A prospective study of brachytelephalangic chondrodysplasia punctata: identification of arylsulfatase E mutations, functional analysis of novel missense alleles, and determination of potential phenocopies
A prospective study of brachytelephalangic chondrodysplasia punctata: identification of arylsulfatase E mutations, functional analysis of novel missense alleles, and determination of potential phenocopies
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DOI：
10.1038/gim.2013.13
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发表时间：
2013-08-01
影响因子：
8.8
通讯作者：
Braverman, Nancy
中科院分区：
文献类型：
--
作者：
Matos-Miranda, Claudia;Nimmo, Graeme;Braverman, Nancy
目的：短趾关节点状软骨发育不良的唯一已知遗传原因是X连锁点状软骨发育不良1（CDPX 1），其由芳基硫酸酯酶E（ARSE）缺乏引起。从历史上看，ARSE突变已确定在只有50%的男性患者，并提出，其余的可能代表表型，由于母胎维生素K缺乏症和母体自身免疫性diseases.Methods：为了进一步评估的原因bracytelephalangic chondrodysplasia punctata，我们建立了一个协作教育和测试翻译程序CDPX 1从2008年至2010年。在确定的29名男性先证者中，17名有ARSE突变，包括10个新的错义等位基因和一个单密码子缺失。为了确定这些和其他错义等位基因的致病性，我们在COS细胞中瞬时表达它们，并使用人工底物4-甲基伞形酮硫酸酯测量芳基硫酸酯酶E活性。此外，收集临床数据，以调查母亲的影响和基因型-表型correlations.Results：在这项研究中，58%的男性有ARSE突变。所有突变等位基因的芳基硫酸酯酶E活性可以忽略不计。基因型与表型间无明显相关。结论：CDPX 1是由芳基硫酸酯酶E活性丧失引起的。约40%的男性患者短趾点状软骨发育不良没有检测到ARSE突变或已知的母亲病因。进一步了解芳基硫酸酯酶E的功能，预计照亮其他病因的短趾软骨发育不良点状。
Purpose: The only known genetic cause of brachytelephalangic chondrodysplasia punctata is X-linked chondrodysplasia punctata 1 (CDPX1), which results from a deficiency of arylsulfatase E (ARSE). Historically, ARSE mutations have been identified in only 50% of male patients, and it was proposed that the remainder might represent phenocopies due to maternal-fetal vitamin K deficiency and maternal autoimmune diseases.Methods: To further evaluate causes of brachytelephalangic chondrodysplasia punctata, we established a Collaboration Education and Test Translation program for CDPX1 from 2008 to 2010. Of the 29 male probands identified, 17 had ARSE mutations that included 10 novel missense alleles and one single-codon deletion. To determine pathogenicity of these and additional missense alleles, we transiently expressed them in COS cells and measured arylsulfatase E activity using the artificial substrate, 4-methylumbelliferyl sulfate. In addition, clinical data were collected to investigate maternal effects and genotype-phenotype correlations.Results: In this study, 58% of males had ARSE mutations. All mutant alleles had negligible arylsulfatase E activity. There were no obvious genotype-phenotype correlations. Maternal etiologies were not reported in most patients.Conclusion: CDPX1 is caused by loss of arylsulfatase E activity. Around 40% of male patients with brachytelephalangic chondrodysplasia punctata do not have detectable ARSE mutations or known maternal etiological factors. Improved understanding of arylsulfatase E function is predicted to illuminate other etiologies for brachytelephalangic chondrodysplasia punctata.