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Mutations in the vitamin D receptor gene in three kindreds associated with hereditary vitamin D resistant rickets

F J Cockerill1, N S Hawa, N Yousaf

  • 1Department of Medicine, University College London Medical School, Middlesex Hospital, United Kingdom.

The Journal of Clinical Endocrinology and Metabolism
|September 1, 1997
PubMed

Insights

Genetic mutations in the vitamin D receptor (VDR) gene cause hereditary vitamin D resistant rickets. Our study identified specific VDR mutations, including STOP codons and deletions, explaining this rare genetic disorder.

Area of Science:

  • Genetics
  • Endocrinology
  • Molecular Biology

Background:

  • Hereditary vitamin D resistant rickets is linked to mutations in the vitamin D receptor (VDR) gene.
  • These mutations affect critical domains of the VDR, including DNA and ligand binding sites.

Purpose of the Study:

  • To identify and characterize the specific mutations in the VDR gene responsible for hereditary vitamin D resistant rickets in three families.
  • To confirm the functional impact of these identified mutations on VDR activity.

Main Methods:

  • Cultured skin fibroblasts were used to assess resistance to 1,25(OH)2D3 and 24-hydroxylase activity.
  • DNA sequencing of the VDR gene coding region was performed to detect mutations.
  • Transactivation studies and gel shift assays were employed to evaluate the functional consequences of the mutations.

Main Results:

  • Patients 1 and 2 had undetectable 1,25(OH)2D3 binding to VDR due to a STOP codon mutation and a frameshift deletion, respectively.
  • Patients 3 and 4, siblings, exhibited a point mutation in the VDR hormone-binding domain, affecting protein interactions.
  • Functional studies confirmed that all identified mutations impaired VDR activity.

Conclusions:

  • Specific mutations in the vitamin D receptor (VDR) gene, including premature termination and hormone-binding domain alterations, cause hereditary vitamin D resistant rickets.
  • These genetic defects disrupt VDR function, leading to impaired response to vitamin D and the associated clinical condition.

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