GLI3 frameshift mutations cause autosomal dominant Pallister-Hall syndrome
GLI3 frameshift mutations cause autosomal dominant Pallister-Hall syndrome
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DOI：
10.1038/ng0397-266
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发表时间：
1997-03-01
期刊：
影响因子：
30.8
通讯作者：
Biesecker, LG
中科院分区：
文献类型：
--
作者：
Kang, S;Graham, JM;Biesecker, LG
Pallister-Hail综合征（PHS，M146510）于1980年首次在6名新生儿中描述。它是一种人类发育的多效性疾病，包括下丘脑错构瘤、中央性多指畸形和其他畸形（1，2）。这种疾病是作为一种常染色体显性遗传性状遗传的，并已被定位到7 p13（S。常染色体显性遗传性帕利斯特-海尔综合征（Autosomal dominant Pallister-Hail syndrome maps to 7 p13）Am. J.哈姆。Genet. 59，A81（1996））。共定位PHS基因座和GLI 3锌指转录因子基因（3）。导致GLI 3基因单倍不足的大缺失或易位与格雷格头多并指综合征（GCPS; M175700）相关（4-6），尽管在具有正常核型的GCPS患者中未发现突变。PHS和GCPS都有多并指畸形、异常颅面特征，并以常染色体显性模式遗传，但它们在临床上是不同的（7，8）。CCPS的多指畸形多为轴前型，PHS的多指畸形多为轴后型或中央型。没有报道的CCPS病例有下丘脑错构瘤，PHS不会导致距离过远或鼻根或前额增宽。PHS和GCPS基因座的共定位使我们研究GLI 3作为PHS的候选基因。在此，我们报告了两个PHS家族的移码突变的GLI 3是3'的锌指编码结构域，包括一个家庭的从头突变。这些数据暗示GLI 3突变是常染色体显性PHS的原因，并表明GLI 3转录因子基因的移码突变可以改变脊椎动物多器官系统的发育。
Pallister-Hail syndrome (PHS, M146510) was first described in 1980 in six newborns. It is a pleiotropic disorder of human development that comprises hypothalamic hamartoma, central polydactyly, and other malformations(1,2). This disorder is inherited as an autosomal dominant trait and has been mapped to 7p13 (S. Kang et al. Autosomal dominant Pallister-Hail syndrome maps to 7p13. Am. J. Hum. Genet. 59, A81 (1996)). colocalizing the PHS locus and the GLI3 zinc finger transcription factor gene(3). Large deletions or translocations resulting in haploinsufficiency of the GLI3 gene have been associated with Greig cephalopolysyndactyly syndrome (GCPS; M175700)(4-6) although no mutations have been identified in GCPS patients with normal karyotypes. Both PHS and GCPS have polysyndactyly, abnormal craniofacial features and are inherited in an autosomal dominant pattern, but they are clinically distinct(7,8). The polydactyly of CCPS is commonly preaxial and that of PHS is typically central or postaxial. No reported cases of CCPS have hypothalamic hamartoma and PHS does not cause hypertelorism or broadening of the nasal root or forehead. The co-localization of the loci for PHS and GCPS led us to investigate GLI3 as a candidate gene for PHS. Herein we report two PHS families with frameshift mutations in GLI3 that are 3' of the zinc finger-encoding domains, including one family with a de novo mutation. These data implicate mutations in GLI3 as the cause of autosomal dominant PHS, and suggest that frameshift mutations of the GLI3 transcription factor gene can alter the development of multiple organ systems in vertebrates.