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

  • Frank RauchEmail author
  • Ghalib Bardai
  • Cheryl Rockman-Greenberg
Original Article


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.


ALPL 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.

Web resources

The Tissue Nonspecific Alkaline Phosphatase Gene Mutations Database: Exome Aggregation Consortium (ExAC) Browser: Online Mendelian Inheritance in Man (OMIM),

Author contributions

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.


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Copyright information

© Springer Japan KK, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Shriners Hospital for ChildrenMcGill UniversityMontrealCanada
  2. 2.Children’s Hospital Research Institute of ManitobaUniversity of ManitobaWinnipegCanada

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