Abstract
Hypophosphatasia (HPP) results from mutations in the ALPL gene, mostly missense mutations. The gene is subject to a very high allelic heterogeneity, and some of these mutations have a dominant negative effect, two features that explain the most part of the clinical heterogeneity. Severe forms of the disease (perinatal and infantile) are inherited as an autosomal recessive trait. In the milder forms, autosomal recessive and autosomal dominant inheritance coexist. Experimental data show that there is a good correlation between the severity of the disease and in vitro alkaline phosphatase activity of the mutant protein. As a consequence of the existence of dominant mutations, moderate forms may be recessively or dominantly inherited and are expected more frequent than severe forms. The incidence of severe forms, inherited as a recessive trait, has been estimated at 1/300,000 in Europe. Genetic counseling is difficult in families where the mode of inheritance is unclear, or in prenatal context because of the prenatal benign form that may mimic severe perinatal HPP. During the ten last years, the mechanism of mineralization has been greatly deciphered, pointing out others gene that could modulate the HPP phenotype and explain particular cases where the phenotype does not correlate with the phenotype.
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Brun-Heath I, Ermonval M, Chabrol E, Xiao J, Palkovits M, Lyck R, Miller F, Couraud PO, Mornet E, Fonta C. Differential expression of the bone and the liver tissue non-specific alkaline phosphatase isoforms in brain tissues. Cell Tissue Res. 2011;343:521–36.
Cai G, Michigami T, Yamamoto T, Yasui N, Satomura K, Yamagata M, Shima M, Nakajima S, Mushiake S, Okada S, Ozono K. Analysis of localization of mutated tissue-nonspecific alkaline phosphatase proteins associated with neonatal hypophosphatasia using green fluorescent protein chimeras. J Clin Endocrinol Metab. 1998;83:3936–42.
Eastman JR, Bixler D. Clinical, laboratory, and genetic investigations of hypophosphatasia: support for autosomal dominant inheritance with homozygous lethality. J Craniofac Genet Dev Biol. 1983;3:213–34.
Eberic FHS, Pralle H, Kabish A. Adult hypophosphatasia without apparent skeletal disease: “odontohypophosphatasia” in four heterozygote members of a family. Klin Wochenschr. 1984;62:371.
Fauvert D, Brun-Heath I, Lia-Baldini AS, Bellazi L, Taillandier A, Serre JL, de Mazancourt P, Mornet E. Mild forms of hypophosphatasia mostly result from dominant negative effect of severe alleles or from compound heterozygosity for severe and moderate alleles. BMC Med Genet. 2009;10:51.
Fraser D. Hypophosphatasia. Am J Med. 1957;22:730–46.
Fukushi M, Amizuka N, Hoshi K, Ozawa H, Kumagai H, Omura S, Misumi Y, Ikehara Y, Oda K. Intracellular retention and degradation of tissue-nonspecific alkaline phosphatase with a Gly317–>Asp substitution associated with lethal hypophosphatasia. Biochem Biophys Res Commun. 1998;246:613–8.
Fukushi-Irie M, Ito M, Amaya Y, Amizuka N, Ozawa H, Omura S, Ikehara Y, Oda K. Possible interference between tissue-non-specific alkaline phosphatase with an Arg54–>Cys substitution and acounterpart with an Asp277–>Ala substitution found in a compound heterozygote associated with severe hypophosphatasia. Biochem J. 2000;348(Pt 3):633–42.
Greenberg CR, Taylor CL, Haworth JC, Seargeant LE, Philipps S, Triggs-Raine B, Chodirker BN. A homoallelic Gly317–>Asp mutation in ALPL causes the perinatal (lethal) form of hypophosphatasia in Canadian mennonites. Genomics. 1993;17:215–7.
Harmey D, Hessle L, Narisawa S, Johnson KA, Terkeltaub R, Millan JL. Concerted regulation of inorganic pyrophosphate and osteopontin by akp2, enpp 1, and ank: an integrated model of the pathogenesis of mineralization disorders. Am J Pathol. 2004;164:1199–209.
Henthorn PS, Raducha M, Fedde KN, Lafferty MA, Whyte MP. Different missense 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;89:9924–8.
Herasse M, Spentchian M, Taillandier A, Mornet E. Evidence of a founder effect for the tissue-nonspecific alkaline phosphatase (TNSALP) gene E174K mutation in hypophosphatasia patients. Eur J Hum Genet. 2002;10:666–8.
Herasse M, Spentchian M, Taillandier A, Keppler-Noreuil K, Fliorito AN, Bergoffen J, Wallerstein R, Muti C, Simon-Bouy B, Mornet E. Molecular study of three cases of odontohypophosphatasia resulting from heterozygosity for mutations in the tissue non-specific alkaline phosphatase gene. J Med Genet. 2003;40:605–9.
Hessle L, Johnson KA, Anderson HC, Narisawa S, Sali A, Goding JW, Terkeltaub R, Millan JL. Tissue-nonspecific alkaline phosphatase and plasma cell membrane glycoprotein-1 are central antagonistic regulators of bone mineralization. Proc Natl Acad Sci USA. 2002;99:9445–9.
Hu JC, Plaetke R, Mornet E, Zhang C, Sun X, Thomas HF, Simmer JP. Characterization of a family with dominant hypophosphatasia. Eur J Oral Sci. 2000;108:189–94.
Ishida Y, Komaru K, Ito M, Amaya Y, Kohno S, Oda K. Tissue-nonspecific alkaline phosphatase with an Asp(289)–>Val mutation fails to reach the cell surface and undergoes proteasome-mediated degradation. J Biochem (Tokyo). 2003;134:63–70.
Ishida Y, Komaru K, Oda K. Molecular characterization of tissue-nonspecific alkaline phosphatase with an Ala to Thr substitution at position 116 associated with dominantly inherited hypophosphatasia. Biochim Biophys Acta. 2011;1812:326–32.
Ito M, Amizuka N, Ozawa H, Oda K. Retention at the cis-Golgi and delayed degradation of tissue-non-specific alkaline phosphatase with an Asn153–>Asp substitution, a cause of perinatal hypophosphatasia. Biochem J. 2002;361:473–80.
Komaru K, Ishida Y, Amaya Y, Goseki-Sone M, Orimo H, Oda K. Novel aggregate formation of a frame-shift mutant protein of tissue-nonspecific alkaline phosphatase is ascribed to three cysteine residues in the C-terminal extension. Retarded secretion and proteasomal degradation. FEBS J. 2005;272:1704–17.
Lia-Baldini AS, Muller F, Taillandier A, Gibrat JF, Mouchard M, Robin B, Simon-Bouy B, Serre JL, Aylsworth AS, Bieth E, Delanote S, Freisinger P, Hu JC, Krohn HP, Nunes ME, Mornet E. A molecular approach to dominance in hypophosphatasia. Hum Genet. 2001;109:99–108.
Lia-Baldini AS, Brun-Heath I, Carrion C, Simon-Bouy B, Serre JL, Nunes ME, Mornet E. A new mechanism of dominance in hypophosphatasia: the mutated protein can disturb the cell localization of the wild-type protein. Hum Genet. 2008;123:429–32.
Matsuura S, Kishi F, Kajii T. Characterization of a 5′-flanking region of the human liver/bone/kidney alkaline phosphatase gene: two kinds of mRNA from a single gene. Biochem Biophys Res Commun. 1990;168:993–1000.
Michigami T, Uchihashi T, Suzuki A, Tachikawa K, Nakajima S, Ozono K. Common mutations F310L and T1559del in the tissue-nonspecific alkaline phosphatase gene are related to distinct phenotypes in Japanese patients with hypophosphatasia. Eur J Pediatr. 2005;164:277–82.
Millan J. Mammalian alkaline phosphatases: from biology to applications in medicine and biotechnology. Weinheim: Wiley-VCH Verlag GmbH; 2006.
Moore CA, Curry CJ, Henthorn PS, Smith JA, Smith JC, O’Lague P, Coburn SP, Weaver DD, Whyte MP. Mild autosomal dominant hypophosphatasia: in utero presentation in two families. Am J Med Genet. 1999;86:410–5.
Mornet E. Hypophosphatasia. Best Pract Res Clin Rheumatol. 2008;22:113–27.
Mornet E, Stura E, Lia-Baldini AS, Stigbrand T, Menez A, Le Du MH. Structural evidence for a functional role of human tissue nonspecific alkaline phosphatase in bone mineralization. J Biol Chem. 2001;276:31171–8.
Mornet E, Yvard A, Taillandier A, Fauvert D, Simon-Bouy B. A molecular-based estimation of the prevalence of hypophosphatasia in the European population. Ann Hum Genet. 2011;75:439–45.
Muller HL, Yamazaki M, Michigami T, Kageyama T, Schonau E, Schneider P, Ozono K. Asp361Val Mutant of alkaline phosphatase found in patients with dominantly inherited hypophosphatasia inhibits the activity of the wild-type enzyme. J Clin Endocrinol Metab. 2000;85:743–7.
Mumm S, Wenkert D, Zhang X, Geimer M, Zerega J, Whyte MP. Hypophosphatasia: the c.1133A>T, D378V transversion is the most common American TNSALP mutation. Paper presented at Fifth International Alkaline Phosphatase Symposium: “Understanding alkaline phosphatase function—Pathophysiology and treatment of Hypophosphatasia and other AP-related diseases” Huningue, France; 2007.
Nasu M, Ito M, Ishida Y, Numa N, Komaru K, Nomura S, Oda K. Aberrant interchain disulfide bridge of tissue-nonspecific alkaline phosphatase with an Arg433–>Cys substitution associated with severe hypophosphatasia. FEBS J. 2006;273:5612–24.
Numa N, Ishida Y, Nasu M, Sohda M, Misumi Y, Noda T, Oda K. Molecular basis of perinatal hypophosphatasia with tissue-nonspecific alkaline phosphatase bearing a conservative replacement of valine by alanine at position 406. Structural importance of the crown domain. FEBS J. 2008;275:2727–37.
Orimo H. The mechanism of mineralization and the role of alkaline phosphatase in health and disease. J Nihon Med Sch. 2010;77:4–12.
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.
Pauli RM, Modaff P, Sipes SL, Whyte MP. Mild hypophosphatasia mimicking severe osteogenesis imperfecta in utero: bent but not broken. Am J Med Genet. 1999;86:434–8.
Petkovic Ramadza D, Stipoljev F, Sarnavka V, Begovic D, Potocki K, Fumic K, Mornet E, Baric I. Hypophosphatasia: phenotypic variability and possible Croatian origin of the c.1402g>A mutation of TNSALP gene. Coll Antropol. 2009;33:1255–8.
Rodrigues TL, Foster BL, Silverio KG, Martins L, Casati MZ, Sallum EA, Somerman MJ, Nociti FH. Correction of hypophosphatasia (Hpp) associated mineralization deficiencies in vitro by phosphate/pyrophosphate modulation in periodontal ligament cells. J Periodontol. 2012;83:653–63.
Satou Y, Al-Shawafi HA, Sultana S, Makita S, Sohda M, Oda K. Disulfide bonds are critical for tissue-nonspecific alkaline phosphatase function revealed by analysis of mutant proteins bearing a C(201)-Y or C(489)-S substitution associated with severe hypophosphatasia. Biochim Biophys Acta. 2012;1822:581–8.
Shibata H, Fukushi M, Igarashi A, Misumi Y, Ikehara Y, Ohashi Y, Oda K. Defective intracellular transport of tissue-nonspecific alkaline phosphatase with an Ala162–>Thr mutation associated with lethal hypophosphatasia. J Biochem (Tokyo). 1998;123:968–77.
Spentchian M, Brun-Heath I, Taillandier A, Fauvert D, Serre JL, Simon-Bouy B, Carvalho F, Grochova I, Mehta SG, Muller G, Oberstein SL, Ogur G, Sharif S, Mornet E. Characterization of missense mutations and large deletions in the ALPL gene by sequencing and quantitative multiplex PCR of short fragments. Genet Test. 2006;10:252–7.
Studer M, Terao M, Gianni M, Garattini E. Characterization of a second promoter for the mouse liver/bone/kidney-type alkaline phosphatase gene: cell and tissue specific expression. Biochem Biophys Res Commun. 1991;179:1352–60.
Taillandier A, Sallinen SL, Brun-Heath I, De Mazancourt P, Serre JL, Mornet E. Childhood hypophosphatasia due to a de novo missense mutation in the tissue-nonspecific alkaline phosphatase gene. J Clin Endocrinol Metab. 2005;90:2436–9.
Takinami H, Goseki-Sone M, Watanabe H, Orimo H, Hamatani R, Fukushi-Irie M, Ishikawa I. The mutant (F310L and V365I) tissue-nonspecific alkaline phosphatase gene from hypophosphatasia. J Med Dent Sci. 2004;51:67–74.
Terao M, Studer M, Gianni M, Garattini E. Isolation and characterization of the mouse liver/bone/kidney-type alkaline phosphatase gene. Biochem J. 1990;268:641–8.
Toh Y, Yamamoto M, Endo H, Misumi Y, Ikehara Y. Isolation and characterization of a rat liver alkaline phosphatase gene. A single gene with two promoters. Eur J Biochem. 1989;182:231–7.
Watanabe A, Satoh S, Fujita A, Naing BT, Orimo H, Shimada T. Perinatal (lethal) type of hypophosphatasia resulting from paternal isodisomy of chromosome 1. Paper presented at 6th alkaline phosphatase and hypophosphatasia symposium, May 16–19. Huningue, France. 2012.
Watanabe H, Takinami H, Goseki-Sone M, Orimo H, Hamatani R, Ishikawa I. Characterization of the mutant (A115V) tissue-nonspecific alkaline phosphatase gene from adult-type hypophosphatasia. Biochem Biophys Res Commun. 2005;327:124–9.
Watanabe A, Karasugi T, Sawai H, Naing BT, Ikegawa S, Orimo H, Shimada T. 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. J Hum Genet. 2011;56:166–8.
Weiss MJ, Cole DE, Ray K, Whyte MP, Lafferty MA, Mulivor RA, Harris H. A missense mutation in the human liver/bone/kidney alkaline phosphatase gene causing a lethal form of hypophosphatasia. Proc Natl Acad Sci USA. 1988;85:7666–9.
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;263:12002–10.
Wenkert D, McAlister WH, Coburn S, Ryan L, Hersh JH, Zerega J, Mumm S, MP W. Non-lethal hypophosphatasia interpreted as severe skeletal dysplasia in utero. Paper presented at fifth international alkaline phosphatase symposium: “Understanding alkaline phosphatase function—Pathophysiology and treatment of Hypophosphatasia and other AP-related diseases” Huningue, France. 2007.
Wenkert D, McAlister WH, Coburn SP, Zerega JA, Ryan LM, Ericson KL, Hersh JH, Mumm S, Whyte MP. Hypophosphatasia: nonlethal disease despite skeletal presentation in utero (17 new cases and literature review). J Bone Miner Res. 2011;26:2389–98.
Whyte MP. Hypophosphatasia and the role of alkaline phosphatase in skeletal mineralization. Endocr Rev. 1994;15:439–61.
Whyte MP, Teitelbaum SL, Murphy WA, Bergfeld MA, Avioli LV. Adult hypophosphatasia. Clinical, laboratory, and genetic investigation of a large kindred with review of the literature. Medicine (Baltimore). 1979;58:329–47.
Whyte MP, Vrabel LA, Schwartz TD. Adult hypophosphatasia: generalized deficiency of alkaline phosphatase activity demonstrated with cultured skin fibroblasts. Trans Assoc Am Phys. 1982;95:253–63.
Whyte MP, Essmyer K, Geimer M, Mumm S. Homozygosity for TNSALP mutation 1348c>T (Arg433Cys) causes infantile hypophosphatasia manifesting transient disease correction and variably lethal outcome in a kindred of black ancestry. J Pediatr. 2006;148:753–8.
Yadav MC, Simao AM, Narisawa S, Huesa C, McKee MD, Farquharson C, Millan JL. Loss of skeletal mineralization by the simultaneous ablation of PHOSPHO1 and alkaline phosphatase function: a unified model of the mechanisms of initiation of skeletal calcification. J Bone Miner Res. 2011;26:286–97.
Zhang H, Ke YH, Wang C, Yue H, Hu WW, Gu JM, Zhang ZL. Identification of the mutations in the tissue-nonspecific alkaline phosphatase gene in two Chinese families with hypophosphatasia. Arch Med Res. 2012;43:21–30.
Zurutuza L, Muller F, Gibrat JF, Taillandier A, Simon-Bouy B, Serre JL, Mornet E. Correlations of genotype and phenotype in hypophosphatasia. Hum Mol Genet. 1999;8:1039–46.
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Mornet, E. Genetics of Hypophosphatasia. Clinic Rev Bone Miner Metab 11, 71–77 (2013). https://doi.org/10.1007/s12018-013-9140-7
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DOI: https://doi.org/10.1007/s12018-013-9140-7