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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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Staining with anti-gamma H2AX (phospho S139) antibody of samples taken from skin (a), esophagus (b) and skeletal muscle (c) during autopsy at age of 11 months shows a strong signal, indicating presence of DNA double strand breaks.
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Figure 6: Staining with anti-gamma H2AX (phospho S139) antibody of samples taken from skin (a), esophagus (b) and skeletal muscle (c) during autopsy at age of 11 months shows a strong signal, indicating presence of DNA double strand breaks.

Mentions: To probe for the presence of DNA dsb, staining with gamma H2AX antibody was done. The staining in different autopsied tissues at the age of 11 months revealed a strong immuno-reactivity consistent with the presence of significant DNA dsb (Fig.6a-c). For further functional analyses, we performed a heterologous expression of either recombinant mCherry-tagged LMNA p.R435C or mCherry-tagged wt LMNA in HEK-293 cells. The localization of the mutant protein at the nuclear envelope was similar to that of wild type, although some p.R435C lamin A aggregates were observed (not shown). This strongly suggests that despite the mutation, LMNA p.R435C is able to assemble in its normal region beneath the nuclear membrane.


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)

Staining with anti-gamma H2AX (phospho S139) antibody of samples taken from skin (a), esophagus (b) and skeletal muscle (c) during autopsy at age of 11 months shows a strong signal, indicating presence of DNA double strand breaks.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: Staining with anti-gamma H2AX (phospho S139) antibody of samples taken from skin (a), esophagus (b) and skeletal muscle (c) during autopsy at age of 11 months shows a strong signal, indicating presence of DNA double strand breaks.
Mentions: To probe for the presence of DNA dsb, staining with gamma H2AX antibody was done. The staining in different autopsied tissues at the age of 11 months revealed a strong immuno-reactivity consistent with the presence of significant DNA dsb (Fig.6a-c). For further functional analyses, we performed a heterologous expression of either recombinant mCherry-tagged LMNA p.R435C or mCherry-tagged wt LMNA in HEK-293 cells. The localization of the mutant protein at the nuclear envelope was similar to that of wild type, although some p.R435C lamin A aggregates were observed (not shown). This strongly suggests that despite the mutation, LMNA p.R435C is able to assemble in its normal region beneath the nuclear membrane.

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