. Un variant clinique du DMC sans microcéphalie ni déficience intellectuelle, mais dont les caractéristiques osseuses sont identiques, la dysplasie de Smith McCort (SMC), peut résulter soit de variants moins délétères du gène DYM (SMC1) soit de variants du gène codant la RAB-GTPase RAB33B (SMC2) suggérant une relation entre les deux protéines. Dans ce travail, j'ai montré que ces deux protéines co-localisent au cis-Golgi, interagissent physiquement, que la DYMECLINE est recrutée au Golgi par RAB33B et intervient dans le contrôle de l'autophagie dans des cellules non neuronales. Dans les neurones déficients pour Dym, les deux protéines sont en revanche faiblement co-localisées et l'autophagie n'est pas perturbée, mais des défauts de transport rétrograde de la membrane plasmique vers le Golgi ont été identifiés, associés à des anomalies de croissance dendritique et des défauts de maturation synaptique. La seconde partie de ma thèse porte sur l'identification d'un variant biallélique du gène GORASP1 chez un patient présentant un nouveau syndrome neurodéveloppemental caractérisé par des atteintes de la substance blanche, neurosensorielles, neuromusculaires et squelettiques. GORASP1 code pour la protéine golgienne GRASP65, connue pour son rôle dans la structure du Golgi, dans la glycosylation des protéines et dans le contrôle de l'entrée en mitose. Malgré ces fonctions apparemment essentielles et ubiquitaires, le gène n'a été impliqué dans aucune pathologie humaine. A partir à la fois des fibroblastes du patient et de cellules RPE où j'ai introduit par CRISPR/Cas9 une mutation imitant le variant du patient, j'ai montré que la protéine GRASP65 n'est plus présente dans les cellules mutées et j'ai identifié dans ces cellules des défauts de glycosylation et de mitose. Ces défauts n'empêchent cependant pas les cellules RPE de proliférer normalement. En étudiant un autre mutant généré par hasard dans les cellules RPE et qui s'est avéré produire une protéine tronquée en C-terminal mais stable, j'ai observé un phénotype de croissance cellulaire plus sévère que lorsque la protéine est totalement absente, suggérant des effets dominants négatifs de la protéine tronquée. En revanche ce mutant stable n'a pas montré de défauts de glycosylation. Cette étude a permis d'impliquer GRASP65 dans une maladie neurodéveloppementale et suggère qu'une absence totale de protéine est parfois moins délétère qu'une protéine tronquée stable
My PhD focuses on the study of two recessive genetic diseases that affect postnatal brain development and result from variants in genes involving the Golgi apparatus. The first disease studied, Dyggve-Melchior-Clausen syndrome (DMC), led in 2003 to the involvement of the first Golgi protein, DYMECLIN, in postnatal microcephaly, and subsequently to the concept of neurodevelopmental Golgipathies. In DMC, neurodevelopmental impairments are associated with intellectual disability and specific skeletal defects, of postnatal onset as well (spondylo-epi-metaphyseal dysplasia) and result from a deficiency in the DYM gene encoding DYMECLIN, this absence of which induces a defect in anterograde transport between the endoplasmic reticulum and the Golgi apparatus, notably in neurons. Smith McCort dysplasia (SMC), a clinical variant of DMC without microcephaly or intellectual deficiency, but with identical skeletal features, can result either from less deleterious variants of the DYM gene (SMC1) or from variants of the gene encoding the RAB-GTPase RAB33B (SMC2), suggesting a relationship between the two proteins. In this work, I have shown that these two proteins co-localize at the cis-Golgi, interact physically, that DYMECLIN is recruited to the Golgi by RAB33B and is involved in the control of autophagy in non-neuronal cells. However, in Dym-deficient neurons, the two proteins are weakly co-localized and autophagy is not disrupted, but defects in retrograde transport from the plasma membrane to the Golgi have been identified, associated with abnormalities in dendritic growth and defects in synaptic maturation. The second part of my thesis concerns the identification of a biallelic variant in the GORASP1 gene in a patient with a new neurodevelopmental syndrome characterized by white matter, neurosensory, neuromuscular and skeletal abnormalities. GORASP1 encodes the Golgi protein GRASP65, known for its role in Golgi structure, protein glycosylation and control of mitosis entry. Despite these apparently essential and ubiquitous functions, the gene has not been implicated in any human pathology so far. Using both patient's fibroblasts and RPE cells in which I introduced by CRISPR/Cas9 a mutation mimicking the patient's variant, I showed that the GRASP65 protein is no longer present in mutated cells, and identified glycosylation and mitosis defects in these cells. However, these defects do not prevent RPE cells from proliferating normally. Studying another mutant generated incidentally in RPE cells, which turned out to produce a C-terminally truncated but stable protein, I observed a more severe cell growth phenotype than when the protein is totally absent, suggesting dominant negative effects of the truncated protein. In contrast, this stable mutant showed no glycosylation defects. This study implicates GRASP65 in a neurodevelopmental disease and suggests that a total absence of the protein is sometimes less deleterious than a stable truncated protein