title: Novel mutations and polymorphisms in genes causing hereditary hemorrhagic telangiectasia.
abstract: Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant vascular disorder caused by mutations in Endoglin (ENG) or activin receptor-like kinase-1 (ALK1, ACVRL1) genes. We performed molecular characterization in clinically affected probands of 31 HHT families and detected a total of 28 different mutations in the two genes, including four shared by more than one family. Twelve mutations were identified in the ENG gene, six of which were novel and comprised two nonsense mutations in exons 6 and 8, deletions in exons 5 and 11, and splice site mutations in exon 12 and intron 8. Eleven of sixteen mutations identified in the ALK1 gene were novel single base pair substitutions in exons 4, 7, 8, and 9. We also describe the first de novo ALK1 mutation that causes a previously unreported c.1133C>A substitution of a highly conserved residue (p.P378H). The proband and his two daughters, who also carried the familial mutation, all suffered from gastrointestinal (GI) bleeding. In addition, we report seven newly identified polymorphisms and summarize all known ones in both genes.
authors.affiliation: Cancer Research Program, The Hospital for Sick Children, and Department of Immunology, University of Toronto, Toronto, Canada M5G 1X8. sabdalla@hotmail.com
authors.forename: Salma A
authors.initials: SA
authors.lastname: Abdalla
authors.forename: Urszula
authors.initials: U
authors.lastname: Cymerman
authors.forename: Diane
authors.initials: D
authors.lastname: Rushlow
authors.forename: Ning
authors.initials: N
authors.lastname: Chen
authors.forename: Gwendolyn P
authors.initials: GP
authors.lastname: Stoeber
authors.forename: Edmond G
authors.initials: EG
authors.lastname: Lemire
authors.forename: Michelle
authors.initials: M
authors.lastname: Letarte
mesh_terms: D030301:Activin Receptors, Type II; D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution; D015703:Antigens, CD / Q000235:genetics*; D004252:DNA Mutational Analysis; D000071063:Endoglin; D005091:Exons / Q000235:genetics; D005260:Female; D006471:Gastrointestinal Hemorrhage / Q000209:etiology; D006801:Humans; D002538:Intracranial Arteriovenous Malformations / Q000209:etiology; D007438:Introns / Q000235:genetics; D008099:Liver / Q000473:pathology; D008168:Lung / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics*; D008875:Middle Aged; D020125:Mutation, Missense; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide; D022821:RNA Splice Sites / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics*; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000150:complications / Q000235:genetics* / Q000473:pathology
chemical_list: D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; D008565:Membrane Proteins; D022821:RNA Splice Sites; D011956:Receptors, Cell Surface; C425364:ACVRL1 protein, human; D030301:Activin Receptors, Type II