title: Two new unrelated cases of hereditary 1,25-dihydroxyvitamin D-resistant rickets with alopecia resulting from the same novel nonsense mutation in the vitamin D receptor gene.
abstract: 1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) an important regulator of bone homeostasis, mediates its actions by binding to the vitamin D receptor (VDR), a nuclear transcription factor. Mutations in the VDR cause the rare genetic disease hereditary vitamin D resistant rickets (HVDRR). In this study, we examined two unrelated young female patients who exhibited severe early onset rickets, hypocalcemia, and hypophosphatemia. Both patients had partial alopecia but with different unusual patterns of scant hair. Sequencing of the VDR gene showed that both patients harbored the same unique nonsense mutation that resulted in a premature stop codon (R50X). Skin fibroblasts from patient #1 were devoid of VDR protein and 1,25(OH)2D3 treatment of these cells failed to induce CYP24A1 gene expression, a marker of 1,25(OH)2D3 action. In conclusion, we identified a novel nonsense mutation in the VDR gene in two patients with HVDRR and alopecia. The mutation truncates the VDR protein and causes 1,25(OH)2D3 resistance.
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Nikta
authors.initials: N
authors.lastname: Forghani
authors.forename: Catherine
authors.initials: C
authors.lastname: Lum
authors.forename: Sowmya
authors.initials: S
authors.lastname: Krishnan
authors.forename: Jining
authors.initials: J
authors.lastname: Wang
authors.forename: Darrel M
authors.initials: DM
authors.lastname: Wilson
authors.forename: Piers R
authors.initials: PR
authors.lastname: Blackett
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Malloy
authors.forename: David
authors.initials: D
authors.lastname: Feldman
mesh_terms: D000505:Alopecia / Q000235:genetics*; D015415:Biomarkers / Q000378:metabolism; D002675:Child, Preschool; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D004351:Drug Resistance; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D018167:Receptors, Calcitriol / Q000235:genetics* / Q000378:metabolism; D012279:Rickets / Q000235:genetics*; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013250:Steroid Hydroxylases / Q000096:biosynthesis; D014807:Vitamin D / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D065668:Vitamin D3 24-Hydroxylase
chemical_list: D015415:Biomarkers; D018389:Codon, Nonsense; D018167:Receptors, Calcitriol; D014807:Vitamin D; C097949:1,25-dihydroxyvitamin D; D013250:Steroid Hydroxylases; C585549:CYP24A1 protein, human; D065668:Vitamin D3 24-Hydroxylase