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...

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Main Authors:	Demir, Korcan, Kattan, Walaa E., Zou, Minjing, Durmaz, Erdem, BinEssa, Huda, Nalbantoğlu, Özlem, Al-Rijjal, Roua A., Meyer, Brian, Özkan, Behzat, Shi, Yufei
Format:	Online
Language:	English
Published:	Public Library of Science 2015
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4489500/

id	pubmed-4489500
recordtype	oai_dc
spelling	pubmed-44895002015-07-14 Novel CYP27B1 Gene Mutations in Patients with Vitamin D-Dependent Rickets Type 1A Demir, Korcan Kattan, Walaa E. Zou, Minjing Durmaz, Erdem BinEssa, Huda Nalbantoğlu, Özlem Al-Rijjal, Roua A. Meyer, Brian Özkan, Behzat Shi, Yufei Research Article 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.L380Afs57). 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.T341Rfs5, 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. Public Library of Science 2015-07-01 /pmc/articles/PMC4489500/ /pubmed/26132292 http://dx.doi.org/10.1371/journal.pone.0131376 Text en © 2015 Demir et al http://creativecommons.org/licenses/by/4.0/ 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 author and source are properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Demir, Korcan Kattan, Walaa E. Zou, Minjing Durmaz, Erdem BinEssa, Huda Nalbantoğlu, Özlem Al-Rijjal, Roua A. Meyer, Brian Özkan, Behzat Shi, Yufei
spellingShingle	Demir, Korcan Kattan, Walaa E. Zou, Minjing Durmaz, Erdem BinEssa, Huda Nalbantoğlu, Özlem Al-Rijjal, Roua A. Meyer, Brian Özkan, Behzat Shi, Yufei Novel CYP27B1 Gene Mutations in Patients with Vitamin D-Dependent Rickets Type 1A
author_facet	Demir, Korcan Kattan, Walaa E. Zou, Minjing Durmaz, Erdem BinEssa, Huda Nalbantoğlu, Özlem Al-Rijjal, Roua A. Meyer, Brian Özkan, Behzat Shi, Yufei
author_sort	Demir, Korcan
title	Novel CYP27B1 Gene Mutations in Patients with Vitamin D-Dependent Rickets Type 1A
title_short	Novel CYP27B1 Gene Mutations in Patients with Vitamin D-Dependent Rickets Type 1A
title_full	Novel CYP27B1 Gene Mutations in Patients with Vitamin D-Dependent Rickets Type 1A
title_fullStr	Novel CYP27B1 Gene Mutations in Patients with Vitamin D-Dependent Rickets Type 1A
title_full_unstemmed	Novel CYP27B1 Gene Mutations in Patients with Vitamin D-Dependent Rickets Type 1A
title_sort	novel cyp27b1 gene mutations in patients with vitamin d-dependent rickets type 1a
description	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.L380Afs57). 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.T341Rfs5, 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.
publisher	Public Library of Science
publishDate	2015
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4489500/
_version_	1613243221540864000

Novel CYP27B1 Gene Mutations in Patients with Vitamin D-Dependent Rickets Type 1A

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