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