Two novel point mutations in the long-range SHH enhancer in three families with triphalangeal thumb and preaxial polydactyly
Two novel point mutations in the long-range SHH enhancer in three families with triphalangeal thumb and preaxial polydactyly
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DOI：
10.1002/ajmg.a.31563
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发表时间：
2007-01-01
影响因子：
2
通讯作者：
Dobbs, Matthew B.
中科院分区：
文献类型：
--
作者：
Gurnett, Christina A.;Bowcock, Anne M.;Dobbs, Matthew B.
sonic hedgehog基因（SHH）的时空表达是由位于SHH上游1mb的调控元件（ZRS）驱动的。高度保守的ZRS中的点突变已经在半半多趾小鼠和四个前轴多指畸形家族中被描述[Lettice等，2003]。四个北美高加索家族被鉴定为常染色体显性三指拇指。通过LMBR1内含子5内774 bp高度保守的ZRS序列分析，对20名受影响家庭成员和36名未受影响家庭成员的DNA进行了评估。在4个家族中发现了3个ZRS突变。在家系A和C中，在靠近ZRS 5'端的bp 739处发现了一个新的A/G转换，该转换与疾病或携带者状态分离。先前描述的谱系A [Dobbs等人，2000]是一个大家庭，有19名受影响的成员，他们表现出较温和的表型，主要包括三指拇指，与其他家族相比外显率低（82%）。谱系C是一个小家族，有两名患病家庭成员患有三指拇指，一名患有三指拇指和前轴多指畸形。在家系B中发现了一种新的C/G突变bp 621，该突变在所有表现为轴前多指畸形和三指拇指的4个受影响个体中分离出来。这两种突变都改变了假定的Cdx转录因子结合位点。突变在ZRS似乎是一个常见的原因家族三指拇指和前轴多指畸形。家系A的突变位于ZRS的5'端附近，提示基因型/表型相关；该家族表现出较高的非外显率和较温和的表型。然而，修饰基因可能有助于这个家族的温和表型。(c) 2006 Wiley-Liss, Inc。
Spatio-temporal expression of sonic hedgehog (SHH) is driven by a regulatory element (ZRS) that lies 1 Mb upstream from SHH. Point mutations within the highly conserved ZRS have been described in the hemimelic extra toes mouse and in four families with preaxial polydactyly [Lettice et al., 2003]. Four North American Caucasian families were identified with autosomal dominant triphalangeal thumb. DNA from 20 affected and 36 unaffected family members was evaluated by sequence analysis of a 774-bp highly conserved ZRS contained within LMBR1 intron 5. Mutations within ZRS were identified in three of four families. In pedigree A and C, a novel A/G transition was identified near the 5' end of ZRS at bp 739 that segregated with disease or carrier status. Pedigree A, described previously [Dobbs et al., 2000], is a large family with 19 affected members who exhibit a milder phenotype, including predominantly triphalangeal thumbs and low penetrance (82%) relative to other families. Pedigree C is a small family with two affected family members with triphalangeal thumb, and one affected with both triphalangeal thumb and preaxial polydactyly. A novel C/G mutation at bp 621 was identified in pedigree B that segregated with the disease in all four affected individuals who manifested both preaxial polydactyly and triphalangeal thumb. Both mutations alter putative Cdx transcription factor binding sites. Mutations within ZRS appear to be a common cause of familial triphalangeal thumb and preaxial polydactyly. A genotype/phenotype correlate is suggested by pedigree A, whose mutation lies near the 5' end of ZRS; this family demonstrates a higher rate of nonpenetrance and milder phenotype. However, modifier genes may be contributing to the milder phenotype in this family. (c) 2006 Wiley-Liss, Inc.