van Bokhoven H, Hamel B C, Bamshad M, Sangiorgi E, Gurrieri F, Duijf P H, Vanmolkot K R, van Beusekom E, van Beersum S E, Celli J, Merkx G F, Tenconi R, Fryns J P, Verloes A, Newbury-Ecob R A, Raas-Rotschild A, Majewski F, Beemer F A, Janecke A, Chitayat D, Crisponi G, Kayserili H, Yates J R, Neri G, Brunner H G
Department of Human Genetics, University Medical Centre, Nijmegen, The Netherlands.
Am J Hum Genet. 2001 Sep;69(3):481-92. doi: 10.1086/323123. Epub 2001 Jul 17.
p63 mutations have been associated with EEC syndrome (ectrodactyly, ectodermal dysplasia, and cleft lip/palate), as well as with nonsyndromic split hand-split foot malformation (SHFM). We performed p63 mutation analysis in a sample of 43 individuals and families affected with EEC syndrome, in 35 individuals affected with SHFM, and in three families with the EEC-like condition limb-mammary syndrome (LMS), which is characterized by ectrodactyly, cleft palate, and mammary-gland abnormalities. The results differed for these three conditions. p63 gene mutations were detected in almost all (40/43) individuals affected with EEC syndrome. Apart from a frameshift mutation in exon 13, all other EEC mutations were missense, predominantly involving codons 204, 227, 279, 280, and 304. In contrast, p63 mutations were detected in only a small proportion (4/35) of patients with isolated SHFM. p63 mutations in SHFM included three novel mutations: a missense mutation (K193E), a nonsense mutation (Q634X), and a mutation in the 3' splice site for exon 5. The fourth SHFM mutation (R280H) in this series was also found in a patient with classical EEC syndrome, suggesting partial overlap between the EEC and SHFM mutational spectra. The original family with LMS (van Bokhoven et al. 1999) had no detectable p63 mutation, although it clearly localizes to the p63 locus in 3q27. In two other small kindreds affected with LMS, frameshift mutations were detected in exons 13 and 14, respectively. The combined data show that p63 is the major gene for EEC syndrome, and that it makes a modest contribution to SHFM. There appears to be a genotype-phenotype correlation, in that there is a specific pattern of missense mutations in EEC syndrome that are not generally found in SHFM or LMS.
p63突变与EEC综合征（缺指（趾）畸形、外胚层发育不良和唇腭裂）以及非综合征性裂手裂足畸形（SHFM）相关。我们对43例患有EEC综合征的个体和家系样本、35例患有SHFM的个体以及3个患有类EEC综合征肢体-乳腺综合征（LMS）的家系进行了p63突变分析，LMS的特征为缺指（趾）畸形、腭裂和乳腺异常。这三种病症的结果有所不同。在几乎所有（40/43）患有EEC综合征的个体中检测到了p63基因突变。除了外显子13中的一个移码突变外，所有其他EEC突变均为错义突变，主要涉及密码子204、227、279、280和304。相比之下，在仅一小部分（4/35）孤立性SHFM患者中检测到了p63突变。SHFM中的p63突变包括三个新突变：一个错义突变（K193E）、一个无义突变（Q634X）和外显子5的3'剪接位点突变。该系列中的第四个SHFM突变（R280H）也在一名患有典型EEC综合征的患者中发现，这表明EEC和SHFM突变谱之间存在部分重叠。最初的LMS家系（van Bokhoven等人，1999年）未检测到p可检测的p63突变，尽管其明确定位于3q27的p63基因座。在另外两个患有LMS的小家系中，分别在外显子13和14中检测到了移码突变。综合数据表明，p63是EEC综合征的主要基因，并且它对SHFM有一定贡献。似乎存在基因型-表型相关性，因为EEC综合征中存在一种特定的错义突变模式，而这种模式在SHFM或LMS中通常不存在。
