TY - JOUR
T1 - Progeroid laminopathy with restrictive dermopathy-like features caused by an isodisomic LMNA mutation p.R435C
AU - Starke, Sven
AU - Meinke, Peter
AU - Camozzi, Daria
AU - Mattioli, Elisabetta
AU - Pfaeffle, Roland
AU - Siekmeyer, Manuela
AU - Hirsch, Wolfgang
AU - Horn, Lars Christian
AU - Paasch, Uwe
AU - Mitter, Diana
AU - Lattanzi, Giovanna
AU - Wehnert, Manfred
AU - Kiess, Wieland
PY - 2013/6
Y1 - 2013/6
N2 - 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.
AB - 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.
KW - 53BP1
KW - DNA damage
KW - LMNA
KW - Progeroid syndrome
KW - uniparental disomy
UR - http://www.scopus.com/inward/record.url?scp=84880587519&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84880587519&partnerID=8YFLogxK
M3 - Article
C2 - 23804595
AN - SCOPUS:84880587519
VL - 5
SP - 445
EP - 459
JO - Aging
JF - Aging
SN - 1945-4589
IS - 6
ER -