Identification of two novel mutations in Shh long-range regulator associated with familial pre-axial polydactyly
Identification of two novel mutations in Shh long-range regulator associated with familial pre-axial polydactyly
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DOI：
10.1111/j.1399-0004.2010.01465.x
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发表时间：
2011-04-01
影响因子：
3.5
通讯作者：
Bezieau, S.
中科院分区：
文献类型：
--
作者：
Albuisson, J.;Isidor, B.;Bezieau, S.
II型轴前性多指（趾）畸形（PPDII，MIM #174500）、Werner mesomelic综合征（MIM #188770）和哈斯多并指（趾）畸形（MIM #186200）是一组密切相关的疾病，由称为ZRS的长程Sonic hedgehog（SHH，MIM *600725）调节因子突变引起。迄今为止，在人类、小鼠、猫和鸡中已经报道了与这些轴前多指（趾）畸形相关的19个ZRS点突变、10个重复和1个三重。其中一些已被证明会导致Shh在小鼠肢芽中的异位表达，导致多指表型，但ZRS突变产生这种表型的确切机制仍然未知。我们提出了两个PPDII家族，在超保守的转录因子SOX 9和PAX3，两个可能的候选人调节SHH表达的预测结合位点的完全渗透点突变。筛选点突变或拷贝数变异的ZRS，高分辨率阵列CGH，并筛选其他保守的非编码序列（CNS）周围SHH在第三个家庭是阴性的。这是第六个可能与7q36连锁的PPDII家系，没有检测到ZRS突变。我们推测，另一个附近的调控序列，或ZRS和SHH之间未检测到的位置效应，可能是负家族性病例与7q36。
Pre-axial polydactyly type II (PPDII, MIM #174500), Werner mesomelic syndrome (MIM %188770) and Haas polysyndactyly (MIM #186200) are a group of closely related conditions caused by mutations in a long-range Sonic hedgehog (SHH, MIM *600725) regulator called ZRS. To date, 19 point mutations, 10 duplications and 1 triplication of the ZRS associated with those pre-axial polydactylies have been reported in humans, mice, cats and chickens. Some of these have been shown to cause ectopic expression of Shh in the limb bud in mice, leading to a polydactylous phenotype, but the precise mechanism by which ZRS mutations generate this phenotype remains unknown. We present two PPDII families with fully penetrant point mutations in ultra-conserved predicted binding sites for transcription factors SOX9 and PAX3, two possible candidates for regulating SHH expression. Screening for point mutations or copy-number variation of the ZRS, high-resolution array-CGH, and screening of other conserved non-coding sequences (CNS) surrounding SHH in a third family are negative. This is the sixth PPDII pedigree with possible linkage to 7q36 that presents with no detectable ZRS mutation. We hypothesize that another nearby regulatory sequence, or an undetected position effect between ZRS and SHH, could be responsible for negative familial cases linked to 7q36.