Mutations in STRA6 Cause a Broad Spectrum of Malformations Including Anophthalmia, Congenital Heart Defects, Diaphragmatic Hernia, Alveolar Capillary Dysplasia, Lung Hypoplasia, and Mental Retardation
| Autor: | Gunnar Houge, Axel von der Wense, Christian Becker, Pierre Bitoun, Francesca Pasutto, Gudrun Nürnberg, David Chitayat, John Tolmie, Peter Meinecke, David R. FitzPatrick, André Reis, Anne Slavotinek, Geert Mortier, Gerhard Hammersen, Sarah Keating, Raoul C.M. Hennekam, Heinrich Sticht, Peter Nürnberg, Heidemarie Schirmer-Zimmermann, Lorena Fernández-Martínez, Gabriele Gillessen-Kaesbach, Frank Brasch, Anita Rauch |
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| Přispěvatelé: | ANS - Amsterdam Neuroscience, APH - Amsterdam Public Health, Paediatric Genetics |
| Rok vydání: | 2007 |
| Předmět: |
Receptors
Cell Surface/genetics Male Alveolar capillary dysplasia Hernia Diaphragmatic/genetics Vitamin A transport Consanguinity Abnormalities Multiple/genetics Missense mutation Genetics(clinical) Diaphragmatic hernia Phosphorylation Lung/abnormalities Lung Genetics (clinical) Genetics Pulmonary Alveoli/blood supply Disease gene identification Heart Defects Congenital/genetics Pedigree Transmembrane domain Female Adult Heart Defects Congenital Mutation/genetics Adolescent Lung/pathology Molecular Sequence Data Receptors Cell Surface Biology Chromosome 15 Report Intellectual Disability medicine Humans Abnormalities Multiple Amino Acid Sequence Membrane Proteins/genetics Hernia Diaphragmatic Anophthalmia Anophthalmos/genetics Sequence Homology Amino Acid Infant Newborn Anophthalmos Infant Membrane Proteins medicine.disease Intellectual Disability/genetics Capillaries Pulmonary Alveoli Mutation Capillaries/abnormalities Membrane Proteins/metabolism |
| Zdroj: | American journal of human genetics, 80(3), 550-560. Cell Press Pasutto, F, Sticht, H, Hammersen, G, Gillessen-Kaesbach, G, Fitzpatrick, D R, Nürnberg, G, Brasch, F, Schirmer-Zimmermann, H, Tolmie, J L, Chitayat, D, Houge, G, Fernández-Martínez, L, Keating, S, Mortier, G, Hennekam, R C M, von der Wense, A, Slavotinek, A, Meinecke, P, Bitoun, P, Becker, C, Nürnberg, P, Reis, A & Rauch, A 2007, ' Mutations in STRA6 cause a broad spectrum of malformations including anophthalmia, congenital heart defects, diaphragmatic hernia, alveolar capillary dysplasia, lung hypoplasia, and mental retardation ', American Journal of Human Genetics, vol. 80, no. 3, pp. 550-60 . https://doi.org/10.1086/512203 |
| ISSN: | 0002-9297 |
| Popis: | We observed two unrelated consanguineous families with malformation syndromes sharing anophthalmia and distinct eyebrows as common signs, but differing for alveolar capillary dysplasia or complex congenital heart defect in one and diaphragmatic hernia in the other family. Homozygosity mapping revealed linkage to a common locus on chromosome 15, and pathogenic homozygous mutations were identified in STRA6, a member of a large group of "stimulated by retinoic acid" genes encoding novel transmembrane proteins, transcription factors, and secreted signaling molecules or proteins of largely unknown function. Subsequently, homozygous STRA6 mutations were also demonstrated in 3 of 13 patients chosen on the basis of significant phenotypic overlap to the original cases. While a homozygous deletion generating a premature stop codon (p.G50AfsX22) led to absence of the immunoreactive protein in patient's fibroblast culture, structural analysis of three missense mutations (P90L, P293L, and T321P) suggested significant effects on the geometry of the loops connecting the transmembrane helices of STRA6. Two further variations in the C-terminus (T644M and R655C) alter specific functional sites, an SH2-binding motif and a phosphorylation site, respectively. STRA6 mutations thus define a pleiotropic malformation syndrome representing the first human phenotype associated with mutations in a gene from the "STRA" group. |
| Databáze: | OpenAIRE |
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