Abstract
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.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Whyte MP . Hypophosphatasia and the role of alkaline phosphatase in skeletal mineralization Endocr Rev 1994 15: 439–461
Greenberg CR, Evans JA, McKendry-Smith S et al. Infantile hypophosphatasia localization within chromosome region 1p36.1.1-34 and prenatal diagnosis using linked DNA markers Am J Hum Genet 1990 46: 286–292
Weiss MJ, Ray K, Henthorn PS, Lamb B, Kadesch T, Harris H . Structure of the human liver/bone/kidney alkaline phosphatase gene J Biol Chem 1988 263: 12002–12010
Mornet E . Hypophosphatasia: the mutations of the tissue-nonspecific alkaline phosphatase gene Hum Mutat 2000 15: 309–315
Goseki-Sone M, Orimo H, Iimura T et al. Hypophosphatasia: identification of five novel mutations (G507A, G705A, A748G, T1155C, G1320A) in the tissues-nonspecific alkaline phosphatase gene among Japanese patients Hum Mut 1998 1 Suppl: S263–S267
Orimo H, Goseki-Sone M, Inoue M, Tsubakio Y, Sakiyama T, Shimada T . Importance of deletion of T at nucleotide 1559 in the tissue-nonspecific alkaline phosphatase gene in Japanese patients with hypophosphatasia J Bone Miner Metab 2002 20: 28–33
Henthorn PS, Raducha M, Fedde KN, Lafferty MA, Whyte MP . Different mutations at the tissue-nonspecific alkaline phosphatase gene locus in autosomal recessively inherited forms of mild and severe hypophosphatasia Proc Natl Acad Sci USA 1992 89: 9924–9928
Zurutuza L, Muller F, Gibrat JF et al. Correlations of genotype and phenotype in hypophosphatasia Hum Mol Genet 1999 8: 1039–1046
Mornet E, Taillandier A, Peyramaure S et al. Identification of fifteen novel mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) gene in European patients with severe hypophosphatasia Eur J Hum Genet 1998 6: 308–314
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Hérasse, M., Spentchian, M., Taillandier, A. et al. Evidence of a founder effect for the tissue-nonspecific alkaline phosphatase (TNSALP) gene E174K mutation in hypophosphatasia patients. Eur J Hum Genet 10, 666–668 (2002). https://doi.org/10.1038/sj.ejhg.5200857
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/sj.ejhg.5200857
Keywords
This article is cited by
-
Clinical and genetic characteristics of hypophosphatasia in Chinese children
Orphanet Journal of Rare Diseases (2021)
-
Hypophosphatasia: a genetic-based nosology and new insights in genotype-phenotype correlation
European Journal of Human Genetics (2021)
-
Two novel mutations in the ALPL gene of unrelated Chinese children with Hypophosphatasia: case reports and literature review
BMC Pediatrics (2019)
-
Genetics of Hypophosphatasia
Clinical Reviews in Bone and Mineral Metabolism (2013)
-
Hypophosphatasia now draws more attention of both clinicians and researchers: A Commentary on prevelance of c. 1559delT in ALPL, a common mutation resulting in the perinatal (lethal) form of hypophosphatasias in Japanese and effects of the mutation on heterozygous carriers
Journal of Human Genetics (2011)
