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J Bone Miner Metab. 2018 Nov;36(6):723-733. doi: 10.1007/s00774-017-0888-6. Epub 2017 Dec 13.

Genetic analysis of adults heterozygous for ALPL mutations.

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Unité de Génétique Constitutionnelle, Service de Biologie, Centre Hospitalier de Versailles, 177 rue de Versailles, 78150, Le Chesnay, France.
Service de Rhumatologie, CHU de Poitiers, 86021, Poitiers cedex, France.
Service de Rhumatologie, hôpital Sud, CHU de Rennes, 16, boulevard de Bulgarie, BP90347, 35203, Rennes cedex 2, France.
Service de Rhumatologie, Hôpital Cochin, Paris, France.
Service de Rhumatologie, CHRU de Lille, Lille, France.
Endocrinologie, Maladies Osseuses, Génétique et Gynécologie Médicale, Hôpital des Enfants, CHU de Toulouse, Toulouse Cedex 9, France.
Service de Rhumatologie, CHU Lyon, Centre Hospitalier Lyon-Sud, Pierre Bénite, France.
Service de Génétique Clinique, Département de Génétique Médicale, maladies rares et médecine personnalisée, CHU Montpellier, université Montpellier, unité Inserm U1183, Montpellier, France.
Department of Genetics, University Hospital, Nîmes, France.
Service de Rhumatologie, CH Public du Cotentin, Cherbourg, France.
Clinical Genetics, Molecular Medicine Center, Western General Hospital, Edinburgh, UK.
Département Biochimie et génétique, CHU d'Angers, Angers, France.
Service de Rhumatologie, CHU de Strasbourg, Strasbourg, France.
Service de Rhumatologie, Hôpital Pierre-Paul Riquet, Toulouse, France.
Center for Metabolic Bone Diseases, University Hospitals Leuven, Leuven, Belgium.
Universitätsklinikum Freiburg, Zentrum für Kinder- und Jugendmedizin, Freiburg, Germany.
Médecine infantile 3, CHU Nancy, Vandoeuvre, France.
Département de Rhumatologie, CHRU Montpellier, Montpellier, France.
Otto-Heubner-Centrum für Kinder und Jugendmedizin Allgemeine Päediatrie Charité, Campus Virchow Klinikum Augustenburger Platz 1, Berlin, Germany.
Department of Human Genetics, Radboudumc, Nijmegen, Netherlands.
Unité de Génétique Constitutionnelle, Service de Biologie, Centre Hospitalier de Versailles, 177 rue de Versailles, 78150, Le Chesnay, France.


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.


Adult hypophosphatasia; Dominant inheritance; Dominant negative effect; Modifier gene

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