Loss-of-Function Mutations in the ALPL Gene Presenting with Adult Onset Osteoporosis and Low Serum Concentrations of Total Alkaline Phosphatase.
ALKALINE PHOSPHATASE
ALPL VARIANTS
BISPHOSPHONATES
HYPOPHOSPHATASIA
OSTEOPOROSIS
Journal
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
ISSN: 1523-4681
Titre abrégé: J Bone Miner Res
Pays: United States
ID NLM: 8610640
Informations de publication
Date de publication:
04 2020
04 2020
Historique:
received:
23
07
2019
revised:
11
11
2019
accepted:
23
11
2019
pubmed:
4
12
2019
medline:
29
7
2021
entrez:
4
12
2019
Statut:
ppublish
Résumé
Hypophosphatasia (HPP) is a rare inherited disorder characterized by rickets and low circulating concentrations of total alkaline phosphatase (ALP) caused by mutations in ALPL. Severe HPP presents in childhood but milder forms can present in adulthood. The prevalence and clinical features of adult HPP are poorly defined. The aim of this study was to evaluate the prevalence and clinical significance of low serum total alkaline phosphatase (ALP) levels in a clinic-based population of adult osteoporotic patients. We searched for patients with low ALP in a cohort of 3285 patients referred to an osteoporosis clinic over a 10-year period and performed mutation screening of ALPL in those with low ALP (≤40 U/L) on two or more occasions. These individuals were matched with four clinic controls with a normal ALP. We also evaluated the prevalence of low ALP and ALPL mutations in 639 individuals from the general population from the same region. We identified 16/3285 (0.49%) clinic patients with low ALP and 14 (87.5%) had potentially pathogenic variants in ALPL. Eight of these individuals were heterozygous for mutations previously described in HPP and 2 were heterozygous for novel mutations (p.Arg301Trp and p.Tyr101X). These mutations were not found in clinic controls or in the general population. Eight patients with low ALP, including 4 with ALPL mutations, were treated with bisphosphonates for an average of 6.5 years. In these individuals, the rate of fractures during treatment was comparable to that in normal ALP clinic controls who were treated with bisphosphonates. We conclude that heterozygous loss-of-function mutations in ALPL are common in osteoporosis patients with low ALP. Further studies are required to determine how best these individuals should be treated. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.
Identifiants
pubmed: 31793067
doi: 10.1002/jbmr.3928
pmc: PMC9328664
doi:
Substances chimiques
ALPL protein, human
EC 3.1.3.1
Alkaline Phosphatase
EC 3.1.3.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
657-661Subventions
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/F019394/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0700704
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/K026992/1
Pays : United Kingdom
Informations de copyright
© 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.
Références
Hum Mol Genet. 1999 Jun;8(6):1039-46
pubmed: 10332035
J Bone Miner Res. 2012 May;27(5):987-94
pubmed: 22322541
Eur J Hum Genet. 1998 Jul-Aug;6(4):308-14
pubmed: 9781036
J Biol Chem. 2014 Aug 29;289(35):24168-79
pubmed: 25023282
Mol Genet Metab. 2002 Feb;75(2):143-53
pubmed: 11855933
J Bone Miner Res. 2012 Jan;27(1):93-103
pubmed: 21956185
Osteoporos Int. 2017 Aug;28(8):2343-2348
pubmed: 28401263
Genet Med. 2015 May;17(5):405-24
pubmed: 25741868
Proc Natl Acad Sci U S A. 1988 Oct;85(20):7666-9
pubmed: 3174660
Bone. 2013 Oct;56(2):390-7
pubmed: 23791648
Eur J Intern Med. 2016 Apr;29:40-5
pubmed: 26783040
Eur J Hum Genet. 2011 Mar;19(3):
pubmed: 20978533
J Clin Endocrinol Metab. 2010 Mar;95(3):1007-12
pubmed: 20089612
Osteoporos Int. 2015 Dec;26(12):2743-57
pubmed: 26245849
Clin Cases Miner Bone Metab. 2009 Sep;6(3):266-9
pubmed: 22461258
J Bone Miner Res. 2009 Jun;24(6):1132-4
pubmed: 19113923
Endocr Rev. 1994 Aug;15(4):439-61
pubmed: 7988481
Pract Lab Med. 2017 Jul 05;9:1-11
pubmed: 29034300
BMC Med Genet. 2009 Jun 06;10:51
pubmed: 19500388
Ann N Y Acad Sci. 2010 Mar;1192:190-200
pubmed: 20392236
Joint Bone Spine. 2016 May;83(3):346-8
pubmed: 26992955
Ann Hum Genet. 2011 May;75(3):439-45
pubmed: 21488855
Bone. 2013 May;54(1):21-7
pubmed: 23352924
Chin J Dent Res. 2012;15(2):99-104
pubmed: 23509830
J Bone Miner Metab. 2019 Sep;37(5):893-899
pubmed: 30719581
Int J Epidemiol. 2018 Aug 1;47(4):1042-1042r
pubmed: 29546429
Metabolism. 2018 May;82:142-155
pubmed: 28939177