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Impaired Vitamin D Signaling in T Cells From a Family With Hereditary Vitamin D Resistant Rickets.

ABSTRACT: The active form of vitamin D, 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃), mediates its immunomodulatory effects by binding to the vitamin D receptor (VDR). Here, we describe a new point mutation in the DNA-binding domain of the VDR and its consequences for 1,25(OH)₂D₃ signaling in T cells from heterozygous and homozygous carriers of the mutation. The mutation did not affect the overall structure or the ability of the VDR to bind 1,25(OH)₂D₃ and the retinoid X receptor. However, the subcellular localization of the VDR was strongly affected and the transcriptional activity was abolished by the mutation. In heterozygous carriers of the mutation, 1,25(OH)₂D₃-induced gene regulation was reduced by ~ 50% indicating that the expression level of wild-type VDR determines 1,25(OH)₂D₃ responsiveness in T cells. We show that vitamin D-mediated suppression of vitamin A-induced gene regulation depends on an intact ability of the VDR to bind DNA. Furthermore, we demonstrate that vitamin A inhibits 1,25(OH)₂D₃-induced translocation of the VDR to the nucleus and 1,25(OH)₂D₃-induced up-regulation of CYP24A1. Taken together, this study unravels novel aspects of vitamin D signaling and function of the VDR in human T cells.

SUBMITTER: Al-Jaberi FAH

PROVIDER: S-EPMC8170129 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Impaired Vitamin D Signaling in T Cells From a Family With Hereditary Vitamin D Resistant Rickets.

Al-Jaberi Fatima A H FAH Kongsbak-Wismann Martin M Aguayo-Orozco Alejandro A Krogh Nicolai N Buus Terkild B TB Lopez Daniel V DV Rode Anna K O AKO Gravesen Eva E Olgaard Klaus K Brunak Søren S Woetmann Anders A Ødum Niels N Bonefeld Charlotte M CM Geisler Carsten C

Frontiers in immunology 20210519

The active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), mediates its immunomodulatory effects by binding to the vitamin D receptor (VDR). Here, we describe a new point mutation in the DNA-binding domain of the VDR and its consequences for 1,25(OH)2D3 signaling in T cells from heterozygous and homozygous carriers of the mutation. The mutation did not affect the overall structure or the ability of the VDR to bind 1,25(OH)2</ ...[more]

PMID: 34093587

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Project description:BackgroundHereditary hypophosphatemia rickets with hypercalciuria (HHRH) is a rare autosomal recessive disorder characterised by reduced renal phosphate reabsorption leading to hypophosphataemia, rickets and bone pain. Here, we present a case of HHRH in a Chinese boy.Case presentationWe report a 11-year-old female proband, who was admitted to our hospital with bilateral genuvarum deformity and short stature. Computed Tomography (CT) showed kidney stones, blood tests showed hypophosphatemia, For a clear diagnosis, we employed high-throughput sequencing technology to screen for variants. Our gene sequencing approach encompassed whole exome sequencing, detection of exon and intron junction regions, and examination of a 20 bp region of adjacent introns. Flanking sequences are defined as ±50 bp upstream and downstream of the 5' and 3' ends of the coding region.The raw sequence data were compared to the known gene sequence data in publicly available sequence data bases using Burrows-Wheeler Aligner software (BWA, 0.7.12-r1039), and the pathogenic variant sites were annotated using Annovar. Subsequently, the suspected pathogenic variants were classified according to ACMG's gene variation classification system. Simultaneously, unreported or clinically ambiguous pathogenic variants were predicted and annotated based on population databases. Any suspected pathogenic variants identified through this analysis were then validated using Sanger sequencing technology. At last, the proband and her affected sister carried pathogenic homozygous variant in the geneSLC34A3(exon 13, c.1402C > T; p.R468W). Their parents were both heterozygous carriers of the variant. Genetic testing revealed that the patient has anLRP5(exon 18, c.3917C > T; p.A1306V) variant of Uncertain significance, which is a rare homozygous variant.ConclusionThis case report aims to raise awareness of the presenting characteristics of HHRH. The paper describes a unique case involving variants in both theSLC34A3andLRP5genes, which are inherited in an autosomal recessive manner. This combination of gene variants has not been previously reported in the literature. It is uncertain whether the presence of these two mutated genes in the same individual will result in more severe clinical symptoms. This report shows that an accurate diagnosis is critical, and with early diagnosis and correct treatment, patients will have a better prognosis.

Dataset Information

Impaired Vitamin D Signaling in T Cells From a Family With Hereditary Vitamin D Resistant Rickets.

Publications

Impaired Vitamin D Signaling in T Cells From a Family With Hereditary Vitamin D Resistant Rickets.

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