The phenotypic spectrum of GLI3 morphopathies includes autosomal dominant preaxial polydactyly type-IV and postaxial polydactyly type-A/B; No phenotype prediction from the position of GLI3 mutations
The phenotypic spectrum of GLI3 morphopathies includes autosomal dominant preaxial polydactyly type-IV and postaxial polydactyly type-A/B; No phenotype prediction from the position of GLI3 mutations
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DOI：
10.1086/302557
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发表时间：
1999-09-01
影响因子：
9.8
通讯作者：
Antonarakis, SE
中科院分区：
文献类型：
--
作者：
Radhakrishna, U;Bornholdt, D;Antonarakis, SE
基因的功能表征通常需要发现其相关表型的全谱。人类 GLI3 基因突变已在 Greig 头多指并指畸形、Pallister-Hall 综合征 (PHS) 和 A 型轴后多指畸形 (PAP-A) 中被发现。我们研究了 GLI3 在 1 个轴前多指 IV 型 (PPD-TV) 家系 (UR003)、3 个显性 PAP-A/B 家系 (UR014、UR015 和 UR016)（PPD-A 和 -B 属于同一家系）和 1 个 PHS 家系中参与其他指异常表型的情况。连锁分析显示没有与 GLI3 连锁多态性发生重组。家族 UR003 有一个 l-nt 移码插入，产生 1,245 个氨基酸的截短蛋白质。在 UR014 家族中发现了由于 l-nt 缺失导致的移码突变，导致蛋白质被截短为 1,280 个氨基酸。 UR015家族在结构域3的高度保守氨基酸中存在无义突变R643X，UR016家族存在错义突变G727R。PHS患者存在无义突变E1147X。这些结果在 GLI3 突变引起的表型谱中添加了两种表型：组合的 PAP-A/B 和 PPD-TV。这些突变不支持 GLI3 突变与所产生的表型之间的关联。我们建议将所有与 GLI3 突变相关的表型称为“GLI3 形态病”，因为由此产生的综合征的表型边界尚未明确定义，并且不存在明显的基因型-表型相关性。
Functional characterization of a gene often requires the discovery of the full spectrum of its associated phenotypes. Mutations in the human GLI3 gene have been identified in Greig cepalopolysyndactyly, Pallister-Hall syndrome (PHS), and postaxial polydactyly type-A (PAP-A). We studied the involvement of GLI3 in additional phenotypes of digital abnormalities in one family (UR003) with preaxial polydactyly type-IV (PPD-TV), three families (UR014, UR015, and UR016) with dominant PAP-A/B (with PPD-A and -B in the same family), and one family with PHS. Linkage analysis showed no recombination with GLI3-linked polymorphisms. Family UR003 had a l-nt frameshift insertion, resulting in a truncated protein of 1,245 amino acids. A frameshift mutation due to a l-nt deletion was found in family UR014, resulting in a truncated protein of 1,280 amino acids. Family UR015 had a nonsense mutation, R643X, and family UR016 had a missense mutation, G727R, in a highly conserved amino acid of domain 3. The patient with PHS had a nonsense mutation, E1147X. These results add two phenotypes to the phenotypic spectrum caused by GLI3 mutations: the combined PAP-A/B and PPD-TV. These mutations do not support the suggested association between the mutations in GLI3 and the resulting phenotypes. We propose that all phenotypes associated with GLI3 mutations be called "GLI3 morphopathies," since the phenotypic borders of the resulting syndromes are not well defined and there is no apparent genotype-phenotype correlation.