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Journal of Bone and Mineral Metabolism

, Volume 36, Issue 6, pp 723–733 | Cite as

Genetic analysis of adults heterozygous for ALPL mutations

  • Agnès Taillandier
  • Christelle Domingues
  • Annika Dufour
  • Françoise Debiais
  • Pascal Guggenbuhl
  • Christian Roux
  • Catherine Cormier
  • Bernard Cortet
  • Valérie Porquet-Bordes
  • Fabienne Coury
  • David Geneviève
  • Jean Chiesa
  • Thierry Colin
  • Elaine Fletcher
  • Agnès Guichet
  • Rose-Marie Javier
  • Michel Laroche
  • Michael Laurent
  • Ekkehart Lausch
  • Bruno LeHeup
  • Cédric Lukas
  • Georg Schwabe
  • Ineke van der Burgt
  • Christine Muti
  • Brigitte Simon-Bouy
  • Etienne Mornet
Original Article

Abstract

Hypophosphatasia (HPP) is a rare inherited metabolic bone disease due to a deficiency of the tissue nonspecific alkaline phosphatase isoenzyme (TNSALP) encoded by the ALPL gene. Patients have consistently low serum alkaline phosphatase (AP), so that this parameter is a good hallmark of the disease. Adult HPP is heterogeneous, and some patients present only mild nonpathognomonic symptoms which are also common in the general population such as joint pain, osteomalacia and osteopenia, chondrocalcinosis, arthropathy and musculoskeletal pain. Adult HPP may be recessively or dominantly inherited; the latter case is assumed to be due to the dominant negative effect (DNE) of missense mutations derived from the functional homodimeric structure of TNSALP. However, there is no biological argument excluding the possibility of other causes of dominant HPP. Rheumatologists and endocrinologists are increasingly solicited for patients with low AP and nonpathognomonic symptoms of HPP. Many of these patients are heterozygous for an ALPL mutation and a challenging question is to determine if these symptoms, which are also common in the general population, are attributable to their heterozygous ALPL mutation or not. In an attempt to address this question, we reviewed a cohort of 61 adult patients heterozygous for an ALPL mutation. Mutations were distinguished according to their statistical likelihood to show a DNE. One-half of the patients carried mutations predicted with no DNE and were slightly less severely affected by the age of onset, serum AP activity and history of fractures. We hypothesized that these mutations result in another mechanism of dominance or are recessive alleles. To identify other genetic factors that could trigger the disease phenotype in heterozygotes for potential recessive mutations, we examined the next-generation sequencing results of 32 of these patients for a panel of 12 genes involved in the differential diagnosis of HPP or candidate modifier genes of HPP. The heterozygous genotype G/C of the COL1A2 coding SNP rs42524 c.1645C > G (p.Pro549Ala) was associated with the severity of the phenotype in patients carrying mutations with a DNE whereas the homozygous genotype G/G was over-represented in patients carrying mutations without a DNE, suggesting a possible role of this variant in the disease phenotype. These preliminary results support COL1A2 as a modifier gene of HPP and suggest that a significant proportion of adult heterozygotes for ALPL mutations may have unspecific symptoms not attributable to their heterozygosity.

Keywords

Adult hypophosphatasia Dominant inheritance Dominant negative effect Modifier gene 

Abbreviations

ALPL

Alkaline phosphatase liver-type

AP

Alkaline phosphatase

DNE

Dominant negative effect

HPP

Hypophosphatasia

NGS

Next-generation sequencing

PB

Prenatal benign

TNSALP

Tissue nonspecific alkaline phosphatase

Notes

Acknowledgements

We thank Carole Charle, Nicole Lavaud and Fabienne Vallon for technical assistance, and the Centre Hospitalier de Versailles for contributing to a version of the manuscript.

Compliance with ethical standards

Conflicts of interest statement

EM received honoraria from Alexion. CR received honoraria from Alexion and research grants from Ultragenix

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Copyright information

© The Japanese Society for Bone and Mineral Research and Springer Japan KK, part of Springer Nature 2017

Authors and Affiliations

  • Agnès Taillandier
    • 1
  • Christelle Domingues
    • 1
  • Annika Dufour
    • 1
  • Françoise Debiais
    • 2
  • Pascal Guggenbuhl
    • 3
  • Christian Roux
    • 4
  • Catherine Cormier
    • 4
  • Bernard Cortet
    • 5
  • Valérie Porquet-Bordes
    • 6
  • Fabienne Coury
    • 7
  • David Geneviève
    • 8
  • Jean Chiesa
    • 9
  • Thierry Colin
    • 10
  • Elaine Fletcher
    • 11
  • Agnès Guichet
    • 12
  • Rose-Marie Javier
    • 13
  • Michel Laroche
    • 14
  • Michael Laurent
    • 15
  • Ekkehart Lausch
    • 16
  • Bruno LeHeup
    • 17
  • Cédric Lukas
    • 18
  • Georg Schwabe
    • 19
  • Ineke van der Burgt
    • 20
  • Christine Muti
    • 1
  • Brigitte Simon-Bouy
    • 1
  • Etienne Mornet
    • 1
  1. 1.Unité de Génétique Constitutionnelle, Service de BiologieCentre Hospitalier de VersaillesLe ChesnayFrance
  2. 2.Service de RhumatologieCHU de PoitiersPoitiers cedexFrance
  3. 3.Service de Rhumatologie, hôpital SudCHU de RennesRennes cedex 2France
  4. 4.Service de RhumatologieHôpital CochinParisFrance
  5. 5.Service de RhumatologieCHRU de LilleLilleFrance
  6. 6.Endocrinologie, Maladies Osseuses, Génétique et Gynécologie MédicaleHôpital des Enfants, CHU de ToulouseToulouse Cedex 9France
  7. 7.Service de RhumatologieCHU Lyon, Centre Hospitalier Lyon-SudPierre BéniteFrance
  8. 8.Service de Génétique Clinique, Département de Génétique Médicale, maladies rares et médecine personnalisée, CHU Montpellieruniversité Montpellier, unité Inserm U1183MontpellierFrance
  9. 9.Department of GeneticsUniversity HospitalNîmesFrance
  10. 10.Service de RhumatologieCH Public du CotentinCherbourgFrance
  11. 11.Clinical Genetics, Molecular Medicine CenterWestern General HospitalEdinburghUK
  12. 12.Département Biochimie et génétiqueCHU d’AngersAngersFrance
  13. 13.Service de RhumatologieCHU de StrasbourgStrasbourgFrance
  14. 14.Service de RhumatologieHôpital Pierre-Paul RiquetToulouseFrance
  15. 15.Center for Metabolic Bone DiseasesUniversity Hospitals LeuvenLeuvenBelgium
  16. 16.Universitätsklinikum Freiburg, Zentrum für Kinder- und JugendmedizinFreiburgGermany
  17. 17.Médecine infantile 3CHU NancyVandoeuvreFrance
  18. 18.Département de RhumatologieCHRU MontpellierMontpellierFrance
  19. 19.Otto-Heubner-Centrum für Kinder und Jugendmedizin Allgemeine Päediatrie CharitéBerlinGermany
  20. 20.Department of Human GeneticsRadboudumcNijmegenNetherlands

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