Progeroid laminopathy with restrictive dermopathy-like features caused by an isodisomic LMNA mutation p.R435C

Abstract

The clinical course of a female patient affected by a progeroid syndrome with Restrictive Dermopathy (RD)-likefeatures was followed up. Besides missing hairiness, stagnating weight and growth, RD-like features including progressiveskin swelling and solidification, acrocontractures, osteolysis and muscular hypotension were observed until the patientdied at the age of 11 months. A homozygous LMNA mutation c.1303C>T (p.R435C) was found by Sanger sequencing.Haplotyping revealed a partial uniparental disomy of chromosome 1 (1q21.3 to 1q23.1) including the LMNA gene. Incontrast to reported RD patients with LMNA mutations, LMNA p.R435C is not located at the cleavage site necessary forprocessing of prelamin A by ZMPSTE24 and leads to a distinct phenotype combining clinical features of RestrictiveDermopathy, Mandibuloacral Dysplasia and Hutchinson-Gilford Progeria. Functionally, LMNA p.R435C is associated withincreasing DNA double strand breaks and decreased recruitment of P53 binding protein 1 (53BP1) to DNA-damage sitesindicating delayed DNA repair. The follow-up of the complete clinical course in the patient combined with functionalstudies showed for the first time that a progressive loss of lamin A rather than abnormal accumulation of prelamin Aspecies could be a pathophysiological mechanism in progeroid laminopathies, which leads to DNA repair deficiency accompanied by advancing tissue degeneration.© Starke et al.