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

Starke S, Meinke P, Camozzi D, Mattioli E, Pfaeffle R, Siekmeyer M, Hirsch W, Horn LC, Paasch U, Mitter D, Lattanzi G, Wehnert M, Kiess W - Aging (Albany NY) (2013)

Bottom Line: A homozygousLMNA 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Women and Child Health, Hospital for Children and Adolescents, Centre of Pediatric Research, University Hospital, University of Leipzig, Leipzig, Germany. Sven.Starke@medizin.uni‐leipzig.de

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 homozygousLMNA 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.

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Pedigree of the affected family. Uniparental isodisomy of chromosome 1q21.3- q23.1 (involving the complete LMNA gene), causing homozygosity of autosomal recessively inherited LMNA mutation, was proven for the index patient. Except for the index patient, none of the displayed individuals showed signs of progeroid disease, or signs of progressive cardiac disease. Dilated cardiomyopathy was excluded by echocardiography in individuals labeled by *.
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Figure 4: Pedigree of the affected family. Uniparental isodisomy of chromosome 1q21.3- q23.1 (involving the complete LMNA gene), causing homozygosity of autosomal recessively inherited LMNA mutation, was proven for the index patient. Except for the index patient, none of the displayed individuals showed signs of progeroid disease, or signs of progressive cardiac disease. Dilated cardiomyopathy was excluded by echocardiography in individuals labeled by *.

Mentions: Sequencing of the LMNA gene in the patient's family showed that besides the mother, also the two sisters, the maternal grandmother, and the maternal grand aunt of the patient were heterozygous for p.R435C (Fig.4). All of them appeared to be healthy. Intriguingly, the patient's mother was heterozygous for the LMNA c.1303C>T (p.R435C) mutation, but the father was homozygous wild-type. Wrong paternity as an explanation of the patient's homozygosity was excluded. Multiplex Ligation-dependent Probe Amplification (MLPA) analysis to check for copy numbers showed two copies of the LMNA gene in the patient and thus excluded a deletion as a reason for the homozygous mutation (Supplementary Material, Fig.S2). Microsatellite marker analysis on chromosome 1 (Supplementary Material, Table S2) revealed a partial uniparental disomy of chromosome 1 (at least from 1q21.3 to 1q23.1) including the LMNA gene (Supplementary Material, Fig.S3), which would explain the homozygous LMNA c.1303C>T (p.R435C) mutation in the patient.


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

Starke S, Meinke P, Camozzi D, Mattioli E, Pfaeffle R, Siekmeyer M, Hirsch W, Horn LC, Paasch U, Mitter D, Lattanzi G, Wehnert M, Kiess W - Aging (Albany NY) (2013)

Pedigree of the affected family. Uniparental isodisomy of chromosome 1q21.3- q23.1 (involving the complete LMNA gene), causing homozygosity of autosomal recessively inherited LMNA mutation, was proven for the index patient. Except for the index patient, none of the displayed individuals showed signs of progeroid disease, or signs of progressive cardiac disease. Dilated cardiomyopathy was excluded by echocardiography in individuals labeled by *.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3824411&req=5

Figure 4: Pedigree of the affected family. Uniparental isodisomy of chromosome 1q21.3- q23.1 (involving the complete LMNA gene), causing homozygosity of autosomal recessively inherited LMNA mutation, was proven for the index patient. Except for the index patient, none of the displayed individuals showed signs of progeroid disease, or signs of progressive cardiac disease. Dilated cardiomyopathy was excluded by echocardiography in individuals labeled by *.
Mentions: Sequencing of the LMNA gene in the patient's family showed that besides the mother, also the two sisters, the maternal grandmother, and the maternal grand aunt of the patient were heterozygous for p.R435C (Fig.4). All of them appeared to be healthy. Intriguingly, the patient's mother was heterozygous for the LMNA c.1303C>T (p.R435C) mutation, but the father was homozygous wild-type. Wrong paternity as an explanation of the patient's homozygosity was excluded. Multiplex Ligation-dependent Probe Amplification (MLPA) analysis to check for copy numbers showed two copies of the LMNA gene in the patient and thus excluded a deletion as a reason for the homozygous mutation (Supplementary Material, Fig.S2). Microsatellite marker analysis on chromosome 1 (Supplementary Material, Table S2) revealed a partial uniparental disomy of chromosome 1 (at least from 1q21.3 to 1q23.1) including the LMNA gene (Supplementary Material, Fig.S3), which would explain the homozygous LMNA c.1303C>T (p.R435C) mutation in the patient.

Bottom Line: A homozygousLMNA 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Women and Child Health, Hospital for Children and Adolescents, Centre of Pediatric Research, University Hospital, University of Leipzig, Leipzig, Germany. Sven.Starke@medizin.uni‐leipzig.de

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 homozygousLMNA 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.

Show MeSH
Related in: MedlinePlus