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Mol Genet Metab. 2014 Jan;111(1):33-40. doi: 10.1016/j.ymgme.2013.10.014. Epub 2013 Nov 4.

Vitamin D receptor mutations in patients with hereditary 1,25-dihydroxyvitamin D-resistant rickets.

Author information

1
Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
2
Department of Pediatric Nephrology, Clinic for Children's Diseases, University Children's Hospital, Medical School of Skopje, Skopje, Macedonia.
3
Department of Endocrinology, Children's Hospital of Michigan, Detroit, MI 48201, USA.
4
Pediatric Endocrinology, Trakya University, Faculty of Medicine, Edirne, Turkey.
5
Department of Pediatrics, University Children's Medical Institute, National University Hospital, Singapore.

Abstract

CONTEXT:

Hereditary vitamin D resistant rickets (HVDRR), also known as vitamin D-dependent rickets type II, is an autosomal recessive disorder characterized by the early onset of rickets with hypocalcemia, secondary hyperparathyroidism and hypophosphatemia and is caused by mutations in the vitamin D receptor (VDR) gene. The human gene encoding the VDR is located on chromosome 12 and comprises eight coding exons and seven introns.

OBJECTIVES, PATIENTS, AND METHODS:

We analyzed the VDR gene of 5 previously unreported patients, two from Singapore and one each from Macedonia (former Yugoslav Republic), Saudi Arabia and Turkey. Each patient had clinical and radiographic features of rickets, hypocalcemia, and the 4 cases that had the measurement showed elevated serum concentrations of 1,25-dihydroxyvitamin D (1,25(OH)(2)D). Mutations were re-created in the WT VDR cDNA and examined for 1,25(OH)(2)D(3)-mediated transactivation in COS-7 monkey kidney cells.

RESULTS:

Direct sequencing identified four novel mutations and two previously described mutations in the VDR gene. The novel mutations included a missense mutation in exon 3 causing the amino acid change C60W; a missense mutation in exon 4 causing the amino acid change D144N; a missense mutation in exon 7 causing the amino acid change N276Y; and a 2bp deletion in exon 3 5'-splice site (IVS3∆+4-5) leading to a premature stop.

CONCLUSIONS:

These 4 unique mutations add to the previous 45 mutations identified in the VDR gene in patients with HVDRR.

KEYWORDS:

HVDRR; Hypocalcemia; Mutations; Rickets; Vitamin D; Vitamin D receptor

PMID:
24246681
PMCID:
PMC3933290
DOI:
10.1016/j.ymgme.2013.10.014
[Indexed for MEDLINE]
Free PMC Article

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