P63 gene mutations and human developmental syndromes
P63 gene mutations and human developmental syndromes
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DOI：
10.1002/ajmg.10778
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发表时间：
2002-10-15
期刊：
影响因子：
--
通讯作者：
van Bokhoven, H
中科院分区：
文献类型：
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作者：
Brunner, HG;Hamel, BCJ;van Bokhoven, H
P63 基因是最近发现的 p53 家族成员。虽然 P53 普遍表达，但 p63 在胚胎外胚层和成人上皮组织的基底再生层中特异性表达。动物模型中 P63 基因功能的完全丧失表明 P63 与外胚层衍生组织的正常发育相关。 p63基因敲除小鼠在出生时死亡，四肢截短，表皮、前列腺、乳房和尿路上皮组织缺失，这显然反映了外胚层干细胞的丧失。许多显性人类综合症已被定位到染色体 3q27，并最终导致 p63 基因的突变。这些综合征具有肢体发育异常和/或外胚层发育不良，包括外指畸形、外胚层发育不良、裂隙综合征；眼睑强直、外胚层发育不良、裂隙综合征;肢端皮肤-指甲-泪腺-牙齿综合征；肢体乳腺综合征；以及非综合征性手/足裂畸形。这些综合征的杂合突变模式各不相同。与这种综合征特异性突变模式一致，p63 蛋白突变的功能后果也各不相同，引发显性失活和功能获得机制，而不是简单的功能丧失。 (C) 2002 Wiley-Liss, Inc.
The P63 gene is a recently discovered member of the p53 family. While P53 is ubiquitously expressed, p63 is expressed specifically in embryonic ectoderm and in the basal regenerative layers of epithelial tissues in the adult. Complete abrogation of P63 gene function in an animal model points to the relevance of P63 for the proper development of ectodermally derived tissues. The p63 knockout mouse dies at birth and has truncation of the limbs, as well as absence of epidermis, prostate, breast, and urothelial tissues, apparently reflecting ectodermal stem cell loss. A number of dominant human syndromes have been mapped to chromosome 3q27 and ultimately to mutations in the p63 gene. These syndromes have abnormal limb development and/or ectodermal dysplasia and include ectrodactyly, ectodermal dysplasia, clefting syndrome; ankyloblepharon, ectodermal dysplasia, clefting syndrome; acro-dermato-ungual-lacrimal-tooth syndrome; limb-mammary syndrome; as well as nonsyndromic split hand/foot malformation. The pattern of heterozygous mutations is distinct for each of these syndromes. Consistent with this syndrome-specific mutational pattern, the functional consequences of mutations on the p63 proteins also vary, invoking dominant-negative and gain-of-function mechanisms rather than a simple loss of function. (C) 2002 Wiley-Liss, Inc.