Mutation spectrum in the ABCC6 gene and genotype–phenotype correlations in a French cohort with pseudoxanthoma elasticum

International audiencePurpose: Pseudoxanthoma elasticum (PXE) is an autosomal recessive disorder caused by variants in the ABCC6 gene. Ectopic mineralization of connective tissues leads to skin, eye, and cardiovascular manifestations with considerable phenotypic variability of unknown cause. We aimed to identify genotype-phenotype correlations in PXE. Methods: A molecular analysis was performed on 458 French PXE probands clinically evaluated using the Phenodex score (PS). Variant topographic analysis and genotype-phenotype correlation analysis were performed according to the number and type of identified variants. Results: Complete molecular analysis of 306 cases allowed the identification of 538 mutational events (88% detection rate) with 142 distinct variants, of which 66 were novel. Missense variant distribution was specific to some regions and residues of ABCC6. For the 220 cases with a complete PS, there was a higher prevalence of eye features in Caucasian patients (P = 0.03) and more severe eye and vascular phenotype in patients with loss-of-function variants (P = 0.02 and 0.05, respectively). Nephrolithiases and strokes, absent from the PS, were prevalent features of the disorder (11 and 10%, respectively). Conclusion: We propose an updated PS including renal and neurological features and adaptation of follow-up according to the genetic and ethnic status of PXE-affected patients

A gene for maturity onset diabetes of the young (MODY) maps to chromosome 12q

Maturity-onset diabetes of the young (MODY) is a subtype of non-insulin dependent diabetes mellitus, with early age of onset. MODY is genetically heterogeneous, associated with glucokinase mutations and a locus on chromosome 20q; in about 50% of cases, its genetic background is unknown. We have studied 12 families in which MODY is unlinked to either glucokinase or chromosome 20q markers, and find significant evidence for linkage with microsatellite markers on chromosome 12q, most likely within a 7 centimogran interval bracketed by D12S86 and D12S342. The disease was estimated to be linked to this chromosome region in approximately 50% of families in a heterogeneity analysis. These MODY patients exhibit major hyperglycaemia with a severe insulin secretory defect, suggesting that the causal gene is implicated in pancreatic beta-cell function