ALPL mutations in adults with rheumatologic disorders and low serum alkaline phosphatase activity
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.
KeywordsALPL Arthritis Collagen type I Hypophosphatasia Rheumatology
The authors greatly appreciate the assistance of Amy Yakimoski (study coordinator) and Erika Bloomfield (administrative support). We respectfully acknowledge the physicians who referred their patients and the patients who participated in the study.
FR wrote the manuscript; GB performed sequence analyses; CRG conceptualized the project, contributed patient information, finalized the report and accepts responsibility for the integrity of the data analysis. All authors have read and approved of the final version of the manuscript.
This study was supported by the Shriners of North America (FR) and Health Research Foundation of Innovative Medicines Canada (CRG).
Compliance with ethical standards
Conflict of interest
Frank Rauch has received consultancy fees from Alexion Inc. Ghalib Bardai declares no conflict of interest. Cheryl Rockman-Greenberg was principal investigator of Alexion-sponsored clinical trials of enzyme replacement therapy for the treatment of HPP, is a member of the Scientific Advisory Board of the Alexion-sponsored International HPP Registry and has received honoraria for Alexion-sponsored webinar and symposia.
- 6.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 46:280–285Google Scholar
- 7.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 10:51CrossRefGoogle Scholar
- 14.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:e1004465CrossRefGoogle Scholar
- 22.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 17:405–424CrossRefGoogle Scholar
- 28.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 348:633–642CrossRefGoogle Scholar