Mutational analysis of PHEX gene in X-linked hypophosphatemia
Mutational analysis of PHEX gene in X-linked hypophosphatemia
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DOI：
10.1210/jc.83.10.3615
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发表时间：
1998-10-01
影响因子：
5.8
通讯作者：
Thakker, RV
中科院分区：
文献类型：
--
作者：
Dixon, PH;Christie, PT;Thakker, RV
低磷血症佝偻病通常是一种x连锁显性疾病（XLH或HYP），与磷酸盐运输中的肾小管缺陷和骨畸形有关。XLH基因，被称为PHEX，或以前称为PEX（与x染色体上的内多肽酶同源的磷酸盐调节基因），编码一种749个氨基酸的蛋白质，该蛋白质被认为由细胞内、跨膜和细胞外结构域组成。在XLH患者中观察到PHEX突变，我们通过单链构象多态性和DNA序列分析对46个无亲缘关系的XLH系和22个无亲缘关系的非家族性XLH患者进行了PHEX突变的研究。我们发现了31个突变（7个无义，6个缺失，2个缺失插入，1个重复，2个插入，4个剪接位点，8个错义，1个在5'未翻译区），其中30个分散在假定的细胞外区域，还有6个多态性，杂合频率从不到1%到43%不等。发现单链构象多态性检测超过60%的这些突变。超过20%的突变是在非家族性XLH患者中观察到的，这些患者代表了PHEX突变的重新发生。5'非翻译区独特的点突变（a—>g）和其他突变表明，显性XLH表型不太可能用单倍体不足或显性负作用来解释。
Hypophosphatemic rickets is commonly an X-linked dominant disorder (XLH or HYP) associated with a renal tubular defect in phosphate transport and bone deformities. The XLH gene, referred to as PHEX, or formerly as PEX (phosphate regulating gene with homologies to endopeptidases on the X-chromosome), encodes a 749-amino acid protein that putatively consists of an intracellular, transmembrane, and extracellular domain. PHEX mutations have been observed in XLH patients, and we have undertaken studies to characterize such mutations in 46 unrelated XLH kindreds and 22 unrelated patients with nonfamilial XLH by single stranded conformational polymorphism and DNA sequence analysis. We identified 31 mutations (7 nonsense, 6 deletions, 2 deletional insertions, 1 duplication, 2 insertions, 4 splice site, 8 missense, and 1 within the 5' untranslated region), of which 30 were scattered throughout the putative extracellular domain, together with 6 polymorphisms that had heterozygosity frequencies ranging from less than 1% to 43%. Single stranded conformational polymorphism was found to detect more than 60% of these mutations. Over 20% of the mutations were observed in non familial XLH patients, who represented de novo occurrences of PHEX mutations. The unique point mutation (a-->g) of the 5' untranslated region together with the other mutations indicates that the dominant XLH phenotype is unlikely to be explained by haplo-insufficiency or a dominant negative effect.