Hypophosphatasia in Japan: ALPL Mutation Analysis in 98 Unrelated Patients
Hypophosphatasia in Japan: ALPL Mutation Analysis in 98 Unrelated Patients
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DOI：
10.1007/s00223-019-00626-w
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发表时间：
2019-11-09
影响因子：
4.2
通讯作者：
Ozono, Keiichi
中科院分区：
文献类型：
--
作者：
Michigami, Toshimi;Tachikawa, Kanako;Ozono, Keiichi
低磷酸酶（HPP）在临床表现上变化很大，一般分为六个亚型。虽然从ALPL基因型预测临床病程是有益的，但这方面的研究有限。在这里，我们旨在阐明日本HPP的特征以及基因型与临床表现的关系。我们分析了98名不相关的日本患者，以调查每种临床形式的百分比，频繁检测到的突变，以及基因型和表型之间的关系。一些已鉴定的突变体通过转染实验进行了鉴定。以围产期重症最为常见（45.9%），其次为围产期良性（22.4%）。在196个等位基因中，89个等位基因中检测到p.Leu520ArgfsX86 (C . 1559delt)， 23个等位基因中检测到p.Phe327Leu （C . 979t >C）。p. phe520argfsx86的纯合子均为围产期重症型，携带其中一个等位基因的p.Phe327Leu的患者均为围产期良性或齿状HPP型。22例围产期良性HPP患者中有20例为p.Phe327Leu和另一种突变的复合杂合。大多数齿龈HPP患者为显性阴性突变的单等位杂合子或具有残余活性突变的复合杂合子。p.Leu520ArgfsX86和p.Phe327Leu突变的高流行率可能是日本HPP患者围产期重症和围产期良性发生率高的原因。尽管ALPL基因分型在一定程度上有利于预测临床病程，但在具有相同基因型的患者中观察到的表型差异表明存在修饰因子。
Hypophosphatasia (HPP) is highly variable in clinical expression and is generally classified into six subtypes. Although it would be beneficial to be able to predict the clinical course from the ALPL genotype, studies on this issue are limited. Here, we aimed to clarify the features of Japanese HPP and the relationships between genotype and clinical manifestations. We analyzed 98 unrelated Japanese patients to investigate the percentage of each clinical form, frequently detected mutations, and the relationship between the genotype and phenotype. Some of the identified mutants were characterized by transfection experiments. Perinatal severe form was the most frequent (45.9%), followed by perinatal benign form (22.4%). Among the 196 alleles, p.Leu520ArgfsX86 (c.1559delT) was detected in 89 alleles, and p.Phe327Leu (c.979T>C) was identified in 23 alleles. All of the homozygotes for p.Leu520ArgfsX86 were classified into perinatal severe form, and patients carrying p.Phe327Leu in one of the alleles were classified into perinatal benign or odonto HPP. Twenty of the 22 patients with perinatal benign HPP were compound heterozygous for p.Phe327Leu and another mutation. Most patients with odonto HPP were found to be monoallelic heterozygotes for dominant-negative mutations or compound heterozygotes with mutants having residual activity. The high prevalence of p.Leu520ArgfsX86 and p.Phe327Leu mutations might underlie the high rate of perinatal severe and perinatal benign forms, respectively, in Japanese HPP. Although ALPL genotyping would be beneficial for predicting the clinical course to an extent, the observed phenotypical variability among patients sharing the same genotypes suggests the presence of modifiers.