Hereditary hemorrhagic telangiectasia is caused by the Q490X mutation of the  ACVRL1 gene in a large Arab family: support of homozygous lethality

In a large Saudi Arabian family with hereditary hemorrhagic telangiectasia (HHT), we identified ACVRL1 ( ALK1) nonsense mutation Q490X in 40 HHT patients and three healthy children, but neither in 11 individuals with epistaxis, 41 other healthy family members, nor in 50 healthy unrelated Saudi Arabi...

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Bibliographic Details
Published in:European journal of medical genetics 2006-07, Vol.49 (4), p.323-330
Main Authors: El-Harith, El-Harith A., Kühnau, Wolfgang, Schmidtke, Jörg, Gadzicki, Dorothea, Ahmed, Mirghani, Krawczak, Michael, Stuhrmann, Manfred
Format: Article
Language:English
Subjects:
Activin Receptors, Type II - genetics
ACVRL1 gene
Biological and medical sciences
Codon, Nonsense
Consanguinity
Dermatology
Epistaxis
Female
Fundamental and applied biological sciences. Psychology
General aspects. Genetic counseling
Genetic Linkage
Genetics of eukaryotes. Biological and molecular evolution
Hereditary diseases of the skin. Congenital diseases of the skin. Haemangioma of the skin, of mucosae and of soft tissue
Hereditary hemorrhagic telangiectasia
Homozygote
Humans
Male
Medical genetics
Medical sciences
Molecular and cellular biology
Pedigree
Saudi Arabia
Telangiectasia, Hereditary Hemorrhagic - genetics
Telangiectasia, Hereditary Hemorrhagic - mortality
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Summary:In a large Saudi Arabian family with hereditary hemorrhagic telangiectasia (HHT), we identified ACVRL1 ( ALK1) nonsense mutation Q490X in 40 HHT patients and three healthy children, but neither in 11 individuals with epistaxis, 41 other healthy family members, nor in 50 healthy unrelated Saudi Arabian controls. Sequence analysis of the entire coding region of the ACVRL1 and ENG genes in five of the 11 epistaxic individuals did not reveal any other disease-causing mutation. Epistaxis seems to be a relatively common phenocopy of HHT in the family under study. One couple, both affected by HHT and carriers of Q490X, had 12 pregnancies. Three of them ended in spontaneous abortion, four in early neonatal death, and only five yielded living offspring, all of which had HHT and were Q490X heterozygous. This observation corroborates previous claims that homozygosity for HHT-causing mutations is lethal.
ISSN:1769-7212
1878-0849
DOI:10.1016/j.ejmg.2005.09.002