Genotype-phenotype correlations for COL4A3-COL4A5 variants resulting in Gly substitutions in Alport syndrome

Alport syndrome is the commonest inherited kidney disease and nearly half the pathogenic variants in the COL4A3-COL4A5 genes that cause Alport syndrome result in Gly substitutions. This study examined the molecular characteristics of Gly substitutions that determine the severity of clinical features. Pathogenic COL4A5 variants affecting Gly in the Leiden Open Variation Database in males with X-linked Alport syndrome were correlated with age at kidney failure (n = 157) and hearing loss diagnosis (n = 80). Heterozygous pathogenic COL4A3 and COL4A4 variants affecting Gly (n = 304) in autosomal dominant Alport syndrome were correlated with the risk of haematuria in the UK 100,000 Genomes Project. Gly substitutions were stratified by exon location (1 to 20 or 21 to carboxyl terminus), being adjacent to a non-collagenous region (interruption or terminus), and the degree of instability caused by the replacement residue. Pathogenic COL4A5 variants that resulted in a Gly substitution with a highly destabilising residue reduced the median age at kidney failure by 7 years (p = 0.002), and age at hearing loss diagnosis by 21 years (p = 0.004). Substitutions adjacent to a non-collagenous region delayed kidney failure by 19 years (p = 0.014). Heterozygous pathogenic COL4A3 and COL4A4 variants that resulted in a Gly substitution with a highly destabilising residue (Arg, Val, Glu, Asp, Trp) were associated with an increased risk of haematuria (p = 0.018), and those adjacent to a non-collagenous region were associated with a reduced risk (p = 0.046). Exon location had no effect. In addition, COL4A5 variants adjacent to non-collagenous regions were over-represented in the normal population in gnomAD (p < 0.001). The nature of the substitution and of nearby residues determine the risk of haematuria, early onset kidney failure and hearing loss for Gly substitutions in X-linked and autosomal dominant Alport syndrome

Expanding the MTM1 mutational spectrum: novel variants including the first multi-exonic duplication and development of a locus-specific database

Myotubular myopathy (MIM#310400), the X-linked form of Centronuclear myopathy (CNM) is mainly characterized by neonatal hypotonia and inability to maintain unassisted respiration. The MTM1 gene, responsible for this disease, encodes myotubularin - a lipidic phosphatase involved in vesicle trafficking regulation and maturation. Recently, it was shown that myotubularin interacts with desmin, being a major regulator of intermediate filaments. We report the development of a locus-specific database for MTM1 using the Leiden Open Variation database software (http://www.lovd.nl/MTM1), with data collated for 474 mutations identified in 472 patients (by June 2012). Among the entries are a total of 25 new mutations, including a large deletion encompassing introns 2-15. During database implementation it was noticed that no large duplications had been reported. We tested a group of eight uncharacterized CNM patients for this specific type of mutation, by multiple ligation-dependent probe amplification (MLPA) analysis. A large duplication spanning exons 1-5 was identified in a boy with a mild phenotype, with results pointing toward possible somatic mosaicism. Further characterization revealed that this duplication causes an in-frame deletion at the mRNA level (r.343_444del). Results obtained with a next generation sequencing approach suggested that the duplication extends into the neighboring MAMLD1 gene and subsequent cDNA analysis detected the presence of a MTM1/MAMLD1 fusion transcript. A complex rearrangement involving the duplication of exon 10 has since been reported, with detection also enabled by MLPA analysis. It is thus conceivable that large duplications in MTM1 may account for a number of CNM cases that have remained genetically unresolved

Recherche par génétique positionnelle de gènes impliqués dans des caractères quantitatifs: A. le caractère culard bovin - B. l'hypertension artérielle du rat

Doctorat en sciences médicalesinfo:eu-repo/semantics/nonPublishe

Institutionalised Adults with Angelman Syndrome

info:eu-repo/semantics/nonPublishe

Novel Homozygous Mutation in the AGPAT2 Gene in a Child With Berardinelli-Seip Congenital Lipodystrophy Syndrome

Berardinelli-Seip congenital lipodystrophy (BSCL) is an autosomal recessive disorder, characterized by the generalized absence of subcutaneous fat and muscular hypertrophy. Meanwhile other signs and symptoms have already been reported with this genetic disorder. Herein, we report an infant with BSCL, who was referred to our center because of acromegaloid and muscular appearance from the age of three months. He had dark skin, hypertrichosis prominent subcutaneous vessels and organomegaly in physical examination. Genetic study showed novel homozygous mutations in the AGPAT2 gene, which confirmed diagnosis of BSCL in this patient. Although clinical suspicious could help us to make diagnosis of congenital disorders, definite diagnosis relies on genetic studies.

Acute portal thrombosis revealing hereditary hemochromatosis: Report of a case

The authors report the case of a 49-year old man in whom an inaugural portal vein thrombosis led to the diagnosis of hereditary hemochromatosis. In this case, the increase in ferritinemia and the T2-weighted MRI hepatic segmental hyposignal were considered as consequences of tissular necrosis while they did probe a real iron overload. Genetic testing, revealing C282Y/H63D compound heterozygoty, provided evidence for a diagnosis of hereditary hemochromatosis. Weekly venesections induced a calculated iron depletion of 3.5 g without occurrence of anemia, further supporting the diagnosis. We suggest that hemochromatosis should be considered in the differential diagnosis of idiopathic portal vein thrombosis when signs of abnormal iron accumulation exist.info:eu-repo/semantics/publishe

Molecular genetics of the s<inf>a</inf>-gene: Cosegregation with hypertension and mapping to rat chromosome 1

Objectives: The SA-gene shows markedly higher levels of expression in the kidneys of spontaneously hypertensive rats (SHR) than in their non-hypertensive reference strain, the Wistar-Kyoto (WKY) rat. Based on the important role of the kidney in blood pressure regulation, the possibility has been raised that this gene, the translational product of which remains unknown, may participate in the pathogenesis of primary hypertension. The present study was conducted to test this hypothesis and to ascertain the chromosomal localization of the SA-gene. Design: A cosegregation study was performed using an F2 intercross between stroke-prone SHR (SHRSP) and WKY rats, and a previously described restriction fragment length polymorphism of the SA-gene for characterization of genotype. Mapping of the SA-gene was accomplished by screening a somatic cell-hybrid panel and by linkage group analysis. Results: A statistically significant difference in systolic blood pressure was found after sodium loading, but not under basal conditions between groups of rats defined by zygosity at the SA locus, consistent with a hypertensive effect of the SHRSP alíele. No effect of SA genotype on diastolic blood pressure was observed. The SA-gene was localized on rat chromosome 1. Conclusions: This study establishes the SA locus on chromosome 1 as a region in which a gene or genes contributing to blood pressure regulation in this model are localized, and provides further evidence for a possible role of the SA-gene in the pathogenesis of hypertension. © Current Science Ltd.SCOPUS: ar.jinfo:eu-repo/semantics/publishe