Research Paper Volume 5, Issue 6 pp 445—459
Progeroid laminopathy with restrictive dermopathy-like features caused by an isodisomic LMNA mutation p.R435C
- 1 Department of Women and Child Health, Hospital for Children and Adolescents, Centre of Pediatric Research, University Hospital, University of Leipzig, Leipzig, Germany
- 2 Department of Pediatric Oncology, Hematology and Hemostaseology, Hospital for Children and Adolescents, University Hospital, University of Leipzig, Leipzig, Germany
- 3 Institute of Human Genetics Greifswald, University Medicine Greifswald and Interfaculty, Institute of Genetics and Functional Genomics, University of Greifswald, Germany
- 4 National Research Council of Italy, CNR, Institute of Molecular Genetics, Unit of Bologna, Italy
- 5 Department of Pediatric Radiology, University Hospital of Leipzig, Leipzig, Germany
- 6 Institute of Pathology, Division of Breast, Gynecologic and Perinatal Pathology, University of Leipzig, Leipzig, Germany
- 7 Department of Dermatology, Venereology, and Allergology, University Hospital of Leipzig, Leipzig, Germany
- 8 Institute of Human Genetics, University Hospital of Leipzig, Leipzig, Germany
Received: April 9, 2013 Accepted: June 13, 2013 Published: June 19, 2013
https://doi.org/10.18632/aging.100566How to Cite
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.