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.