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Hypophosphatasia: a genetic-based nosology and new insights in genotype-phenotype correlation

European Journal of Human Genetics volume 29, pages 289–299 (2021)Cite this article

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Abstract

Hypophosphatasia (HPP) is caused by pathogenic variants in the ALPL gene. There is a large continuum in the severity, ranging from a lethal perinatal form to dental issues. We analyzed a cohort of 424 HPP patients from European geographic origin or ancestry. Using 3D modeling and results of functional tests we classified ALPL pathogenic variants according to their dominant negative effect (DNE) and their severity. The cohort was described by the genotypes resulting from alleles s (severe recessive), Sd (severe dominant), and m (moderate). Many recurrent variants showed a regional anchor pointing out founder effects rather than multiple mutational events. Homozygosity was an aggravating factor of the severity and moderate alleles were rare both in number and frequency. Pathogenic variants with DNE were found in both recessive and dominant HPP. Sixty percent of the adults tested were heterozygous for a variant showing no DNE, suggesting another mechanism of dominance like haploinsufficiency. Adults with dominant HPP without DNE were found statistically less severely affected than adults with DNE variants. Adults with dominant HPP without DNE represent a new clinical entity mostly diagnosed from 2010s, characterized by nonspecific signs of HPP and low alkaline phosphatase, and for which a high prevalence is expected. In conclusion, the genetic composition of our cohort suggests a nosology with 3 clinical forms: severe HPP is recessive and rare, moderate HPP is recessive or dominant and more common, and mild HPP, characterized by low alkaline phosphatase and unspecific clinical signs, is dominantly inherited and very common.

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Fig. 1: Distribution of recurrent ALPL variants according to the geographic origin of patients.
Fig. 2: Composition of genotypes in HPP phenotypes.
Fig. 3: Comparison of the distributions of genotypes in moderate HPP with our previous study (Fauvert et al. 2009).
Fig. 4: Comparison of moderate and mild genotypes for 3 markers of HPP severity.
Fig. 5: The 3 forms of HPP according to genetic data.

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References

  1. Mornet E. Hypophosphatasia. Orphanet J Rare Dis. 2007;2:40.

    PubMed  PubMed Central  Google Scholar 

  2. Mornet E, Nunes ME. Hypophosphatasia. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, et al., editors. GeneReviews((R)). Seattle (WA); University of Washington, 1993.

  3. Whyte MP. Hypophosphatasia: an overview For 2017. Bone. 2017;102:15–25.

    CAS  PubMed  Google Scholar 

  4. 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.

    PubMed  Google Scholar 

  5. Fraser D. Hypophosphatasia. Am J Med. 1957;22:730–46.

    CAS  PubMed  Google Scholar 

  6. Mornet E. Hypophosphatasia: the mutations in the tissue-nonspecific alkaline phosphatase gene. Hum Mutat. 2000;15:309–15.

    CAS  PubMed  Google Scholar 

  7. Mornet E. Genetics of hypophosphatasia. Arch Pediatr. 2017;24:5S51–5S6.

    CAS  PubMed  Google Scholar 

  8. Mornet E. Hypophosphatasia. Metabolism 2018;82:142–55.

    CAS  PubMed  Google Scholar 

  9. Linglart A, Biosse-Duplan M. Hypophosphatasia. Curr Osteoporos Rep. 2016;14:95–105.

    PubMed  Google Scholar 

  10. Whyte MP, Zhang F, Wenkert D, McAlister WH, Mack KE, Benigno MC, et al. Hypophosphatasia: validation and expansion of the clinical nosology for children from 25 years experience with 173 pediatric patients. Bone. 2015;75:229–39.

    CAS  PubMed  Google Scholar 

  11. Taillandier A, Domingues C, Dufour A, Debiais F, Guggenbuhl P, Roux C, et al. Genetic analysis of adults heterozygous for ALPL mutations. J Bone Min Metab. 2018;36:723–33.

    CAS  Google Scholar 

  12. Whyte MP, Greenberg CR, Salman NJ, Bober MB, McAlister WH, Wenkert D, et al. Enzyme-replacement therapy in life-threatening hypophosphatasia. N Engl J Med. 2012;366:904–13.

    CAS  PubMed  Google Scholar 

  13. Whyte MP. Atypical femoral fractures, bisphosphonates, and adult hypophosphatasia. J Bone Min Res. 2009;24:1132–4.

    Google Scholar 

  14. Sutton RA, Mumm S, Coburn SP, Ericson KL, Whyte MP. “Atypical femoral fractures” during bisphosphonate exposure in adult hypophosphatasia. J Bone Min Res. 2012;27:987–94.

    CAS  Google Scholar 

  15. Deeb AA, Bruce SN, Morris AA, Cheetham TD. Infantile hypophosphatasia: disappointing results of treatment. Acta Paediatr. 2000;89:730–3.

    CAS  PubMed  Google Scholar 

  16. Baujat G, Michot C, Le Quan Sang KH, Cormier-Daire V. Perinatal and infantile hypophosphatasia: clinical features and treatment. Arch Pediatr. 2017;24:5S61–5S5.

    CAS  PubMed  Google Scholar 

  17. Linglart A, Salles JP. Hypophosphatasia: the contribution of imaging. Arch Pediatr. 2017;24:5S74–5S9.

    CAS  PubMed  Google Scholar 

  18. Bloch-Zupan A. Hypophosphatasia: diagnosis and clinical signs - a dental surgeon perspective. Int J Paediatr Dent. 2016;26:426–38.

    PubMed  Google Scholar 

  19. Briot K, Roux C. Adult hypophosphatasia. Curr Opin Rheumatol. 2016;28:448–51.

    PubMed  Google Scholar 

  20. Dahir KM, Tilden DR, Warner JL, Bastarache L, Smith DK, Gifford A, et al. Rare variants in the gene ALPL that cause hypophosphatasia are strongly associated with ovarian and uterine disorders. J Clin Endocrinol Metab. 2018;103:2234–43.

    PubMed  PubMed Central  Google Scholar 

  21. Zurutuza L, Muller F, Gibrat JF, Taillandier A, Simon-Bouy B, Serre JL, et al. Correlations of genotype and phenotype in hypophosphatasia. Hum Mol Genet. 1999;8:1039–46.

    CAS  PubMed  Google Scholar 

  22. Yang H, Wang L, Geng J, Yu T, Yao RE, Shen Y, et al. Characterization of six missense mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) gene in Chinese children with hypophosphatasia. Cell Physiol Biochem. 2013;32:635–44.

    CAS  PubMed  Google Scholar 

  23. Takinami H, Goseki-Sone M, Watanabe H, Orimo H, Hamatani R, Fukushi-Irie M, et al. The mutant (F310L and V365I) tissue-nonspecific alkaline phosphatase gene from hypophosphatasia. J Med Dent Sci. 2004;51:67–74.

    PubMed  Google Scholar 

  24. 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.

    CAS  PubMed  Google Scholar 

  25. Taillandier A, Lia-Baldini AS, Mouchard M, Robin B, Muller F, Simon-Bouy B, et al. Twelve novel mutations in the tissue-nonspecific alkaline phosphatase gene (ALPL) in patients with various forms of hypophosphatasia. Hum Mutat. 2001;18:83–4.

    CAS  PubMed  Google Scholar 

  26. Lia-Baldini AS, Muller F, Taillandier A, Gibrat JF, Mouchard M, Robin B, et al. A molecular approach to dominance in hypophosphatasia. Hum Genet. 2001;109:99–108.

    CAS  PubMed  Google Scholar 

  27. Fukushi-Irie M, Ito M, Amaya Y, Amizuka N, Ozawa H, Omura S, et al. 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;348:633–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Fauvert D, Brun-Heath I, Lia-Baldini AS, Bellazi L, Taillandier A, Serre JL, et al. 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.

    PubMed  PubMed Central  Google Scholar 

  29. Orimo H, Girschick HJ, Goseki-Sone M, Ito M, Oda K, Shimada T. Mutational analysis and functional correlation with phenotype in German patients with childhood-type hypophosphatasia. J Bone Min Res. 2001;16:2313–9.

    CAS  Google Scholar 

  30. 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.

    CAS  PubMed  Google Scholar 

  31. Brun-Heath I, Taillandier A, Serre JL, Mornet E. Characterization of 11 novel mutations in the tissue non-specific alkaline phosphatase gene responsible for hypophosphatasia and genotype-phenotype correlations. Mol Genet Metab. 2005;84:273–7.

    CAS  PubMed  Google Scholar 

  32. Mentrup B, Girschick H, Jakob F, Hofmann C. A homozygous intronic branch-point deletion in the ALPL gene causes infantile hypophosphatasia. Bone. 2017;94:75–83.

    CAS  PubMed  Google Scholar 

  33. Spentchian M, Merrien Y, Herasse M, Dobbie Z, Glaser D, Holder SE, et al. Severe hypophosphatasia: characterization of fifteen novel mutations in the ALPL gene. Hum Mutat. 2003;22:105–6.

    CAS  PubMed  Google Scholar 

  34. Del Angel G, Reynders J, Negron C, Steinbrecher T, Mornet E. Large-scale in vitro functional testing and novel variant scoring via protein modeling provide insights into alkaline phosphatase activity in hypophosphatasia. Hum Mutat. 2020;41:1250–62.

  35. Taillandier A, Domingues C, De Cazanove C, Porquet-Bordes V, Monnot S, Kiffer-Moreira T, et al. Molecular diagnosis of hypophosphatasia and differential diagnosis by targeted Next Generation Sequencing. Mol Genet Metab. 2015;116:215–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Derouault P, Parfait B, Moulinas R, Barrot CC, Sturtz F, Merillou S, et al. ‘COV’COP’ allows to detect CNVs responsible for inherited diseases among amplicons sequencing data. Bioinformatics. 2017;33:1586–8.

    CAS  PubMed  Google Scholar 

  37. den Dunnen JT, Dalgleish R, Maglott DR, Hart RK, Greenblatt MS, McGowan-Jordan J, et al. HGVS Recommendations for the Description of Sequence Variants: 2016 Update. Hum Mutat. 2016;37:564–9.

    Google Scholar 

  38. Mornet E, Stura E, Lia-Baldini AS, Stigbrand T, Menez A, Le DuMH. Structural evidence for a functional role of human tissue nonspecific alkaline phosphatase in bone mineralization. J Biol Chem. 2001;276:31171–8.

    CAS  PubMed  Google Scholar 

  39. Zhang H, Ke YH, Wang C, Yue H, Hu WW, Gu JM, et al. Identification of the mutations in the tissue-nonspecific alkaline phosphatase gene in two Chinese families with hypophosphatasia. Arch Med Res. 2012;43:21–30.

    PubMed  Google Scholar 

  40. 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.

    CAS  PubMed  Google Scholar 

  41. Orton NC, Innes AM, Chudley AE, Bech-Hansen NT. Unique disease heritage of the Dutch-German Mennonite population. Am J Med Genet A. 2008;146A:1072–87.

    PubMed  Google Scholar 

  42. Wenkert D, McAlister WH, Coburn SP, Zerega JA, Ryan LM, Ericson KL, et al. Hypophosphatasia: nonlethal disease despite skeletal presentation in utero (17 new cases and literature review). J Bone Min Res. 2011;26:2389–98.

    CAS  Google Scholar 

  43. Riancho-Zarrabeitia L, Garcia-Unzueta M, Tenorio JA, Gomez-Gerique JA, Ruiz Perez VL, Heath KE, et al. Clinical, biochemical and genetic spectrum of low alkaline phosphatase levels in adults. Eur J Intern Med. 2016;29:40–5.

    CAS  PubMed  Google Scholar 

  44. Mornet E. Molecular Genetics of Hypophosphatasia and Phenotype-Genotype Correlations. Subcell Biochem. 2015;76:25–43.

    CAS  PubMed  Google Scholar 

  45. Tenorio J, Alvarez I, Riancho-Zarrabeitia L, Martos-Moreno GA, Mandrile G, de la Flor Crespo M, et al. Molecular and clinical analysis of ALPL in a cohort of patients with suspicion of Hypophosphatasia. Am J Med Genet A. 2017;173:601–10.

    CAS  PubMed  Google Scholar 

  46. Avigad S, Kleiman S, Weinstein M, Cohen BE, Schwartz G, Woo SL, et al. Compound heterozygosity in nonphenylketonuria hyperphenylalanemia: the contribution of mutations for classical phenylketonuria. Am J Hum Genet. 1991;49:393–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Allen KJ, Gurrin LC, Constantine CC, Osborne NJ, Delatycki MB, Nicoll AJ, et al. Iron-overload-related disease in HFE hereditary hemochromatosis. N Engl J Med. 2008;358:221–30.

    CAS  PubMed  Google Scholar 

  48. Ohno K, Suzuki K. Multiple abnormal beta-hexosaminidase alpha chain mRNAs in a compound-heterozygous Ashkenazi Jewish patient with Tay-Sachs disease. J Biol Chem. 1988;263:18563–7.

    CAS  PubMed  Google Scholar 

  49. Mornet E, Crete P, Kuttenn F, Raux-Demay MC, Boue J, White PC, et al. Distribution of deletions and seven point mutations on CYP21B genes in three clinical forms of steroid 21-hydroxylase deficiency. Am J Hum Genet. 1991;48:79–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Komaru K, Ishida-Okumura Y, Numa-Kinjoh N, Hasegawa T, Oda K. Molecular and cellular basis of hypophosphatasia. J Oral Biosci. 2019;61:141–8.

    PubMed  Google Scholar 

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Acknowledgements

The authors would like to thank the clinicians from 32 countries who gave us the opportunity to test their patients.

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  1. Unité de Génétique Constitutionnelle, Service de Biologie, Centre Hospitalier de Versailles, 78150, Le Chesnay, France

    Etienne Mornet, Agnès Taillandier, Christelle Domingues, Annika Dufour, Emmanuelle Benaloun, Nicole Lavaud, Fabienne Wallon, Nathalie Rousseau, Carole Charle, Mihelaiti Guberto, Christine Muti & Brigitte Simon-Bouy

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Correspondence to Etienne Mornet.

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EM received honoraria from Alexion Pharmaceutical for expertize and presentations.

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Mornet, E., Taillandier, A., Domingues, C. et al. Hypophosphatasia: a genetic-based nosology and new insights in genotype-phenotype correlation. Eur J Hum Genet 29, 289–299 (2021). https://doi.org/10.1038/s41431-020-00732-6

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