A recurrent homozygous LMNA missense variant p.Thr528Met causes atypical progeroid syndrome characterized by mandibuloacral dysostosis, severe muscular dystrophy, and skeletal deformities

• Published in: American journal of medical genetics. Part A Vol. 191; no. 9; pp. 2274 - 2289
• Main Authors: Saadi, Abdelkrim, Navarro, Claire, Ozalp, Ozge, Lourenco, Charles Marques, Fayek, Racha, Da Silva, Nathalie, Chaouch, Athmane, Benahmed, Meryem, Kubisch, Christian, Munnich, Arnold, Lévy, Nicolas, Roll, Patrice, Pacha, Lamia Ali, Chaouch, Malika, Lessel, Davor, De Sandre‐Giovannoli, Annachiara
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01-09-2023; Wiley Subscription Services, Inc; Wiley
• Subjects: Aging; cell nucleus; Creatine; Creatine kinase; Dysostosis; Fibroblasts; Genetics; Heterozygosity; Human genetics; Human health and pathology; Immunofluorescence; Isoforms; Lamins; Life Sciences; Lipodystrophy; Muscular dystrophy; Osteolysis; Phenotypes; premature aging; Progeria; Progeroid syndromes; progeria; cell nucleus; muscular dystrophy; lamins; premature aging
• DOI: 10.1002/ajmg.a.63335
• EISSN: 1552-4833
• ISSN: 1552-4825

Atypical progeroid syndromes (APS) are premature aging syndromes caused by pathogenic LMNA missense variants, associated with unaltered expression levels of lamins A and C, without accumulation of wild‐type or deleted prelamin A isoforms, as observed in Hutchinson‐Gilford progeria syndrome (HGPS) or HGPS‐like syndromes. A specific LMNA missense variant, (p.Thr528Met), was previously identified in a compound heterozygous state in patients affected by APS and severe familial partial lipodystrophy, whereas heterozygosity was recently identified in patients affected by Type 2 familial partial lipodystrophy. Here, we report four unrelated boys harboring homozygosity for the p.Thr528Met, variant who presented with strikingly homogeneous APS clinical features, including osteolysis of mandibles, distal clavicles and phalanges, congenital muscular dystrophy with elevated creatine kinase levels, and major skeletal deformities. Immunofluorescence analyses of patient‐derived primary fibroblasts showed a high percentage of dysmorphic nuclei with nuclear blebs and typical honeycomb patterns devoid of lamin B1. Interestingly, in some protrusions emerin or LAP2α formed aberrant aggregates, suggesting pathophysiology‐associated clues. These four cases further confirm that a specific LMNA variant can lead to the development of strikingly homogeneous clinical phenotypes, in these particular cases a premature aging phenotype with major musculoskeletal involvement linked to the homozygous p.Thr528Met variant.