A rare case of hypohidrotic ectodermal dysplasia caused by compound heterozygous mutations in the EDAR gene
A rare case of hypohidrotic ectodermal dysplasia caused by compound heterozygous mutations in the EDAR gene
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DOI：
10.1111/j.0022-202x.2004.23405.x
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发表时间：
2004-10-01
影响因子：
6.5
通讯作者：
Kuwano, R
中科院分区：
文献类型：
--
作者：
Shimomura, Y;Sato, N;Kuwano, R
少汗性外胚层发育不良(HED)是一种以毛发、牙齿和汗腺发育异常为特征的遗传性疾病。虽然大多数HED病例表现为X连锁隐性遗传，但也存在常染色体显性遗传和常染色体隐性遗传。X连锁HED是由EDA基因突变引起的，常染色体形式是由EDAR基因或EDARADD基因突变引起的。在这项研究中，我们在一名日本女性HED患者中发现了EDAR基因的复合杂合子突变。在母亲等位基因上，是内含子2的一个新的剪接供体位点突变，导致产生外显子2跳过的不稳定转录本；在父亲等位基因上，是在EDAR的死亡区域内的一个新的R375H转换。通过在组织培养细胞中的表达研究，我们发现EDAR中的R375H替换导致其与EDARADD的亲和力丧失，并降低了下游靶标NF-kappaB的活性。我们的研究结果表明，在我们的患者中，EDAR的两个等位基因都是非功能性的，导致了HED表型。
Hypohidrotic ectodermal dysplasia (HED) is a genetic disease characterized by abnormal hair, teeth, and sweat gland development. Although most cases of HED display X-linked recessive inheritance, autosomal dominant and autosomal recessive forms also exist. X-linked HED is caused by mutations in the EDA gene, and the autosomal forms result from mutations in either the EDAR gene or the EDARADD gene. In this study, we identified compound heterozygous mutations in the EDAR gene in a Japanese female patient with HED. On the maternal allele is a novel splice donor site mutation of intron 2 leading to the generation of unstable transcripts with exon 2 skipping; on the paternal allele is a novel R375H transition within the death domain of EDAR. Using expression studies in tissue culture cells, we found that the R375H substitution in EDAR caused loss of its affinity for EDARADD and reduced activation of the downstream target NF-kappaB. Our findings indicate that both alleles of EDAR are non-functional in our patient, resulting in the HED phenotype.