Résumé :
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Heart-hand syndrome (HHS) is a heterogeneous group of genetic disorders characterized by congenital cardiac and limb deformities. Five subtypes are currently reported, among them the Slovenian type (HHS-S) associating bracydactyly and cardiac conduction defects. Due to cardiac involvement similarities between laminopathies and HHS-S, we clinically reassessed 12 members and then analyzed LMNA gene in the original HHS-S family. We then used Universal mutation Database (UMD®) software to perform in silico predictions. We finally studied fibroblasts from 2 affected members and control subject by immunofluorescence, western blot and RT-PCR techniques to study the consequences of the identified LMNA variant at molecular, protein and cellular levels. In addition to the HHS, one patient showed proximal myopathy. At the molecular level, we identified a new LMNA intronic variant (IVS9-12 T>G) heterozygous in all affected subjects. UMD® software predicted creation of a new cryptic acceptor splice site 11 nucleotides upstream of the wild type site. mRNA study revealed the presence of a frameshift in the LMNA mRNA leading to a premature stop codon and the production of a truncated protein of 550 amino acids observed on fibroblast western. Fibroblasts showed nuclear abnormalities similar to what is classically observed in laminopathies. Finally, we identified a new intronic LMNA variant that lead to the production of a truncated lamin A/C that is expressed in patient fibroblasts. HHS-S might be considered as a new lamins A/C related disorder thus widening the clinical spectrum of laminopathies.
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