title: FGFR1 Analyses in Four Patients with Hypogonadotropic Hypogonadism with Split-Hand/Foot Malformation: Implications for the Promoter Region.
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.
authors.affiliation: Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, 431-3192, Japan.
authors.forename: Kohnosuke
authors.initials: K
authors.lastname: Ohtaka
authors.affiliation: Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, 431-3192, Japan.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Fujisawa
authors.affiliation: Department of Medical Genetics and Genomics, Kitasato University Graduate School of Medical Sciences, Sagamihara, 252-0375, Japan.
authors.forename: Fumio
authors.initials: F
authors.lastname: Takada
authors.affiliation: Division of Endocrinology and Metabolism, Tokyo Metropolitan Children's Medical Center, Tokyo, 183-8561, Japan.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Hasegawa
authors.affiliation: Division of Endocrinology and Metabolism, Tokyo Metropolitan Children's Medical Center, Tokyo, 183-8561, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Miyoshi
authors.affiliation: Department of Pediatrics, Keio University School of Medicine, Tokyo, 160-8582, Japan.
authors.forename: Tomonobu
authors.initials: T
authors.lastname: Hasegawa
authors.affiliation: Division of Rheumatology, Endocrinology and Nephrology, Hokkaido University Graduate School of Medicine, Sapporo, 060-8638, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Miyoshi
authors.affiliation: Division of Rheumatology, Endocrinology and Nephrology, Hokkaido University Graduate School of Medicine, Sapporo, 060-8638, Japan.
authors.forename: Hiraku
authors.initials: H
authors.lastname: Kameda
authors.affiliation: Division of Life Sciences, Graduate School of Life Sciences, Kyoto Sangyo University, Kyoto, 603-8555, Japan.
authors.forename: Misuzu
authors.initials: M
authors.lastname: Kurokawa-Seo
authors.affiliation: Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, 157-8535, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Fukami
authors.affiliation: Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, 431-3192, Japan.|Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, 157-8535, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Ogata
mesh_terms: D000293:Adolescent; D000328:Adult; D015415:Biomarkers; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D007006:Hypogonadism / Q000175:diagnosis* / Q000235:genetics*; D007223:Infant; D017880:Limb Deformities, Congenital / Q000175:diagnosis* / Q000235:genetics*; D008297:Male; D009154:Mutation; D010641:Phenotype; D011401:Promoter Regions, Genetic; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics*; D017422:Sequence Analysis, DNA; D013577:Syndrome
chemical_list: D015415:Biomarkers; D051496:Receptor, Fibroblast Growth Factor, Type 1
keywords: FGFR1; hypogonadotropic hypogonadism; microdeletion; promoter; split-hand/foot malformation