Ikegawa S, Ohashi H, Ogata T, Honda A, Tsukahara M, Kubo T, Kimizuka M, Shimode M, Hasegawa T, Nishimura G, Nakamura Y
Laboratory of Genome Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
Am J Med Genet. 2000 Oct 2;94(4):300-5. doi: 10.1002/1096-8628(20001002)94:4<300::aid-ajmg7>3.0.co;2-3.
Chondrodysplasia punctata (CDP) is a heterogeneous group of skeletal dysplasias characterized by stippled epiphyses. A subtype of CDP, X-linked dominant chondrodysplasia punctata (CDPX2), known also as Conradi-Hünermann-Happle syndrome, is a rare skeletal dysplasia characterized by short stature, craniofacial defects, cataracts, ichthyosis, coarse hair, and alopecia. The cause of CDPX2 was unknown until recent identification of mutations in the gene encoding Delta(8),Delta(7) sterol isomerase emopamil-binding protein (EBP). Twelve different EBP mutations have been reported in 14 patients with CDPX2 or unclassified CDP, but with no evidence of correlation between phenotype and nature of the mutation. To characterize additional mutations and investigate possible phenotype-genotype correlation, we sequenced the entire EBP gene in 8 Japanese individuals with CDP; 5 of them presented with a CDPX2 phenotypes. We found EBP mutations in all 5 CDPX2 individuals, but none in non-CDPX2 individuals. Three of these CDPX2 individuals carried novel nonsense mutations in EBPand the other two, separate missense mutations that had been reported also in different ethnic groups. Our results, combined with previous information, suggest all EBP mutations that produce truncated proteins result in typical CDPX2, whereas the phenotypes resulted from missense mutations are not always typical for CDPX2. Patients with nonsense mutations showed abnormal sterol profiles consistent with a defect in Delta(8), Delta(7) sterol isomerase. X-inactivation patterns of the patients showed no skewing, an observation that supports the assumption that inactivation of the EBP gene occurs at random in affected individuals.
点状软骨发育不良（CDP）是一组以骨骺点状化为特征的骨骼发育异常疾病。CDP的一个亚型，X连锁显性点状软骨发育不良（CDPX2），也称为康拉迪-于纳曼-哈普尔综合征，是一种罕见的骨骼发育异常疾病，其特征为身材矮小、颅面缺陷、白内障、鱼鳞病、毛发粗糙和脱发。直到最近发现编码δ(8),δ(7)固醇异构酶依莫帕米结合蛋白（EBP）的基因突变，CDPX2的病因仍不清楚。在14例CDPX2或未分类的CDP患者中报道了12种不同的EBP突变，但没有证据表明突变的性质与表型之间存在相关性。为了鉴定更多的突变并研究可能的表型-基因型相关性，我们对8例日本CDP患者的整个EBP基因进行了测序；其中5例表现为CDPX2表型。我们在所有5例CDPX2患者中发现了EBP突变，但在非CDPX2患者中未发现。这5例CDPX2患者中有3例携带EBP的新无义突变，另外2例携带不同种族也有报道的错义突变。我们的结果与之前的信息相结合，表明所有产生截短蛋白的EBP突变都会导致典型的CDPX2，而错义突变导致的表型并不总是CDPX2的典型表现。有无义突变的患者显示出异常的固醇谱，与δ(8),δ(7)固醇异构酶缺陷一致。患者的X染色体失活模式没有偏斜，这一观察结果支持了在受影响个体中EBP基因随机失活这一假设。
