Aging
Navigate
Submit an Article
Research Paper|Volume 5, Issue 6|pp 445—459

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

Sven Starke1,2, Peter Meinke3, Daria Camozzi4, Elisabetta Mattioli4, Roland Pfaeffle1, Manuela Siekmeyer1, Wolfgang Hirsch5, Lars Christian Horn6, Uwe Paasch7, Diana Mitter8, Giovanna Lattanzi4, Manfred Wehnert3, Wieland Kiess1
  • 1Department of Women and Child Health, Hospital for Children and Adolescents, Centre of Pediatric Research, University Hospital, University of Leipzig, Leipzig, Germany
  • 2Department of Pediatric Oncology, Hematology and Hemostaseology, Hospital for Children and Adolescents, University Hospital, University of Leipzig, Leipzig, Germany
  • 3Institute of Human Genetics Greifswald, University Medicine Greifswald and Interfaculty, Institute of Genetics and Functional Genomics, University of Greifswald, Germany
  • 4National Research Council of Italy, CNR, Institute of Molecular Genetics, Unit of Bologna, Italy
  • 5Department of Pediatric Radiology, University Hospital of Leipzig, Leipzig, Germany
  • 6Institute of Pathology, Division of Breast, Gynecologic and Perinatal Pathology, University of Leipzig, Leipzig, Germany
  • 7Department of Dermatology, Venereology, and Allergology, University Hospital of Leipzig, Leipzig, Germany
  • 8Institute of Human Genetics, University Hospital of Leipzig, Leipzig, Germany

* * Equal contribution

Received: April 9, 2013Accepted: June 13, 2013Published: June 19, 2013
https://doi.org/10.18632/aging.100566

Copyright: © 2013 Starke et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

The clinical course of a female patient affected by a progeroid syndrome with Restrictive Dermopathy (RD)-like features was followed up. Besides missing hairiness, stagnating weight and growth, RD-like features including progressive skin swelling and solidification, acrocontractures, osteolysis and muscular hypotension were observed until the patient died 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. In contrast to reported RD patients with LMNA mutations, LMNA p.R435C is not located at the cleavage site necessary for processing of prelamin A by ZMPSTE24 and leads to a distinct phenotype combining clinical features of Restrictive Dermopathy, Mandibuloacral Dysplasia and Hutchinson-Gilford Progeria. Functionally, LMNA p.R435C is associated with increasing DNA double strand breaks and decreased recruitment of P53 binding protein 1 (53BP1) to DNA-damage sites indicating delayed DNA repair. The follow-up of the complete clinical course in the patient combined with functional studies showed for the first time that a progressive loss of lamin A rather than abnormal accumulation of prelamin A species could be a pathophysiological mechanism in progeroid laminopathies, which leads to DNA repair deficiency accompanied by advancing tissue degeneration.