Division of Endocrinology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
Department of Internal Medicine and Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee.
J Clin Endocrinol Metab. 2018 Jun 1;103(6):2234-2243. doi: 10.1210/jc.2017-02676.
Mutations in alkaline phosphatase (AlkP), liver/bone/kidney (ALPL), which encodes tissue-nonspecific isozyme AlkP, cause hypophosphatasia (HPP). HPP is suspected by a low-serum AlkP. We hypothesized that some patients with bone or dental disease have undiagnosed HPP, caused by ALPL variants.
Our objective was to discover the prevalence of these gene variants in the Vanderbilt University DNA Biobank (BioVU) and to assess phenotypic associations.
We identified subjects in BioVU, a repository of DNA, that had at least one of three known, rare HPP disease-causing variants in ALPL: rs199669988, rs121918007, and/or rs121918002. To evaluate for phenotypic associations, we conducted a sequential phenome-wide association study of ALPL variants and then performed a de-identified manual record review to refine the phenotype.
Out of 25,822 genotyped individuals, we identified 52 women and 53 men with HPP disease-causing variants in ALPL, 7/1000. None had a clinical diagnosis of HPP. For patients with ALPL variants, the average serum AlkP levels were in the lower range of normal or lower. Forty percent of men and 62% of women had documented bone and/or dental disease, compatible with the diagnosis of HPP. Forty percent of the female patients had ovarian pathology or other gynecological abnormalities compared with 15% seen in controls.
Variants in the ALPL gene cause bone and dental disease in patients with and without the standard biomarker, low plasma AlkP. ALPL gene variants are more prevalent than currently reported and underdiagnosed. Gynecologic disease appears to be associated with HPP-causing variants in ALPL.
碱性磷酸酶（AlkP）的突变，该基因编码组织非特异性同工酶 AlkP，导致低磷酸血症（HPP）。低血清 AlkP 怀疑患有 HPP。我们假设一些患有骨骼或牙齿疾病的患者存在未确诊的 HPP，这是由 ALPL 变体引起的。
我们的目的是在范德比尔特大学 DNA 生物库（BioVU）中发现这些基因变异体的流行率，并评估表型相关性。
我们在 BioVU 中鉴定了至少携带三种已知的 ALPL 罕见 HPP 致病变异体之一的个体：rs199669988、rs121918007 和/或 rs121918002。为了评估表型相关性，我们对 ALPL 变体进行了顺序表型全基因组关联研究，然后进行了匿名手动记录审查以完善表型。
在 25822 名基因分型个体中，我们鉴定出 52 名女性和 53 名男性患有 ALPL 的 HPP 致病变异体，发病率为 7/1000。没有人被诊断患有 HPP。对于患有 ALPL 变体的患者，平均血清 AlkP 水平处于正常或更低范围。40%的男性和 62%的女性有记录的骨骼和/或牙齿疾病，与 HPP 的诊断相符。与对照组的 15%相比，40%的女性患者有卵巢病理学或其他妇科异常。
ALPL 基因的变异导致有或没有标准生物标志物（低血浆 AlkP）的患者出现骨骼和牙齿疾病。ALPL 基因变异比目前报告的更常见且诊断不足。妇科疾病似乎与 ALPL 引起的 HPP 变异有关。
