Absence of Mutation in Coding Regions of CYP2R1 Gene in Apparent Autosomal Dominant Vitamin D 25-Hydroxylase Deficiency Rickets

Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
The Journal of Clinical Endocrinology and Metabolism (Impact Factor: 6.21). 03/2012; 97(5):E796-801. DOI: 10.1210/jc.2011-2716
Source: PubMed


This is a case report of a proband and his family presenting with apparent autosomal dominant 25-hydroxylase enzyme deficiency and bone disease.
The aim of the study was to present an alternative pattern of transmission of 25-hydroxylase enzyme deficiency other than autosomal recessive.
We diagnosed our patient with 25-hydroxylase enzyme deficiency, treated him, and examined his DNA for mutations. Evaluations at other institutions, clinical history of all family members, and laboratory testing for the mother, aunt, and maternal grandmother were reviewed. Family consent was obtained for all testing and record review.
The patient was evaluated serially in an outpatient clinic. Routine laboratory studies for proband, mother, and maternal grandmother were obtained. Genetic testing was performed in another institution after obtaining family consent. Interventions: No research intervention was performed.
Routine clinical care included an evaluation of growth pattern. Laboratory evaluation included 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D [1,25(OH)(2)D], alkaline phosphatase, intact PTH, phosphate, calcium, ionized calcium, and magnesium levels.
Results showed consistently low 25-hydroxylase enzyme function. They also showed elevated alkaline phosphatase and PTH, as well as decreased phosphate and calcium. These abnormalities were corrected with 1,25(OH)(2)D therapy.
We conclude that 25-hydroxylase enzyme deficiency can be inherited in an autosomal dominant pattern. This case raises a question about different tributary pathways affecting the function of the 25-hydroxylase enzyme. Physiological dosing of 1,25(OH)(2)D was sufficient for treatment. There were no detectable mutations in any of the coding regions of the gene or its intronic junctions.

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Available from: Susan R Rose, Nov 16, 2015
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    ABSTRACT: Vitamin D deficiency has been recognized as a major public health issue worldwide. Recent studies have indicated that genetic factors might play an important role in determining serum 25-hydroxy vitamin D [25(OH)D] levels in Caucasians and African Americans. However, the genes that contribute to the variation in serum 25(OH)D levels in Chinese are unknown. In this study, we screened 15 key genes within the vitamin D metabolic pathway using 96 single-nucleotide polymorphism (SNP) markers in a group of 2,897 unrelated healthy Chinese subjects. Significant confounding factors that may influence the variability in serum 25(OH)D levels were used as covariates for association analyses. An association test for quantitative traits was performed to evaluate the association between candidate genes and serum 25(OH)D levels. In the present study, variants and/or haplotypes in GC, CYP2R1 and DHCR7/NADSYN1 were identified as being associated with 25(OH)D levels. Participants with 3 or 4 risk alleles of the two variants (GC-rs4588 and CYP2R1-rs10766197) had an increased chance of presenting with a 25(OH)D concentration lower than 20 ng/mL (2.121, 1.586-2.836, p = 6.1 × 10(-8) ) compared with those lacking the risk alleles. Each additional copy of a risk allele was significantly associated with a 0.12-fold decrease in the log-25(OH)D concentration (p = 3.7 × 10(-12) ). Haplotype TGA of GC rs705117-rs2282679-rs1491710, haplotype GAGTAC of GC rs842999-rs705120-rs222040-rs4588-rs7041-rs10488854, haplotype CA of GC rs1155563-rs222029, and haplotype AAGA of CYP2R1 rs7936142-rs12794714-rs2060793-rs16930609 were genetic risk factors toward a lower 25(OH)D concentration. In contrary, haplotype TGGGCCC of DHCR7/NADSYN1 rs1790349-rs7122671-rs1790329-rs11606033-rs2276360-rs1629220-rs2282618 were genetic protective factors. The results suggest that the GC, CYP2R1 and DHCR7/NADSYN1 genes might contribute to variability in the serum 25(OH)D levels in a healthy Chinese population in Shanghai. These markers could be used as tools in Mendelian randomization analyses of vitamin D, and they could potentially be drug targets in the Chinese population in Shanghai. © 2013 American Society for Bone and Mineral Research.
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