Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes:: Robust phenotype prediction from the type and position of GLI3 mutations
Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes:: Robust phenotype prediction from the type and position of GLI3 mutations
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DOI：
10.1086/429346
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发表时间：
2005-04-01
影响因子：
9.8
通讯作者：
Biesecker, LG
中科院分区：
文献类型：
--
作者：
Johnston, JJ;Olivos-Glander, I;Biesecker, LG
GLI 3锌指转录因子基因的突变导致Greig头多指并指综合征（GCPS）和Pallister-Hall综合征（PHS），这是一种可变但不同的临床实体。我们假设GLI 3突变预测一个截短的功能性阻遏蛋白导致PHS和GLI 3的功能性单倍不足导致GCPS。为了验证这些假设，我们对PHS和GCPS患者进行了GLI 3突变筛查。患者组由135名个体组成：89名GCPS患者和46名PHS患者。我们检测到47个病理性突变（在60个先证者中）;当这些与以前发表的突变相结合时，两个基因型-表型相关性是明显的。首先，GCPS是由许多类型的改变引起的，包括易位、大缺失、外显子缺失和重复、小框内缺失、错义、移码/无义和剪接突变。相反，PHS仅由移码/无义和剪接突变引起。其次，在移码/无义突变中，存在明显的基因型-表型相关性。基因的前三分之一突变（来自开放阅读框[ORF]核苷酸[nt] 1 - 1997）导致GCPS，基因的后三分之一突变（来自ORF nt 1998 - 3481）主要导致PHS。令人惊讶的是，GCPS患者在该基因的3'3分之一（ORF nt 3481之后）有12个突变，而PHS患者在该区域没有突变。这些结果证明了GLI 3突变的基因型和表型的强相关性，并强烈支持这两种等位基因疾病具有不同的发病机制模式的假设。
Mutations in the GLI3 zinc-finger transcription factor gene cause Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS), which are variable but distinct clinical entities. We hypothesized that GLI3 mutations that predict a truncated functional repressor protein cause PHS and that functional haploinsufficiency of GLI3 causes GCPS. To test these hypotheses, we screened patients with PHS and GCPS for GLI3 mutations. The patient group consisted of 135 individuals: 89 patients with GCPS and 46 patients with PHS. We detected 47 pathological mutations ( among 60 probands); when these were combined with previously published mutations, two genotype- phenotype correlations were evident. First, GCPS was caused by many types of alterations, including translocations, large deletions, exonic deletions and duplications, small in-frame deletions, and missense, frameshift/ nonsense, and splicing mutations. In contrast, PHS was caused only by frameshift/ nonsense and splicing mutations. Second, among the frameshift/ nonsense mutations, there was a clear genotype- phenotype correlation. Mutations in the first third of the gene ( from open reading frame [ORF] nucleotides [nt] 1 - 1997) caused GCPS, and mutations in the second third of the gene ( from ORF nt 1998 - 3481) caused primarily PHS. Surprisingly, there were 12 mutations in patients with GCPS in the 3' third of the gene ( after ORF nt 3481), and no patients with PHS had mutations in this region. These results demonstrate a robust correlation of genotype and phenotype for GLI3 mutations and strongly support the hypothesis that these two allelic disorders have distinct modes of pathogenesis.