Mutational Analysis of the PHEX Gene: Novel Point Mutations and Detection of Large Deletions by MLPA in Patients with X-Linked Hypophosphatemic Rickets
Mutational Analysis of the PHEX Gene: Novel Point Mutations and Detection of Large Deletions by MLPA in Patients with X-Linked Hypophosphatemic Rickets
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DOI：
10.1007/s00223-009-9260-8
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发表时间：
2009-09-01
影响因子：
4.2
通讯作者：
Raue, F.
中科院分区：
文献类型：
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作者：
Clausmeyer, S.;Hesse, V.;Raue, F.
X连锁低磷血症性佝偻病（HYP，XLH）是一种磷酸盐稳态紊乱，以肾性磷酸盐消耗和低磷血症为特征，血清1，25-二羟基维生素D3水平正常至低。本研究的目的是检测XLH发病机制中的关键酶PHEX基因的失活突变。16例患者，代表8个家庭，提出了怀疑XLH的生化和临床证据。所有16人都被转诊进行PHEX基因突变分析。我们检测到三个新的致病突变，C59 S，Q394 X和W 602，可以预测功能丧失。在两个健康先证者中发现的G28 S变异可能是一种罕见的多态性。另一个突变A363 V与C59 S突变位于同一等位基因上，因此其功能后果无法证明。此外，我们检测到外显子15中三个核苷酸的缺失，导致氨基酸苏氨酸535的丢失。在没有任何染色体畸变的男性患者中，这种突变的杂合性表明其作为嵌合体存在。使用多重连接依赖性探针扩增（MLPA）分析检测新的大缺失。这些缺失中的两个，外显子22单独缺失或外显子21和22一起缺失，可能导致C末端截短蛋白的翻译。两个大的缺失分别包括外显子1-9和外显子4-20，并且推测导致无功能的蛋白质。我们的结论是，分子遗传学分析证实了XLH的临床诊断，并应包括序列分析以及大缺失的搜索，这是由MLPA促进。
X-Linked hypophosphatemic rickets (HYP, XLH) is a disorder of phosphate homeostasis, characterized by renal phosphate wasting and hypophosphatemia, with normal to low 1,25-dihydroxy vitamin D3 serum levels. The purpose of our study was the detection of inactivating mutations in the PHEX gene, the key enzyme in the pathogenesis of XLH. The 16 patients, representing eight families, presented with suspected XLH from biochemical and clinical evidence. All 16 were referred for mutational analysis of the PHEX gene. We detected three novel disease-causing mutations, C59S, Q394X, and W602, for which a loss of function can be predicted. A G28S variation, found in two healthy probands, may be a rare polymorphism. Another mutation, A363 V, is localized on the same allele as the C59S mutation, thus its functional consequences cannot be proven. Furthermore, we detected a deletion of three nucleotides in exon 15 which resulted in the loss of amino acid threonine 535. Heterozygosity of this mutation in a male patient without any chromosomal aberrations suggests its presence as a mosaic. Novel large deletions were detected using multiplex ligation-dependent probe amplification (MLPA) analysis. Two of these deletions, loss of exon 22 alone or exons 21 and 22 together, may result in the translation of a C-terminal truncated protein. Two large deletions comprise exons 1-9 and exons 4-20, respectively, and presumably result in a nonfunctional protein. We conclude that molecular genetic analysis confirms the clinical diagnosis of XLH and should include sequence analysis as well as the search for large deletions, which is facilitated by MLPA.