Analysis of lymphoedema-distichiasis families forFOXC2 mutations reveals small insertions and deletions throughout the gene

Abstract

Lymphoedema-distichiasis (LD) is a dominantly inherited form of primary lymphoedema with onset of lower limb swelling at puberty or later. There is variable penetrance of this disorder, but the most consistently inherited feature is distichiasis, viz. fine hairs arising inappropriately from the meibomian glands. We established linkage of this disorder to 16q24.3 and the gene has recently been identified as the forkhead transcription factor FOXC2. We report the mutational analysis of 14 families with LD. All but one of these pedigrees have small insertions or deletions in the gene, which seem likely to produce haploinsufficiency. The mutation sites are scattered throughout the gene. There is one family with a mis-sense mutation in the forkhead domain of the protein. This base alteration is not a common polymorphism, is co-inherited with the disease and produces a non-conservative amino acid change.

Analysis of the phenotypic abnormalities in lymphoedema-distichiasis syndrome in 74 patients with FOXC2 mutations or linkage to 16q24

“…The methods used for identifying the mutations have been previously described in detail. 11 Families and sporadic cases were included in the study if a mutation in FOXC2 was identified or linkage to the gene confirmed (one family). There were a total of 74 affected subjects (43M:31F).…”

“…Subsequently, seven mutations were found in this gene in seven additional families with lymphoedema-distichiasis. 9 10 A further 34 novel mutations in FOXC2, primarily small insertions and deletions, have now been characterised in our series of patients 11 ( R Bell, personal communication). Another recent study looked at 86 families with primary lymphoedema and eleven of these families were shown to have a mutation in FOXC2.…”

The New Era of the Lymphatic System: No Longer Secondary to the Blood Vascular System

“…Lymphedema -distichiasis syndrome, a subset of lymphedema praecox, is a rare autosomal dominant disease characterized by swollen limbs and double rows of eyelashes (Robinow et al 1970;Hoover and Kelley 1971;Jester 1977) and has been genetically linked to the FOXC2 gene, which encodes a member of the Forkhead/Winged-Helix family of transcription factors that are involved in diverse developmental pathways (Fang et al 2000;Bell et al 2001;Finegold et al 2001). Consistently, Foxc2-deficient mice display lymphatic dysfunction, including abnormal mural cell coverage on lymphatic capillaries, defective valves of the collecting lymphatic vessels, and irregular lymphatic patterning ).…”

Linkage and sequence analysis indicate that CCBE1 is mutated in recessively inherited generalised lymphatic dysplasia

“…In humans, only three causative genes have been identified for disorders where lymphoedema is the primary phenotype; VEGFR3 in Milroy disease (Ferrell et al 1998, Irrthum et al 2000, FOXC2 for Lymphoedema distichiasis (Fang et al 2000, Bell et al 2001, Erickson et al 2001, Brice et al 2002) and mutations in SOX18 are responsible for causing the rare syndrome, hypotrichosislymphoedema-telangiectasia (Irrthum et al 2003). There are many other forms of primary lymphoedema where the genetic cause is unknown and the phenotype not well delineated.…”