title: Hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR) caused by aVDRmutation: A novel mechanism of dominant inheritance.
abstract: Hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR) is caused by mutations in theVDRgene, and its inheritance is autosomal recessive. In this report, we aimed to confirm whether HVDRR is occasionally inherited as a dominant trait. An 18-month-old Japanese boy was evaluated for short stature and bowlegs. His father had been treated for rickets during childhood, and his paternal grandfather had bowlegs. We diagnosed him with HVDRR based on laboratory data and radiographic evidence of rickets. Sequence analyses ofVDRwere performed, and the functional consequences of the detected mutations were analyzed for transcriptional activity, ligand binding, and interaction with the retinoid X receptor, cofactors, and the vitamin D response element (VDRE). A novel mutation (Q400LfsX7) and a reported variant (R370H) were identified in the patient. Heterozygous Q400LfsX7 was detected in his father, and heterozygous R370H was detected in his healthy mother. Functional studies revealed that the transcriptional activity of Q400LfsX7-VDR was markedly disturbed. The mutant had a dominant-negative effect on wild-type-VDR, and the ligand binding affinity of Q400LfsX7-VDR was completely impaired. Interestingly, Q400LfsX7-VDR had a strong interaction with corepressor NCoR and could interact with VDRE without the ligand. R370H-VDR was functionally similar to wild-type-VDR. In conclusion, we found a dominant-negative mutant of VDR causing dominantly inherited HVDRR through a constitutive corepressor interaction, a mechanism similar to that in dominantly inherited thyroid hormone receptor mutations. Our report together with a reported pedigree suggested a distinct inheritance of HVDRR and enriched our understanding of VDR abnormalities.
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Isojima
authors.affiliation: Division of Biochemistry, Department of Biochemical Sciences, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan.
authors.forename: Michiyasu
authors.initials: M
authors.lastname: Ishizawa
authors.affiliation: Department of Pediatrics, School of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Yoshimura
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Mayuko
authors.initials: M
authors.lastname: Tamura
authors.affiliation: Department of Pediatrics, School of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Hirose
authors.affiliation: Division of Biochemistry, Department of Biochemical Sciences, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Makishima
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Kitanaka
keywords: Dominant negative effect; Hereditary vitamin D resistant rickets; Vitamin D receptor