Ohtaka Kohnosuke, Fujisawa Yasuko, Takada Fumio, Hasegawa Yukihiro, Miyoshi Tatsuya, Hasegawa Tomonobu, Miyoshi Hideaki, Kameda Hiraku, Kurokawa-Seo Misuzu, Fukami Maki, Ogata Tsutomu
Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, 431-3192, Japan.
Department of Medical Genetics and Genomics, Kitasato University Graduate School of Medical Sciences, Sagamihara, 252-0375, Japan.
Hum Mutat. 2017 May;38(5):503-506. doi: 10.1002/humu.23178. Epub 2017 Feb 3.
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.
成纤维细胞生长因子受体1（FGFR1）的杂合性功能丧失突变会导致多种疾病，包括伴有手足裂畸形的低促性腺激素性性腺功能减退（HH-SHFM）。我们对4例日本HH-SHFM患者（病例1-4）以及仅患有HH的病例4的母亲进行了FGFR1检测。病例1和病例2具有杂合性功能丧失突变且无显性负效应（c.289G>A，p.[G97S]；以及c.2231G>C，p.[R744T]），病例3有一个剪接供体位点突变（c.1663+1G>T）。值得注意的是，病例4有一个母系遗传的8312 bp微缺失，该缺失涉及非编码外显子1U并损害了FGFR1的表达。此外，与外显子1U周围存在转录相关组蛋白标记（如H3K4Me3、H3K4Me1和H3K27Ac）以及多个转录因子结合位点一致，功能研究表明包含转录起始位点的414 bp片段具有显著的反式激活功能。这些结果支持FGFR1突变与HH-SHFM的相关性，并表明外显子1U周围存在FGFR1核心启动子元件。
