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.

Purpose: Interferon regulatory factor 6 encodes a member of the IRF family of transcription factors. Mutations in interferon regulatory factor 6 cause Van der Woude and popliteal pterygium syndrome, two related orofacial clefting disorders. Here, we compared and contrasted the frequency and distribution of exonic mutations in interferon regulatory factor 6 between two large geographically distinct collections of families with Van der Woude and between one collection of families with popliteal pterygium syndrome. Methods: We performed direct sequence analysis of interferon regulatory factor 6 exons on samples from three collections, two with Van der Woude and one with popliteal pterygium syndrome. Results: We identified mutations in interferon regulatory factor 6 exons in 68% of families in both Van der Woude collections and in 97% of families with popliteal pterygium syndrome. In sum, 106 novel disease-causing variants were found. The distribution of mutations in the interferon regulatory factor 6 exons in each collection was not random; exons 3, 4, 7, and 9 accounted for 80%. In the Van der Woude collections, the mutations were evenly divided between protein truncation and missense, whereas most mutations identified in the popliteal pterygium syndrome collection were missense. Further, the missense mutations associated with popliteal pterygium syndrome were localized significantly to exon 4, at residues that are predicted to bind directly to DNA. Conclusion: The nonrandom distribution of mutations in the interferon regulatory factor 6 exons suggests a two-tier approach for efficient mutation screens for interferon regulatory factor 6. The type and distribution of mutations are consistent with the hypothesis that Van der Woude is caused by haploinsufficiency of interferon regulatory factor 6. On the other hand, the distribution of popliteal pterygium syndrome-associated mutations suggests a different, though not mutually exclusive, effect on interferon regulatory factor 6 function. Genet Med 2009:11(4):241-247.

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Cleft lip with or without cleft palate is the most frequent craniofacial malformation in humans (B1/700). Its etiology is multifactorial; some are a result of a genetic mutation, while others may be due to environmental factors, with genetic predisposition playing an important role. The prevalence varies widely between populations and the mode of inheritance remains controversial. The interferon regulatory factor-6 (IRF6) gene has been shown to harbor mutations in patients with van der Woude syndrome, a dominant form of clefts associated with small pits of the lower lip. Moreover IRF6 has been associated with nonsyndromic cleft of the palate (CL/P) in two separate studies. We investigated the role of IRF6 in a set of 195 trios from Belgium. Cleft occurred as an isolated feature. We studied association of the IRF6 locus using two variants: one in the IRF6 gene and the other 100 kpb 3 0 of the gene. Our independent study group confirms that the IRF6 locus is associated with nonsyndromic cleft lip with or without palate. This result, with previous studies performed in the United States and Italy, shows for the first time the implication of IRF6 in isolated CL/P in northern Europe. It is likely that association to this locus can be identified in various populations and that the IRF6 locus thus represents an important genetic modifier for this multifactorial malformation.