A Gene for Inherited Cutaneous Venous Anomalies (“Glomangiomas”) Localizes to Chromosome 1p21-22

Abstract

Venous malformations (VMs) are localized defects of vascular morphogenesis. They can occur in every organ system, most commonly in skin and muscle. They can cause pain and bleeding, and in some critical locations they can be life threatening. Usually venous anomalies occur sporadically, but families with dominant inheritance have been identified. Using linkage analysis, we have established in earlier reports that some families with inherited VMs show linkage to chromosome 9p21; the mutation causes ligand-independent activation of an endothelial cell-specific receptor tyrosine kinase, TIE-2. Here we show that VMs with glomus cells (known as "glomangiomas"), inherited as an autosomal dominant trait in five families, are not linked to 9p21 but, instead, link to a new locus, on 1p21-p22, called "VMGLOM" (LOD score 12.70 at recombination fraction.00). We exclude three known positional candidate genes, DR1 (depressor of transcription 1), TGFBR3 (transforming growth factor-beta receptor, type 3), and TFA (tissue factor). We hypothesize that cutaneous venous anomalies (i.e., glomangiomas) are caused by mutations in a novel gene that may act to regulate angiogenesis, in concert with the TIE-2 signaling pathway.

Linkage disequilibrium narrows locus for venous malformation with glomus cells (VMGLOM) to a single 1.48 Mbp YAC

“…These findings narrow the locus by 2 cM from AFMA205XD5-D1S236 [Boon, 1999 No 811] to AFMB337XE1-D1S236, a region of about 3 cM (on the basis of the Whitehead/MIT physical map). Comparison of the haplotypes linked to the condition in the 12 families revealed two distinct haplotypes, A and B, shared by seven families (Bl, Bt, Sh, F, T, Bln, Sch), and by four families (Al, Ba, Del, Ad), respectively ( Figure 2).…”

“…5 The number of affected males and females in the 12 families was 35 and 40, respectively, and 59% (26/44) of children of an affected parent had the disorder. Examination of the seven new pedigrees revealed that the condition skipped a generation twice (individuals Del5 and Bln104, Figure 1).…”

“…The autosomal dominant pattern of inheritance with high penetrance and the absence of sex bias are consistent with our previous data. 5 None of the seven new families formally excluded linkage to the VMGLOM locus. Lod scores for marker D1S188 are given for different recombination fractions in Table 1.…”

“…6 Calculations were performed using the MLINK program of the LINKAGE package, 7 with parameters as described. 5 Phenocopies were not allowed and three penetrance classes were defined on the basis of Iqbal et al 8 (Table 1).…”

“…4 In addition to this locus, we discovered a second 4-6 cM locus on chromosome 1p21-p22 that is linked to venous malformations in five families (VMGLOM, OMIM No 138000). 5 Although the cutaneous lesions in these families clinically looked very similar to the 9p-linked VMs, histologic analysis of the lesions revealed the presence of 'glomus cells' around the lumens of the distorted vessels, hence the traditional histopathologic name 'glomangioma'. The causative gene is unknown and we are using positional cloning for its identification.…”