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      Vitamin D-dependent rickets (VDDR) type 1: case series of two siblings with a CYP27B1 mutation and review of the literature Translated title: Raquitismo dependente de vitamina D: tipo 1: série de casos de dois irmãos com mutação CYP27B1 e revisão da literatura

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          Abstract

          Two siblings presented with clinical and biochemical features of rickets, initially suspected as hypophosphatemic rickets. There was no improvement initially, hence the siblings were reinvestigated and later diagnosed as having vitamin D-dependent rickets (VDDR) type 1 due to a rare mutation in the CYP27B1 gene encoding the 1α-hydroxylase enzyme. Both siblings improved with calcitriol supplementation. The initial presentation of VDDR is often confusing and algorithmic evaluation helps in diagnosis. We also present a brief review of the literature, including genetics.

          Resumo

          Dois irmãos apresentaram características clínicas e bioquímicas do raquitismo, com suspeita clínica inicial de raquitismo hipofosfatêmico. Não houve melhora no início, portanto os irmãos foram reavaliados e, posteriormente, diagnosticados com raquitismo dependente de vitamina D (VDDR) tipo 1 devido a uma rara mutação no gene CYP27B1, que codifica a enzima 1a-hidroxilase. Ambos os irmãos melhoraram com a suplementação de calcitriol. A apresentação inicial do VDDR geralmente é confusa e a avaliação algorítmica ajuda no diagnóstico. Também apresentamos uma breve revisão da literatura, incluindo genética.

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          Most cited references13

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          Regulation of vitamin D metabolism.

          L. Henry (2011)
          Fundamental to understanding the way in which perturbations in the vitamin D endocrine system can affect human health is an appreciation of the steps involved in the production of the well-recognized active hormonal form, 1,25-dihydroxyvitamin D(3). Thus this paper focuses first on the nature and regulation of the two enzymes responsible for the production of 1,25-dihydroxyvitamin D(3), the 25-hydroxylase in the liver and the 1α-hydroxylase in the kidney. The most important regulators of the 1α-hydroxylase in the kidney are 1,25-dihydroxyvitamin D(3) itself, parathyroid hormone and FGF23. The extent and importance of extra-renal, 1,25-dihydroxyvitamin D(3) synthesis is then considered. Finally the features of the 24R-hydroxylase, which produces 24R,25-dihydroxyvitamin D(3) in the kidney and is induced by and inactivated, 1,25-dihydroxyvitamin D(3)in target cells are described. Copyright © 2011 Elsevier Ltd. All rights reserved.
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            Genetics of vitamin D 1alpha-hydroxylase deficiency in 17 families.

            Vitamin D-dependent rickets type I (VDDR-I), also known as pseudo-vitamin D-deficiency rickets, appears to result from deficiency of renal vitamin D 1alpha-hydroxylase activity. Prior work has shown that the affected gene lies on 12q13.3. We recently cloned the cDNA and gene for this enzyme, mitochondrial P450c1alpha, and we and others have found mutations in its gene in a few patients. To determine whether all patients with VDDR-I have mutations in P450c1alpha, we have analyzed the P450c1alpha gene in 19 individuals from 17 families representing various ethnic groups. The whole gene was PCR amplified and subjected to direct sequencing; candidate mutations were confirmed by repeat PCR of the relevant exon from genomic DNA from the patients and their parents. Microsatellite haplotyping with the markers D12S90, D12S305, and D12S104 was also done in all families. All patients had P450c1alpha mutations on both alleles. In the French Canadian population, among whom VDDR-I is common, 9 of 10 alleles bore the haplotype 4-7-1 and carried the mutation 958DeltaG. This haplotype and mutation were also seen in two other families and are easily identified because the mutation ablates a TaiI/MaeII site. Six families of widely divergent ethnic backgrounds carried a 7-bp duplication in association with four different microsatellite haplotypes, indicating a mutational hot spot. We found 14 different mutations, including 7 amino acid replacement mutations. When these missense mutations were analyzed by expressing the mutant enzyme in mouse Leydig MA-10 cells and assaying 1alpha-hydroxylase activity, none retained detectable 1alpha-hydroxylase activity. These studies show that most if not all patients with VDDR-I have severe mutations in P450c1alpha, and hence the disease should be referred to as "1alpha-hydroxylase deficiency."
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              Novel CYP27B1 Gene Mutations in Patients with Vitamin D-Dependent Rickets Type 1A

              The CYP27B1 gene encodes 25-hydroxyvitamin D-1α-hydroxylase. Mutations of this gene cause vitamin D-dependent rickets type 1A (VDDR-IA, OMIM 264700), which is a rare autosomal recessive disorder. To investigate CYP27B1 mutations, we studied 8 patients from 7 unrelated families. All coding exons and intron-exon boundaries of CYP27B1 gene were amplified by PCR from peripheral leukocyte DNA and subsequently sequenced. Homozygous mutations in the CYP27B1 gene were found in all the patients and heterozygous mutations were present in their normal parents. One novel single nucleotide variation (SNV, c.1215 T>C, p.R379R in the last nucleotide of exon 7) and three novel mutations were identified:, a splice donor site mutation (c.1215+2T>A) in intron 7, a 16-bp deletion in exon 6 (c.1022-1037del16), and a 2-bp deletion in exon 5 (c.934_935delAC). Both c.1215 T>C and c.1215+2T>A were present together in homozygous form in two unrelated patients, and caused exon 7 skipping. However, c.1215 T>C alone has no effect on pre-mRNA splicing. The skipping of exon 7 resulted in a shift of downstream reading frame and a premature stop codon 57 amino acids from L380 (p.L380Afs*57). The intra-exon deletions of c.1022-1037del16 and c.934_935delAC also resulted in a frameshift and the creation of premature stop codons at p.T341Rfs*5, and p.T312Rfs*19, respectively, leading to the functional inactivation of the CYP27B1 gene. Clinically, all the patients required continued calcitriol treatment and the clinical presentations were consistent with the complete loss of vitamin D1α-hydroxylase activity. In conclusion, three novel mutations have been identified. All of them caused frameshift and truncated proteins. The silent c.1215 T>C SNV has no effect on pre-mRNA splicing and it is likely a novel SNP. The current study further expands the CYP27B1 mutation spectrum.
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                Author and article information

                Journal
                J Bras Nefrol
                J Bras Nefrol
                jbn
                Jornal Brasileiro de Nefrologia
                Sociedade Brasileira de Nefrologia
                0101-2800
                2175-8239
                11 September 2020
                Oct-Dec 2020
                : 42
                : 4
                : 494-497
                Affiliations
                [1 ]Lady Hardinge Medical College and associated Kalawati Saran Children Hospital, Department of Pediatrics, Division of Pediatric Nephrology, New Delhi, India.
                [2 ]Seoul National University Children’s Hospital, Department of Pediatrics, Seoul, Korea.
                [3 ]Seoul National University College of Medicine, Kidney Research Institute, Medical Research Centre, Seoul, Korea.
                [4 ]University College of Medical Sciences, Department of Biochemistry, New Delhi, India.
                Author notes
                Correspondence to: Abhijeet Saha. E-mail: drabhijeetsaha@ 123456yahoo.com

                Author’s Contribution

                Rachita Singh Dhull, Reena Jain, Bobbity Deepthi, Hae II Cheong, Abhijeet Saha, Mohit Mehndiratta, Srikanta Basu contributed substantially to the conception or design of the study; collection, analysis, or interpretation of data; writing or critical review of the manuscript; and final approval of the version to be published.

                Author information
                http://orcid.org/0000-0002-0251-2822
                Article
                10.1590/2175-8239-JBN-2020-0001
                7860650
                32926064
                e3b0ea54-11f6-4ac4-9c4b-b8025294c5af

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 09 May 2020
                : 24 June 2020
                Categories
                Case Report

                familial hypophosphatemic rickets,children,25-hydroxyvitamin d3 1-alpha-hydroxylase,mutagenesis, insertional,raquitismo hipofosfatêmico familiar,crianças,25-hidroxivitamina d3 1-alfa-hidroxilase,mutagênese insercional

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