Mutations in a novel factor, glomulin, are responsible for glomuvenous malformations ("glomangiomas").
Glomuvenous malformations (GVMs) are cutaneous venous lesions characterized by the presence of smooth-muscle--like glomus cells in the media surrounding distended vascular lumens. We have shown that heritable GVMs link to a 4--6-cM region in chromosome 1p21-22. We also identified linkage disequilibrium that allowed a narrowing of this VMGLOM locus to 1.48 Mb. Herein, we report the identification of the mutated gene, glomulin, localized on the basis of the YAC and PAC maps. An incomplete cDNA sequence for glomulin had previously been designated "FAP48," for "FKBP-associated protein of 48 kD." The complete cDNA for glomulin contains an open reading frame of 1,785 nt encoding a predicted protein of 68 kD. The gene consists of 19 exons in which we identified 14 different germline mutations in patients with GVM. In addition, we found a somatic "second hit" mutation in affected tissue of a patient with an inherited genomic deletion. Since all but one of the mutations result in premature stop codons, and since the localized nature of the lesions could be explained by Knudson's two-hit model, GVMs are likely caused by complete loss of function of glomulin. The abnormal phenotype of vascular smooth-muscle cells (VSMCs) in GVMs suggests that glomulin plays an important role in differentiation of these cells--and, thereby, in vascular morphogenesis--especially in cutaneous veins.
Brouillard
Pascal
P
Laboratory of Human Molecular Genetics, Christian de Duve Institute of Cellular Pathology and Université catholique de Louvain, Avenue Hippocrate 74(+5), B-1200 Brussels, Belgium.
Boon
Laurence M
LM
Mulliken
John B
JB
Enjolras
Odile
O
Ghassibé
Michella
M
Warman
Matthew L
ML
Tan
O T
OT
Olsen
Bjorn R
BR
Vikkula
Miikka
M
D048868:Adaptor Proteins, Signal Transducing; D001483:Base Sequence; D003001:Cloning, Molecular; D018388:Codon, Terminator / Q000235:genetics; D004252:DNA Mutational Analysis; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D005091:Exons / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D018095:Germ-Line Mutation / Q000235:genetics; D005918:Glomus Tumor / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D007438:Introns / Q000235:genetics; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D016366:Open Reading Frames / Q000235:genetics; D010375:Pedigree; D019683:Penetrance; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D022021:Tacrolimus Binding Proteins / Q000032:analysis / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D018388:Codon, Terminator; C103024:GLMN protein, human; D012333:RNA, Messenger; D022021:Tacrolimus Binding Proteins