Evidence of a founder effect for the tissue-nonspecific alkaline phosphatase (TNSALP) gene E174K mutation in hypophosphatasia patients
Evidence of a founder effect for the tissue-nonspecific alkaline phosphatase (TNSALP) gene E174K mutation in hypophosphatasia patients
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DOI：
10.1038/sj.ejhg.5200857
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发表时间：
2002-10-01
影响因子：
5.2
通讯作者：
Mornet, E
中科院分区：
文献类型：
--
作者：
Hérasse, M;Spentchian, M;Mornet, E
低磷酸酶症是一种罕见的先天性代谢缺陷，其特征是由于组织非特异性碱性磷酸酶（TNSALP）基因突变引起的肝、骨或肾型碱性磷酸酶缺乏引起的骨矿化缺陷。该疾病的临床表现是高度可变的，范围从具有低矿化骨骼的死产到仅在成年后期发展的病理性骨骼骨折。这种临床异质性是由于TNSALP基因中的强等位基因异质性。我们发现突变E174K在白种人患者中最常见，31%的轻度低磷酸酶症患者携带突变E174K。由于该突变在不同地理来源的患者中发现，我们研究了它是否具有独特的起源，或者由于从头突变的复发而具有多个起源。在E174K携带者和正常无关个体中检测了S93S、472+12delG和V505A三种基因内多态性。我们的研究结果表明，所有的E174K突变是由一个共同的祖先单倍型，也发现在正常和hypophosphatasia染色体的低频率。我们的结论是TNSALP基因E174K突变是一个相对古老的祖先突变的结果，发生在西欧北部的一条染色体上，并蔓延到整个欧洲其他地区，并进入新世界作为人类移民的结果。
Hypophosphatasia is a rare inborn error of metabolism characterised by defective bone mineralisation caused by a deficiency of liver-, bone- or kidney-type alkaline phosphatase due to mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) gene. The clinical expression of the disease is highly variable, ranging from stillbirth with a poorly mineralised skeleton to pathologic skeletal fractures which develop in late adulthood only. This clinical heterogeneity is due to the strong allelic heterogeneity in the TNSALP gene. We found that mutation E174K is the most frequent in Caucasian patients, and that it was carried by 31% of our patients with mild hypophosphatasia. Because the mutation was found in patients of various geographic origins, we investigated whether it had a unique origin or rather multiple origins due to recurrence of de novo mutations. Three intragenic polymorphisms, S93S, 472+12delG and V505A, were genotyped in patients carrying E174K and in normal unrelated individuals. Our results show that all the E174K mutations are carried by a common ancestral haplotype, also found at low frequency in normal and hypophosphatasia chromosomes. We conclude that the TNSALP gene E174K mutation is the result of a relatively ancient ancestral mutation that occurred on a single chromosome in the north of Western Europe and spread throughout the rest of Europe and into the New World as a result of human migration.