FGFR1 Analyses in Four Patients with Hypogonadotropic Hypogonadism with Split-Hand/Foot Malformation: Implications for the Promoter Region

Kohnosuke Ohtaka, Yasuko Fujisawa, Fumio Takada, Yukihiro Hasegawa, Tatsuya Miyoshi, Tomonobu Hasegawa, Hideaki Miyoshi, Hiraku Kameda, Misuzu Kurokawa-Seo, Maki Fukami, Tsutomu Ogata

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Abstract

Heterozygous loss-of-function mutations of FGFR1 (fibroblast growth factor receptor 1) 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 noncoding 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.

Original languageEnglish
JournalHuman Mutation
DOIs
Publication statusAccepted/In press - 2017

Keywords

  • FGFR1
  • Hypogonadotropic hypogonadism
  • Microdeletion
  • Promoter
  • Split-hand/foot malformation

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Ohtaka, K., Fujisawa, Y., Takada, F., Hasegawa, Y., Miyoshi, T., Hasegawa, T., Miyoshi, H., Kameda, H., Kurokawa-Seo, M., Fukami, M., & Ogata, T. (Accepted/In press). FGFR1 Analyses in Four Patients with Hypogonadotropic Hypogonadism with Split-Hand/Foot Malformation: Implications for the Promoter Region. Human Mutation. https://doi.org/10.1002/humu.23178