Shriners Hospital for Children, McGill University, 1003 Decarie, Montreal, QC, H4A 0A9, Canada.
Children's Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, MB, Canada.
J Bone Miner Metab. 2019 Sep;37(5):893-899. doi: 10.1007/s00774-019-00991-4. Epub 2019 Feb 4.
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.
组织非特异性碱性磷酸酶（ALP）由 ALPL 编码，对于骨稳态很重要，并与 I 型胶原相互作用。在本研究中，我们对 24 名持续低血清 ALP（<40 U/L）和多种风湿症状的成年人（年龄 22-80 岁；20 名女性）的 ALPL 和一组 I 型胶原相关基因进行了测序。我们在其中 14 名（58%）个体中发现了 ALPL 的杂合致病性或可能致病性变异。此外，7 名研究参与者在与 I 型胶原相关的基因中存在具有不确定意义的潜在破坏性杂合变异。ALPL 变异阳性的患者与未检测到 ALPL 变异的患者的年龄和血清 ALP 水平相似，但血清吡哆醛-5-磷酸浓度更高（中位数 214 nmol/L 比 64 nmol/L；p=0.02；U 检验）。总之，杂合 ALPL 变异在具有风湿症状和低血清 ALP 活性的个体中很常见。参与 I 型胶原产生的基因中的变异可能对这些 ALPL 变异的临床后果具有修饰作用。
