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

Sven Starke, Peter Meinke, Daria Camozzi, Elisabetta Mattioli, Roland Pfaeffle, Manuela Siekmeyer, Wolfgang Hirsch, Lars Christian Horn, Uwe Paasch, Diana Mitter, Giovanna Lattanzi, Manfred Wehnert, Wieland Kiess

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)445-459
Number of pages15
JournalAging
Volume5
Issue number6
Publication statusPublished - Jun 2013

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Keywords

  • 53BP1
  • DNA damage
  • LMNA
  • Progeroid syndrome
  • uniparental disomy

ASJC Scopus subject areas

  • Ageing
  • Cell Biology

Cite this

Starke, S., Meinke, P., Camozzi, D., Mattioli, E., Pfaeffle, R., Siekmeyer, M., Hirsch, W., Horn, L. C., Paasch, U., Mitter, D., Lattanzi, G., Wehnert, M., & Kiess, W. (2013). Progeroid laminopathy with restrictive dermopathy-like features caused by an isodisomic LMNA mutation p.R435C. Aging, 5(6), 445-459.