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Hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR) caused by a VDR
mutation: A novel mechanism of dominant inheritance
#MMPMID28377956
Isojima T
; Ishizawa M
; Yoshimura K
; Tamura M
; Hirose S
; Makishima M
; Kitanaka S
Bone Rep
2015[Jun]; 2
(?): 68-73
PMID28377956
show ga
Hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR) is caused by
mutations in the VDR gene, 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 of VDR were 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.
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