FGFR1 analyses in four patients with hypogonadotropic hypogonadism with split-hand/foot malformation: Implications for the promoter region

Heterozygous loss-of-function mutations of FGFR1 cause various disorders including hypogonadotropic hypogonadism with split-hand/foot malformation (HH-SHFM). We examined FGFR1 in four Japanese patients with HH-SHFM (cases 1–4) and the mother of case 4 with HH only. Cases 1 and 2 had heterozygous loss-of-function mutations with no dominant negative effect [c.289G>A, p.(G97S); and c.2231G>C, p.(R744T)], and case 3 had a splice donor site mutation [c.1663+1G>T]. Notably, case 4 had a maternally inherited 8,312 bp microdeletion that involved non-coding exon 1U and impaired FGFR1 expression. Furthermore, consistent with the presence of transcription-related histone marks (e.g. H3K4Me3, H3K4Me1, and H3K27Ac) and multiple transcription factor binding sites around exon 1U, functional studies demonstrated a marked transactivation function of a 414 bp segment harboring the transcription start site. These results support the relevance of FGFR1 mutations to HH-SHFM, and argue for the presence of the FGFR1 core-promoter elements around exon 1U. This article is protected by copyright. All rights reserved