title: Allelic and locus heterogeneity in inherited venous malformations.
abstract: Venous malformations are low-flow vascular lesions consisting of disorganized thin-walled vascular channels. These can occur sporadically but also as an autosomal dominant condition termed venous malformations, cutaneous and mucosal (VMCM; OMIM 600195). In two large unrelated kindreds mapping to chromosome 9, the identical R849W missense mutation was identified in the first kinase domain of Tie2, an endothelial cell-specific receptor tyrosine kinase. We report here the identification of four new kindreds with inherited venous malformations. Unlike the initial two families described, these four families demonstrate allelic and locus heterogeneity. In one of these families, the R849W mutation co-segregates with the disease phenotype. Three other families with venous malformations lack this mutation. One of these families is linked to markers near TIE2 on chromosome 9. In this family, we identified a novel mutation within the first kinase domain of Tie2 resulting in a Y897S change. Results from COS-1 cell transfections using expression constructs containing either the R849W or the Y897S mutation suggest that the receptors containing either mutation show ligand-independent hyperphosphorylation. These results suggest a gain-of-function mechanism for development of venous malformations in these families. Of the two remaining families, one excludes linkage to the TIE2 locus, establishing the existence of at least one additional locus for dominantly inherited venous malformations.
authors.affiliation: Department of Genetics, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: J T
authors.initials: JT
authors.lastname: Calvert
authors.forename: T J
authors.initials: TJ
authors.lastname: Riney
authors.forename: C D
authors.initials: CD
authors.lastname: Kontos
authors.forename: E H
authors.initials: EH
authors.lastname: Cha
authors.forename: V G
authors.initials: VG
authors.lastname: Prieto
authors.forename: C R
authors.initials: CR
authors.lastname: Shea
authors.forename: J N
authors.initials: JN
authors.lastname: Berg
authors.forename: N C
authors.initials: NC
authors.lastname: Nevin
authors.forename: S A
authors.initials: SA
authors.lastname: Simpson
authors.forename: K A
authors.initials: KA
authors.lastname: Pasyk
authors.forename: M C
authors.initials: MC
authors.lastname: Speer
authors.forename: K G
authors.initials: KG
authors.lastname: Peters
authors.forename: D A
authors.initials: DA
authors.lastname: Marchuk
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008024:Ligands; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010766:Phosphorylation; D016415:Sequence Alignment; D014162:Transfection; D014652:Vascular Diseases / Q000235:genetics* / Q000473:pathology
chemical_list: D008024:Ligands