Skip to main content
Top
Published in: Journal of Bone and Mineral Metabolism 5/2019

01-09-2019 | Arthritis | Original Article

ALPL mutations in adults with rheumatologic disorders and low serum alkaline phosphatase activity

Authors: Frank Rauch, Ghalib Bardai, Cheryl Rockman-Greenberg

Published in: Journal of Bone and Mineral Metabolism | Issue 5/2019

Login to get access

Abstract

Tissue-nonspecific alkaline phosphatase (ALP), encoded by ALPL, is important for bone homeostasis and interacts with collagen type I. In the present study, we sequenced ALPL and a panel of collagen type I-related genes in 24 adults (age 22–80 years; 20 female) with persistently low serum ALP (< 40 U/L) and a range of rheumatologic symptoms. We found heterozygous pathogenic or likely pathogenic variants in ALPL in 14 (58%) of these individuals. In addition, 7 study participants had potentially damaging heterozygous variants of uncertain significance in genes related to collagen type I. Patients who were positive for ALPL variants had similar age and serum ALP levels to patients in whom no ALPL variants were detected, but had higher serum pyridoxal-5-phosphate concentrations (median 214 nmol/L vs. 64 nmol/L; p = 0.02; U test). In summary, heterozygous ALPL variants are frequent in individuals with rheumatologic symptoms and low ALP serum activity. It is possible that variants in genes that are involved in collagen type I production have a modifying effect on the clinical consequences of such ALPL variants.
Literature
1.
go back to reference Whyte MP (2016) Hypophosphatasia: aetiology, nosology, pathogenesis, diagnosis and treatment. Nat Rev Endocrinol 12:233–246CrossRefPubMed Whyte MP (2016) Hypophosphatasia: aetiology, nosology, pathogenesis, diagnosis and treatment. Nat Rev Endocrinol 12:233–246CrossRefPubMed
3.
go back to reference Greenberg CR, Taylor CL, Haworth JC, Seargeant LE, Philipps S, Triggs-Raine B, Chodirker BN (1993) A homoallelic Gly317 → Asp mutation in ALPL causes the perinatal (lethal) form of hypophosphatasia in Canadian mennonites. Genomics 17:215–217CrossRefPubMed Greenberg CR, Taylor CL, Haworth JC, Seargeant LE, Philipps S, Triggs-Raine B, Chodirker BN (1993) A homoallelic Gly317 → Asp mutation in ALPL causes the perinatal (lethal) form of hypophosphatasia in Canadian mennonites. Genomics 17:215–217CrossRefPubMed
4.
go back to reference Chodirker BN, Roy D, Greenberg CR, Cheang M, Evans JA, Reed MH (1991) Computer assisted analysis of hand radiographs in infantile hypophosphatasia carriers. Pediatr Radiol 21:216–219CrossRefPubMed Chodirker BN, Roy D, Greenberg CR, Cheang M, Evans JA, Reed MH (1991) Computer assisted analysis of hand radiographs in infantile hypophosphatasia carriers. Pediatr Radiol 21:216–219CrossRefPubMed
5.
go back to reference Chodirker BN, Coburn SP, Seargeant LE, Whyte MP, Greenberg CR (1990) Increased plasma pyridoxal-5′-phosphate levels before and after pyridoxine loading in carriers of perinatal/infantile hypophosphatasia. J Inherit Metab Dis 13:891–896CrossRefPubMed Chodirker BN, Coburn SP, Seargeant LE, Whyte MP, Greenberg CR (1990) Increased plasma pyridoxal-5′-phosphate levels before and after pyridoxine loading in carriers of perinatal/infantile hypophosphatasia. J Inherit Metab Dis 13:891–896CrossRefPubMed
6.
go back to reference Chodirker BN, Evans JA, Seargeant LE, Cheang MS, Greenberg CR (1990) Hyperphosphatemia in infantile hypophosphatasia: implications for carrier diagnosis and screening. Am J Hum Genet 46:280–285PubMedPubMedCentral Chodirker BN, Evans JA, Seargeant LE, Cheang MS, Greenberg CR (1990) Hyperphosphatemia in infantile hypophosphatasia: implications for carrier diagnosis and screening. Am J Hum Genet 46:280–285PubMedPubMedCentral
7.
go back to reference Fauvert D, Brun-Heath I, Lia-Baldini AS, Bellazi L, Taillandier A, Serre JL, de Mazancourt P, Mornet E (2009) 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 10:51CrossRefPubMedPubMedCentral Fauvert D, Brun-Heath I, Lia-Baldini AS, Bellazi L, Taillandier A, Serre JL, de Mazancourt P, Mornet E (2009) 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 10:51CrossRefPubMedPubMedCentral
8.
go back to reference McKiernan FE, Berg RL, Fuehrer J (2014) Clinical and radiographic findings in adults with persistent hypophosphatasemia. J Bone Miner Res 29:1651–1660CrossRefPubMed McKiernan FE, Berg RL, Fuehrer J (2014) Clinical and radiographic findings in adults with persistent hypophosphatasemia. J Bone Miner Res 29:1651–1660CrossRefPubMed
9.
go back to reference McKiernan FE, Dong J, Berg RL, Scotty E, Mundt P, Larson L, Rai I (2017) Mutational and biochemical findings in adults with persistent hypophosphatasemia. Osteoporos Int 28:2343–2348CrossRefPubMed McKiernan FE, Dong J, Berg RL, Scotty E, Mundt P, Larson L, Rai I (2017) Mutational and biochemical findings in adults with persistent hypophosphatasemia. Osteoporos Int 28:2343–2348CrossRefPubMed
10.
go back to reference Nielson CM, Zmuda JM, Carlos AS, Wagoner WJ, Larson EA, Orwoll ES, Klein RF (2012) Rare coding variants in ALPL are associated with low serum alkaline phosphatase and low bone mineral density. J Bone Miner Res 27:93–103CrossRefPubMed Nielson CM, Zmuda JM, Carlos AS, Wagoner WJ, Larson EA, Orwoll ES, Klein RF (2012) Rare coding variants in ALPL are associated with low serum alkaline phosphatase and low bone mineral density. J Bone Miner Res 27:93–103CrossRefPubMed
11.
go back to reference Tenorio J, Alvarez I, Riancho-Zarrabeitia L, Martos-Moreno GA, Mandrile G et al (2017) Molecular and clinical analysis of ALPL in a cohort of patients with suspicion of Hypophosphatasia. Am J Med Genet A 173:601–610CrossRefPubMed Tenorio J, Alvarez I, Riancho-Zarrabeitia L, Martos-Moreno GA, Mandrile G et al (2017) Molecular and clinical analysis of ALPL in a cohort of patients with suspicion of Hypophosphatasia. Am J Med Genet A 173:601–610CrossRefPubMed
12.
go back to reference Linder CH, Enander K, Magnusson P (2016) Glycation contributes to interaction between human bone alkaline phosphatase and collagen type I. Calcif Tissue Int 98:284–293CrossRef Linder CH, Enander K, Magnusson P (2016) Glycation contributes to interaction between human bone alkaline phosphatase and collagen type I. Calcif Tissue Int 98:284–293CrossRef
13.
go back to reference Pokidysheva E, Boudko S, Vranka J, Zientek K, Maddox K, Moser M, Fassler R, Ware J, Bachinger HP (2014) Biological role of prolyl 3-hydroxylation in type IV collagen. Proc Natl Acad Sci USA 111:161–166CrossRefPubMed Pokidysheva E, Boudko S, Vranka J, Zientek K, Maddox K, Moser M, Fassler R, Ware J, Bachinger HP (2014) Biological role of prolyl 3-hydroxylation in type IV collagen. Proc Natl Acad Sci USA 111:161–166CrossRefPubMed
14.
go back to reference Cabral WA, Perdivara I, Weis M, Terajima M, Blissett AR, Chang W, Perosky JE, Makareeva EN, Mertz EL, Leikin S, Tomer KB, Kozloff KM, Eyre DR, Yamauchi M, Marini JC (2014) Abnormal type I collagen post-translational modification and crosslinking in a cyclophilin B KO mouse model of recessive osteogenesis imperfecta. PLoS Genet 10:e1004465CrossRefPubMedPubMedCentral Cabral WA, Perdivara I, Weis M, Terajima M, Blissett AR, Chang W, Perosky JE, Makareeva EN, Mertz EL, Leikin S, Tomer KB, Kozloff KM, Eyre DR, Yamauchi M, Marini JC (2014) Abnormal type I collagen post-translational modification and crosslinking in a cyclophilin B KO mouse model of recessive osteogenesis imperfecta. PLoS Genet 10:e1004465CrossRefPubMedPubMedCentral
15.
go back to reference Brenner RE, Vetter U, Nerlich A, Worsdorfer O, Teller WM, Muller PK (1990) Altered collagen metabolism in osteogenesis imperfecta fibroblasts: a study on 33 patients with diverse forms. Eur J Clin Investig 20:8–14CrossRef Brenner RE, Vetter U, Nerlich A, Worsdorfer O, Teller WM, Muller PK (1990) Altered collagen metabolism in osteogenesis imperfecta fibroblasts: a study on 33 patients with diverse forms. Eur J Clin Investig 20:8–14CrossRef
16.
go back to reference Bardai G, Moffatt P, Glorieux FH, Rauch F (2016) DNA sequence analysis in 598 individuals with a clinical diagnosis of osteogenesis imperfecta: diagnostic yield and mutation spectrum. Osteoporos Int 27:3607–3613CrossRefPubMed Bardai G, Moffatt P, Glorieux FH, Rauch F (2016) DNA sequence analysis in 598 individuals with a clinical diagnosis of osteogenesis imperfecta: diagnostic yield and mutation spectrum. Osteoporos Int 27:3607–3613CrossRefPubMed
17.
go back to reference Rauch F, Lalic L, Glorieux FH, Moffatt P, Roughley P (2014) Targeted sequencing of a pediatric metabolic bone gene panel using a desktop semiconductor next-generation sequencer. Calcif Tissue Int 95:323–331CrossRefPubMed Rauch F, Lalic L, Glorieux FH, Moffatt P, Roughley P (2014) Targeted sequencing of a pediatric metabolic bone gene panel using a desktop semiconductor next-generation sequencer. Calcif Tissue Int 95:323–331CrossRefPubMed
18.
go back to reference Kumar P, Henikoff S, Ng PC (2009) Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 4:1073–1081CrossRefPubMed Kumar P, Henikoff S, Ng PC (2009) Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 4:1073–1081CrossRefPubMed
19.
go back to reference Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR (2010) A method and server for predicting damaging missense mutations. Nat Methods 7:248–249CrossRefPubMedPubMedCentral Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR (2010) A method and server for predicting damaging missense mutations. Nat Methods 7:248–249CrossRefPubMedPubMedCentral
20.
21.
22.
go back to reference Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17:405–424CrossRefPubMedPubMedCentral Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17:405–424CrossRefPubMedPubMedCentral
23.
go back to reference Mumm S, Jones J, Finnegan P, Henthorn PS, Podgornik MN, Whyte MP (2002) Denaturing gradient gel electrophoresis analysis of the tissue nonspecific alkaline phosphatase isoenzyme gene in hypophosphatasia. Mol Genet Metab 75:143–153CrossRefPubMed Mumm S, Jones J, Finnegan P, Henthorn PS, Podgornik MN, Whyte MP (2002) Denaturing gradient gel electrophoresis analysis of the tissue nonspecific alkaline phosphatase isoenzyme gene in hypophosphatasia. Mol Genet Metab 75:143–153CrossRefPubMed
24.
go back to reference Henthorn PS, Raducha M, Fedde KN, Lafferty MA, Whyte MP (1992) 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 89:9924–9928CrossRefPubMedPubMedCentral Henthorn PS, Raducha M, Fedde KN, Lafferty MA, Whyte MP (1992) 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 89:9924–9928CrossRefPubMedPubMedCentral
25.
go back to reference Schmidt T, Mussawy H, Rolvien T, Hawellek T, Hubert J, Ruther W, Amling M, Barvencik F (2017) Clinical, radiographic and biochemical characteristics of adult hypophosphatasia. Osteoporos Int 28:2653–2662CrossRefPubMed Schmidt T, Mussawy H, Rolvien T, Hawellek T, Hubert J, Ruther W, Amling M, Barvencik F (2017) Clinical, radiographic and biochemical characteristics of adult hypophosphatasia. Osteoporos Int 28:2653–2662CrossRefPubMed
26.
go back to reference Taillandier A, Domingues C, Dufour A, Debiais F, Guggenbuhl P et al (2018) Genetic analysis of adults heterozygous for ALPL mutations. J Bone Miner Metab 36:723–733CrossRefPubMed Taillandier A, Domingues C, Dufour A, Debiais F, Guggenbuhl P et al (2018) Genetic analysis of adults heterozygous for ALPL mutations. J Bone Miner Metab 36:723–733CrossRefPubMed
27.
go back to reference Silvent J, Gasse B, Mornet E, Sire JY (2014) Molecular evolution of the tissue-nonspecific alkaline phosphatase allows prediction and validation of missense mutations responsible for hypophosphatasia. J Biol Chem 289:24168–24179CrossRefPubMedPubMedCentral Silvent J, Gasse B, Mornet E, Sire JY (2014) Molecular evolution of the tissue-nonspecific alkaline phosphatase allows prediction and validation of missense mutations responsible for hypophosphatasia. J Biol Chem 289:24168–24179CrossRefPubMedPubMedCentral
28.
go back to reference Fukushi-Irie M, Ito M, Amaya Y, Amizuka N, Ozawa H, Omura S, Ikehara Y, Oda K (2000) Possible interference between tissue-non-specific alkaline phosphatase with an Arg54 → Cys substitution and a counterpart with an Asp277 → Ala substitution found in a compound heterozygote associated with severe hypophosphatasia. Biochem J 348:633–642CrossRefPubMedPubMedCentral Fukushi-Irie M, Ito M, Amaya Y, Amizuka N, Ozawa H, Omura S, Ikehara Y, Oda K (2000) Possible interference between tissue-non-specific alkaline phosphatase with an Arg54 → Cys substitution and a counterpart with an Asp277 → Ala substitution found in a compound heterozygote associated with severe hypophosphatasia. Biochem J 348:633–642CrossRefPubMedPubMedCentral
29.
go back to reference Riancho-Zarrabeitia L, Garcia-Unzueta M, Tenorio JA, Gomez-Gerique JA, Ruiz Perez VL, Heath KE, Lapunzina P, Riancho JA (2016) Clinical, biochemical and genetic spectrum of low alkaline phosphatase levels in adults. Eur J Intern Med 29:40–45CrossRefPubMed Riancho-Zarrabeitia L, Garcia-Unzueta M, Tenorio JA, Gomez-Gerique JA, Ruiz Perez VL, Heath KE, Lapunzina P, Riancho JA (2016) Clinical, biochemical and genetic spectrum of low alkaline phosphatase levels in adults. Eur J Intern Med 29:40–45CrossRefPubMed
Metadata
Title
ALPL mutations in adults with rheumatologic disorders and low serum alkaline phosphatase activity
Authors
Frank Rauch
Ghalib Bardai
Cheryl Rockman-Greenberg
Publication date
01-09-2019
Publisher
Springer Japan
Published in
Journal of Bone and Mineral Metabolism / Issue 5/2019
Print ISSN: 0914-8779
Electronic ISSN: 1435-5604
DOI
https://doi.org/10.1007/s00774-019-00991-4

Other articles of this Issue 5/2019

Journal of Bone and Mineral Metabolism 5/2019 Go to the issue
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.