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Mutations in the vitamin D receptor gene in four patients with hereditary 1,25-dihydroxyvitamin D-resistant rickets
Luciana Cosentino de Macedo1, Fernanda Caroline Soardi, Nayla Ananias
1Center for Investigation in Pediatrics, Campinas, SP, Brazil.
Abstract:
Mutations in the vitamin D receptor (VDR) are associated to the hereditary 1,25-dihydroxivitamin D-resistant rickets. The objectives of this work are: search for mutations in the VDR and analyze their functional consequences in four Brazilian children presented with rickets and alopecia. The coding region of the VDR was amplified by PCR e direct sequenced. We identified three mutations: two patients had the same mutation in exon 7 at aminoacid position 259 (p.Q259E); one patient had a mutation in exon 8 at codon 319 (p.G319V) and another one had a mutation in exon 3 leading to a truncated protein at position 73 (p.R73X). Functional studies of the mutant receptors of fibroblast primary culture, from patients' skin biopsy treated with increasing doses of 1,25(OH)2 vitamin D showed that VDR mutants were unable to be properly activated and presented a reduction in 24-hydroxylase expression level.
Insights
Genetic mutations in the vitamin D receptor (VDR) cause hereditary rickets. This study identified novel VDR mutations in Brazilian children, revealing impaired receptor function and reduced 24-hydroxylase expression.
Area of Science:
- Genetics
- Molecular Biology
- Endocrinology
Background:
- Hereditary 1,25-dihydroxyvitamin D-resistant rickets is linked to vitamin D receptor (VDR) gene mutations.
- Early diagnosis and understanding of VDR mutations are crucial for managing this rare condition.
Observation:
- Four Brazilian children presented with rickets and alopecia, suggesting a potential VDR-related disorder.
- Genetic sequencing identified three distinct mutations in the VDR gene among the patients.
Findings:
- Two patients shared a p.Q259E mutation in exon 7.
- One patient had a p.G319V mutation in exon 8, and another presented a p.R73X mutation in exon 3, leading to a truncated protein.
- Functional analysis demonstrated that these VDR mutants were improperly activated and showed reduced 24-hydroxylase expression.
Implications:
- These findings expand the spectrum of known VDR mutations associated with hereditary vitamin D-resistant rickets.
- Understanding the functional consequences of these mutations aids in diagnosing and potentially managing affected individuals.
- This research highlights the importance of genetic analysis in pediatric rickets cases with unusual presentations like alopecia.
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