The mutational spectrum of the Sonic Hedgehog gene in holoprosencephaly:: SHH mutations cause a significant proportion of autosomal dominant holoprosencephaly
The mutational spectrum of the Sonic Hedgehog gene in holoprosencephaly:: SHH mutations cause a significant proportion of autosomal dominant holoprosencephaly
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DOI：
10.1093/hmg/8.13.2479
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发表时间：
1999-12-01
影响因子：
3.5
通讯作者：
Muenke, M
中科院分区：
文献类型：
--
作者：
Nanni, L;Ming, JE;Muenke, M
无前脑畸形(HPE)是一种常见的人类前脑和面中部发育异常，大脑半球不能分成明显的左右半脑。我们以前曾报道过单倍体功能不全是HPE的原因之一。我们现在已经对344名无关的患者进行了SHH基因的完整编码区和内含子-外显子连接的突变分析。在这里，我们描述了另外13个带有SHH突变的无关患者，包括无义和错义突变、缺失和插入。这些突变发生在整个基因范围内。根据突变类型或位置的相关性，没有明显的特定的基因型-表型关联。结合我们以往的研究，我们在344例无血缘关系的HPE病例中共鉴定出23个突变，其中14例为家族性HPE，9例为散发性HPE。根据结构异常，在显示常染色体显性遗传的HPE谱的27个家系中，有10个(37%)检测到SHH突变。有趣的是，三名SHH突变患者的另一个基因也出现了异常，该基因在前脑发育过程中表达。我们认为，多个基因产物和/或环境因素的相互作用可能决定特定个体的最终表型结果，这些因素之间的差异可能导致HPE临床特征的广泛差异。
Holoprosencephaly (HPE) is a common developmental anomaly of the human forebrain and midface where the cerebral hemispheres fail to separate into distinct left and right halves. We have previously reported haploinsufficiency for Sonic Hedgehog (SHH) as a cause for HPE. We have now performed mutational analysis of the complete coding region and intron-exon junctions of the SHH gene in 344 unrelated affected individuals. Herein, we describe 13 additional unrelated affected individuals with SHH mutations, including nonsense and missense mutations, deletions and an insertion. These mutations occur throughout the extent of the gene. No specific genotype-phenotype association is evident based on the correlation of the type or position of the mutations. In conjunction with our previous studies, we have identified a total of 23 mutations in 344 unrelated cases of HPE, They account for 14 cases of familial HPE and nine cases of sporadic HPE. Mutations in SHH were detected in 10 of 27 (37%) families showing autosomal dominant transmission of the HPE spectrum, based on structural anomalies. Interestingly, three of the patients with an SHH mutation also had abnormalities in another gene that is expressed during forebrain development. We suggest that the interactions of multiple gene products and/or environmental elements may determine the final phenotypic outcome for a given individual and that variations among these factors: may cause the wide variability in the clinical features seen in HPE.