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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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Related in: MedlinePlus

LMNA-staining of skin samples taken at age of 4 (a) and 11 (b) months respectively, shows decreasing amount and signal intensity of LNMA-positive nuclei in the dermo-epidermal junction zone compared to control skin (c). As a secondary finding, the rete ridges are progressively flattened, the skin appendages are poorly developed. LMNA-staining of samples taken from esophagus (d) and skeletal muscle (e) during autopsy does not detect any LMNA signal.
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Figure 5: LMNA-staining of skin samples taken at age of 4 (a) and 11 (b) months respectively, shows decreasing amount and signal intensity of LNMA-positive nuclei in the dermo-epidermal junction zone compared to control skin (c). As a secondary finding, the rete ridges are progressively flattened, the skin appendages are poorly developed. LMNA-staining of samples taken from esophagus (d) and skeletal muscle (e) during autopsy does not detect any LMNA signal.

Mentions: During the course of the disease, the skin became generally inflexible and firm, apparently encasing the patient and resulting in mounting flexion contractures and defective positions of the joints. The miniaturized mouth could not be closed anymore, and was fixed in an o-shaped position. The respiratory chest movements were almost abolished by thoracic rigidity. Finally, at the age of 11 months, the patient acutely developed pneumonia and died as a result of global respiratory insufficiency. Strikingly at that point, chest x-rays that had been normal at the age of four months now revealed the absence of clavicles and a deformity of both humeri (Fig.2c, d). Except for slightly elevated erythrocyte sedimentation rate, white blood cell and platelet count, laboratory findings revealed normal results at all time. The histology of skin samples taken at the age of 11 months showed progressively flattened rete ridges and poorly developed skin appendages (Fig.5b).


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)

LMNA-staining of skin samples taken at age of 4 (a) and 11 (b) months respectively, shows decreasing amount and signal intensity of LNMA-positive nuclei in the dermo-epidermal junction zone compared to control skin (c). As a secondary finding, the rete ridges are progressively flattened, the skin appendages are poorly developed. LMNA-staining of samples taken from esophagus (d) and skeletal muscle (e) during autopsy does not detect any LMNA signal.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: LMNA-staining of skin samples taken at age of 4 (a) and 11 (b) months respectively, shows decreasing amount and signal intensity of LNMA-positive nuclei in the dermo-epidermal junction zone compared to control skin (c). As a secondary finding, the rete ridges are progressively flattened, the skin appendages are poorly developed. LMNA-staining of samples taken from esophagus (d) and skeletal muscle (e) during autopsy does not detect any LMNA signal.
Mentions: During the course of the disease, the skin became generally inflexible and firm, apparently encasing the patient and resulting in mounting flexion contractures and defective positions of the joints. The miniaturized mouth could not be closed anymore, and was fixed in an o-shaped position. The respiratory chest movements were almost abolished by thoracic rigidity. Finally, at the age of 11 months, the patient acutely developed pneumonia and died as a result of global respiratory insufficiency. Strikingly at that point, chest x-rays that had been normal at the age of four months now revealed the absence of clavicles and a deformity of both humeri (Fig.2c, d). Except for slightly elevated erythrocyte sedimentation rate, white blood cell and platelet count, laboratory findings revealed normal results at all time. The histology of skin samples taken at the age of 11 months showed progressively flattened rete ridges and poorly developed skin appendages (Fig.5b).

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