Mutations in PHF6 are associated with Börjeson–Forssman –Lehmann syndrome

Abstract

Börjeson-Forssman-Lehmann syndrome (BFLS; OMIM 301900) is characterized by moderate to severe mental retardation, epilepsy, hypogonadism, hypometabolism, obesity with marked gynecomastia, swelling of subcutaneous tissue of the face, narrow palpebral fissure and large but not deformed ears. Previously, the gene associated with BFLS was localized to 17 Mb in Xq26-q27 (refs 2-4). We have reduced this interval to roughly 9 Mb containing more than 62 genes. Among these, a novel, widely expressed zinc-finger (plant homeodomain (PHD)-like finger) gene (PHF6) had eight different missense and truncation mutations in seven familial and two sporadic cases of BFLS. Transient transfection studies with PHF6 tagged with green fluorescent protein (GFP) showed diffuse nuclear staining with prominent nucleolar accumulation. Such localization, and the presence of two PHD-like zinc fingers, is suggestive of a role for PHF6 in transcription.

The Börjeson–Forssman–Lehman syndrome (BFLS, MIM #301900)

“…The PHF6 mutations do not seem to cluster although mutations in or around exon 2 and in exon 10 account for 13/19 (68.4%) mutations found so far. Where it was possible to investigate this, 1,5 it was confirmed that identical mutations are not identical by descent and arose independently. Some of these mutations, 1,5 experience with mutation screening tells us that there are no known familial cases with clinically diagnosed BFL syndrome where mutations in the PHF6 gene were not found.…”

“…Where it was possible to investigate this, 1,5 it was confirmed that identical mutations are not identical by descent and arose independently. Some of these mutations, 1,5 experience with mutation screening tells us that there are no known familial cases with clinically diagnosed BFL syndrome where mutations in the PHF6 gene were not found. This, together with the identification of the PHF6 mutation in the original BFLS family 5,10 suggests that unlike many other XLMR syndromes 11 BFLS is not genetically heterogeneous.…”

“…However, this is only speculation, which needs further experimental substantiation. 1 More recently, Landais et al 6 reported the existence of six other isoforms of the Phf6 gene in mouse. Their function is not clear although five of them (t1, t4, t5, t6 and t7) can potentially give rise to alternative Phf6 protein isoforms.…”

“…The PHF6 gene was identified in 2002 by Lower et al 1 It is a member of a large family of zinc-finger genes. PHF6 is transcribed as a B4.5 kb mRNA, which shows a ubiquitous expression pattern as tested by Northern blot hybridization 1 and RT PCR.…”

“…1 Its ubiquitous expression pattern together with high conservation, and in particular, within the plant homeodomain (PHD) finger domains, suggests an important cellular role.…”