Hypophosphatasia in Japan: ALPL Mutation Analysis in 98 Unrelated Patients View Full Text


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Article Info

DATE

2019-11-09

AUTHORS

Toshimi Michigami, Kanako Tachikawa, Miwa Yamazaki, Masanobu Kawai, Takuo Kubota, Keiichi Ozono

ABSTRACT

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. More... »

PAGES

221-231

References to SciGraph publications

  • 2016-02-19. Hypophosphatasia — aetiology, nosology, pathogenesis, diagnosis and treatment in NATURE REVIEWS ENDOCRINOLOGY
  • 2010-12-23. Prevalence of c.1559delT in ALPL, a common mutation resulting in the perinatal (lethal) form of hypophosphatasia in Japanese and effects of the mutation on heterozygous carriers in JOURNAL OF HUMAN GENETICS
  • 2015-10-12. Lethal hypophosphatasia successfully treated with enzyme replacement from day 1 after birth in EUROPEAN JOURNAL OF PEDIATRICS
  • 2015-07-29. Molecular Genetics of Hypophosphatasia and Phenotype-Genotype Correlations in NEURONAL TISSUE-NONSPECIFIC ALKALINE PHOSPHATASE (TNAP)
  • 2017-12-13. Genetic analysis of adults heterozygous for ALPL mutations in JOURNAL OF BONE AND MINERAL METABOLISM
  • 2007-10-04. Hypophosphatasia in ORPHANET JOURNAL OF RARE DISEASES
  • 2001-07. A molecular approach to dominance in hypophosphatasia in HUMAN GENETICS
  • 2006-01-01. Hypophosphatasia in ATLAS OF GENETIC DIAGNOSIS AND COUNSELING
  • 2014-02-26. Unexpected high intrafamilial phenotypic variability observed in hypophosphatasia in EUROPEAN JOURNAL OF HUMAN GENETICS
  • 1998-07. Identification of fifteen novel mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) gene in European patients with severe hypophosphatasia in EUROPEAN JOURNAL OF HUMAN GENETICS
  • 2013-10-22. Benign prenatal hypophosphatasia: a treatable disease not to be missed in PEDIATRIC RADIOLOGY
  • 2005-01-20. Common mutations F310L and T1559del in the tissue-nonspecific alkaline phosphatase gene are related to distinct phenotypes in Japanese patients with hypophosphatasia in EUROPEAN JOURNAL OF PEDIATRICS
  • 2009-06-06. Mild forms of hypophosphatasia mostly result from dominant negative effect of severe alleles or from compound heterozygosity for severe and moderate alleles in BMC MEDICAL GENOMICS
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    http://scigraph.springernature.com/pub.10.1007/s00223-019-00626-w

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    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/31707452


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