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  Further expansion of the phenotypic spectrum associated with mutations in ALDH18A1, encoding Delta(1)-pyrroline-5-carboxylate synthase (P5CS)

Skidmore, D. L., Chitayat, D., Morgan, T., Hinek, A., Fischer, B., Dimopoulou, A., et al. (2011). Further expansion of the phenotypic spectrum associated with mutations in ALDH18A1, encoding Delta(1)-pyrroline-5-carboxylate synthase (P5CS). Am J Med Genet A, 155A(8), 1848-56. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/21739576 http://onlinelibrary.wiley.com/store/10.1002/ajmg.a.34057/asset/34057_ftp.pdf?v=1&t=gyzw7q5r&s=9ef966b24682bad7bd9ff67845e66b17ddde46c8.

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Skidmore, D. L., Author
Chitayat, D., Author
Morgan, T., Author
Hinek, A., Author
Fischer, B., Author
Dimopoulou, A., Author
Somers, G., Author
Halliday, W., Author
Blaser, S., Author
Diambomba, Y., Author
Lemire, E. G., Author
Kornak, U.1, Author           
Robertson, S. P., Author
Affiliations:
1Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              

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Free keywords: Abnormalities, Multiple/*genetics; Amino Acid Sequence; Base Sequence; Cell Proliferation; Cells, Cultured; Consanguinity; Contracture/genetics; Cornea/abnormalities/surgery; Corneal Transplantation; Cutis Laxa/diagnosis/*genetics; Face/abnormalities; Fatal Outcome; *Frameshift Mutation; Heart Septal Defects, Ventricular/genetics; Homozygote; Humans; Infant, Newborn; Molecular Sequence Data; Ornithine-Oxo-Acid Transaminase/*genetics; Phenotype; RNA Splice Sites/genetics
 Abstract: We report on the third case of cutis laxa and progeroid features caused by a homozygous mutation in ALDH18A1 that encodes Delta(1)-pyrroline-5-carboxylate-synthase (P5CS). This severely affected child, born to consanguineous parents of Pakistani origin, presented with lax, wrinkled and thin skin with dilated and tortuous subcutaneous blood vessels, corneal clouding, and hypotonia. The child had severe global developmental delay and feeding difficulties and died in infancy for an unknown reason. The proband was homozygous for a mutation in ALDH18A1, c.1923 + 1G > A which results in the production of two anomalous transcripts that are predicted to encode proteins lacking the catalytic site for the enzyme. The cellular phenotype is characterized by diminished production of collagen types I and III, altered elastin ultrastructure, and diminished cell proliferation of cultured dermal fibroblasts. This severe clinical and cellular phenotype overlaps with a broad group of neurocutaneous syndromes that include cutis laxa type II, wrinkly skin syndrome, de Barsy syndrome, and gerodermia osteodysplastica. The findings presented here emphasize the pleiotropic presentation of this group of conditions and suggest that multiple components of the extracellular matrix are perturbed in these disorders.

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 Dates: 2011
 Publication Status: Published in print
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Title: Am J Med Genet A
Source Genre: Journal
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Pages: - Volume / Issue: 155A (8) Sequence Number: - Start / End Page: 1848 - 56 Identifier: ISSN: 1552-4833 (Electronic) 1552-4825 (Linking)