Monreal A W, Zonana J, Ferguson B
Department of Molecular and Medical Genetics, Oregon Health Sciences University, Portland, OR 97201-3098, USA.
Am J Hum Genet. 1998 Aug;63(2):380-9. doi: 10.1086/301984.
X-linked hypohidrotic ectodermal dysplasia (XLHED), the most common of the ectodermal dysplasias, results in the abnormal development of teeth, hair, and eccrine sweat glands. The gene responsible for this disorder, EDA1, was identified by isolation of a single cDNA that was predicted to encode a 135-amino-acid protein. Mutations in this splice form were detected in <10% of families with XLHED. The subsequent cloning of the murine homologue of the EDA1 gene (Tabby [Ta]) allowed us to identify a second putative isoform of the EDA1 protein (isoform II) in humans. This EDA1 cDNA is predicted to encode a 391-residue protein, of which 256 amino acids are encoded by the new exons. The putative protein is 94% identical to the Ta protein and includes a collagen-like domain with 19 repeats of a Gly-X-Y motif in the presumptive extracellular domain. The genomic structure of the EDA1 gene was established, and the complete sequence of the seven new exons was determined in 18 XLHED-affected males. Putative mutations, including 12 missense, one nonsense, and four deletion mutations, were identified in approximately 95% of the families. The results suggest that EDA1 isoform II plays a critical role in tooth, hair, and sweat gland morphogenesis, whereas the biological significance of isoform I remains unclear. Identification of mutations in nearly all of the XLHED families studied suggests that direct molecular diagnosis of the disorder is feasible. Direct diagnosis will allow carrier detection in families with a single affected male and will assist in distinguishing XLHED from the rarer, clinically indistinguishable, autosomal recessive form of the disorder.
X连锁少汗型外胚层发育不良（XLHED）是最常见的外胚层发育不良症，会导致牙齿、毛发和外分泌汗腺发育异常。导致这种疾病的基因EDA1是通过分离一个预测编码135个氨基酸的单一cDNA鉴定出来的。在不到10%的XLHED家族中检测到这种剪接形式的突变。随后对EDA1基因的小鼠同源物（Tabby [Ta]）进行克隆，使我们能够在人类中鉴定出EDA1蛋白的第二种假定异构体（异构体II）。这个EDA1 cDNA预测编码一个391个残基的蛋白，其中256个氨基酸由新的外显子编码。该假定蛋白与Ta蛋白有94%的同源性，并且在假定的细胞外结构域包含一个具有19个Gly-X-Y基序重复的胶原样结构域。确定了EDA1基因的基因组结构，并在18名受XLHED影响的男性中测定了七个新外显子的完整序列。在大约95%的家族中鉴定出了假定的突变，包括12个错义突变、1个无义突变和4个缺失突变。结果表明，EDA1异构体II在牙齿、毛发和汗腺形态发生中起关键作用，而异构体I的生物学意义仍不清楚。在几乎所有研究的XLHED家族中鉴定出突变表明，对该疾病进行直接分子诊断是可行的。直接诊断将有助于在仅有一名受影响男性的家族中检测携带者，并有助于将XLHED与该疾病较罕见的、临床难以区分的常染色体隐性形式区分开来。
