Journal article
Rare Variants in the Gene ALPL That Cause Hypophosphatasia Are Strongly Associated with Ovarian and Uterine Disorders
The journal of clinical endocrinology and metabolism, Vol.103(6), pp.2234-2243
06/2018
DOI: 10.1210/jc.2017-02676
PMCID: PMC6456921
PMID: 29659871
Abstract
Context: 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.
Objective: Our objective was to discover the prevalence of these gene variants in the Vanderbilt University DNA Biobank (BioVU) and to assess phenotypic associations.
Design: 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.
Results: 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.
Conclusions: 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.
Details
- Title: Subtitle
- Rare Variants in the Gene ALPL That Cause Hypophosphatasia Are Strongly Associated with Ovarian and Uterine Disorders
- Creators
- Kathryn M. Dahir - Vanderbilt University Medical CenterDaniel R. Tilden - Vanderbilt University Medical CenterJeremy L. Warner - Vanderbilt University Medical CenterLisa Bastarache - Vanderbilt University Medical CenterDerek K. Smith - Vanderbilt University Medical CenterAliya Gifford - Vanderbilt University Medical CenterAndrea H. Ramirez - Vanderbilt University Medical CenterJill S. Simmons - Vanderbilt University Medical CenterMargo M. Black - Vanderbilt University Medical CenterJohn H. Newman - Vanderbilt University Medical CenterJosh C. Denny - Vanderbilt University Medical Center
- Resource Type
- Journal article
- Publication Details
- The journal of clinical endocrinology and metabolism, Vol.103(6), pp.2234-2243
- DOI
- 10.1210/jc.2017-02676
- PMID
- 29659871
- PMCID
- PMC6456921
- NLM abbreviation
- J Clin Endocrinol Metab
- ISSN
- 0021-972X
- eISSN
- 1945-7197
- Number of pages
- 10
- Grant note
- R01 LM010685 / National Institutes of Health (100000002) S10RR025141 / National Institutes of Health (100000002) UL1TR000445 / National Center for Advancing Translational Sciences (http://data.elsevier.com/vocabulary/SciValFunders/100006108) R01 LM010685; S10RR025141 / National Institutes of Health (http://data.elsevier.com/vocabulary/SciValFunders/100000002) Vanderbilt University Medical Center (http://data.elsevier.com/vocabulary/SciValFunders/100013017)
- Language
- English
- Date published
- 06/2018
- Academic Unit
- Preventive and Community Dentistry; Dental Research
- Record Identifier
- 9984966849502771
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