PMID- 10369874
OWN - NLM
STAT- MEDLINE
DCOM- 19990816
LR  - 20190513
IS  - 0964-6906 (Print)
IS  - 0964-6906 (Linking)
VI  - 8
IP  - 7
DP  - 1999 Jul
TI  - Allelic and locus heterogeneity in inherited venous malformations.
PG  - 1279-89
AB  - 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.
FAU - Calvert, J T
AU  - Calvert JT
AD  - Department of Genetics, Duke University Medical Center, Durham, NC 27710, USA.
FAU - Riney, T J
AU  - Riney TJ
FAU - Kontos, C D
AU  - Kontos CD
FAU - Cha, E H
AU  - Cha EH
FAU - Prieto, V G
AU  - Prieto VG
FAU - Shea, C R
AU  - Shea CR
FAU - Berg, J N
AU  - Berg JN
FAU - Nevin, N C
AU  - Nevin NC
FAU - Simpson, S A
AU  - Simpson SA
FAU - Pasyk, K A
AU  - Pasyk KA
FAU - Speer, M C
AU  - Speer MC
FAU - Peters, K G
AU  - Peters KG
FAU - Marchuk, D A
AU  - Marchuk DA
LA  - eng
GR  - HL55265/HL/NHLBI NIH HHS/United States
GR  - M01 RR00042/RR/NCRR NIH HHS/United States
GR  - HL03557/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (Ligands)
SB  - IM
MH  - Amino Acid Sequence
MH  - Amino Acid Substitution
MH  - Animals
MH  - Base Sequence
MH  - COS Cells
MH  - Female
MH  - *Genetic Variation
MH  - Humans
MH  - Ligands
MH  - Male
MH  - Molecular Sequence Data
MH  - Mutation
MH  - Pedigree
MH  - Phosphorylation
MH  - Sequence Alignment
MH  - Transfection
MH  - Vascular Diseases/*genetics/pathology
EDAT- 1999/06/17 00:00
MHDA- 1999/06/17 00:01
CRDT- 1999/06/17 00:00
PHST- 1999/06/17 00:00 [pubmed]
PHST- 1999/06/17 00:01 [medline]
PHST- 1999/06/17 00:00 [entrez]
AID - ddc149 [pii]
AID - 10.1093/hmg/8.7.1279 [doi]
PST - ppublish
SO  - Hum Mol Genet. 1999 Jul;8(7):1279-89. doi: 10.1093/hmg/8.7.1279.