Recently, we generated a mouse model of HVDRR without alopecia wherein a mutant human VDR lacking 1,25(OH)<sub>2</sub>D<sub>3</sub>-binding activity was expressed in the absence of endogenous mouse VDR.
Point mutation of rat Hr at conserved residues corresponding to natural mutants causing alopecia in mice (G985W and a C-terminal deletion DeltaAK) and in humans (P95S, C422Y, E611G, R640Q, C642G, N988S, D1030N, A1040T, V1074M, and V1154D), as well as alteration of residues in the C-terminal Jumonji C domain implicated in histone demethylation activity (C1025G/E1027G and H1143G) revealed that all Hr mutants retained VDR association, and that transrepressor activity was selectively abrogated in C642G, G985W, N988S, D1030N, V1074M, H1143G, and V1154D.
Vitamin D receptor knockout mice express a hair follicle cycling defect and a hyperproliferative phenotype resulting in disordered skin structure, epidermal thickening, and alopecia.
In particular, the missing protein part alters the VDR heterodimerization with the retinoid X receptor which has been correlated with the presence of alopecia.
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.
Hereditary 1, 25-dihydroxyvitamin D-resistant rickets (HVDRR), a rare recessive disease, is caused by mutation in the VDR gene encoding the vitamin D receptor leading to the resistance to vitamin D. We described a female toddler with initial presentation of leg tenderness and clinical features of HVDRR including severe rickets, hypocalcemia and hypophosphatemia without alopecia.
In contrast to the vitamin D receptor null mice that developed alopecia, however, the vitamin D receptor null/human vitamin D receptor mice displayed a normal hair coat, and their hair shaft and skin histology were indistinguishable from those of the wild-type mice.
Hereditary vitamin D-resistant rickets (HVDRR) is an autosomal recessive disorder characterized by the early onset of rickets and is caused by mutations in the vitamin D receptor (VDR) gene.Some HVDRR patients also have alopecia.
Overall, VDR KO mice showed several aging related phenotypes, including poorer survival, early alopecia, thickened skin, enlarged sebaceous glands and development of epidermal cysts.
Since the patient did not have alopecia or papular lesions of the skin generally found in patients with premature stop mutations this suggests that this distally truncated VDR can still regulate the hair cycle and epidermal differentiation possibly through its interactions with RXR and HR to suppress gene transactivation.
A novel mutation in helix 12 of the vitamin D receptor impairs coactivator interaction and causes hereditary 1,25-dihydroxyvitamin D-resistant rickets without alopecia.
Deficiency of vitamin D and mutations in the genes like VDR (type II genetic rickets) are known to cause rickets like lowered serum calcium, alopecia and impaired bone formation.
The data indicate that VDR mutations that cause defects in DNA binding, RXR heterodimerization or absence of the VDR cause alopecia while mutations that alter VDR affinity for 1,25(OH)(2)D(3) or disrupt coactivator interactions do not cause alopecia.
Atrichia with papular lesions (APL) and hereditary vitamin D-resistant rickets have a similar congenital hair loss disorder caused by mutations in hairless (HR) and vitamin D receptor (VDR) genes, respectively.