title: Sequence analysis of four vitamin D family genes (VDR, CYP24A1, CYP27B1 and CYP2R1) in Vogt-Koyanagi-Harada (VKH) patients: identification of a potentially pathogenic variant in CYP2R1.
abstract: BACKGROUND
  VKH is a rare autoimmune disease. Decreased level of vitamin D has recently been found to be involved in the pathogenesis of Vogt-Koyanagi-Harada (VKH) disease. This study was designed to screen the vitamin D pathway genes for pathogenic mutations, if any, in VKH patients.
  
  
  METHODS
  Genomic DNA was extracted from blood samples collected from patients with VKH disease and healthy controls. Entire coding region, exon-intron junctions of four genes were sequenced in DNA from 39 Saudi VKH patients and 50 ethnically matched healthy individuals. All patients and controls were unrelated.
  
  
  RESULTS
  Vitamin D levels in VKH patients were found either insufficient (21-29 ng/mL) or deficient (<20 ng/mL). Sequencing analysis of the VDR, CYP24A1, CYP27B1 and CYP2R1 detected twelve nucleotide changes in these genes in our cohort of 39 patients; 4 of which were non-coding, 6 were synonymous coding and 2 were non-synonymous coding sequence changes. All synonymous coding variants were benign polymorphisms with no apparent clinical significance. A non-synonymous coding sequence variant (c.2 T > C; p.1Met?) found in VDR is an initiation coding change and was detected in control individuals as well, while another variant (c.852G > A; p.284 M > I) found in CYP2R1 is predicted to be disease causing by mutationtaster software. This potentially pathogenic variant was found in 17 out of 39 VKH patients.
  
  
  CONCLUSIONS
  Screening of four Vitamin D pathway genes in 39 VKH patients shows that a potentially pathogenic sequence variant in CYP2R1 may cause VKH in a subset of patients. These findings support the previous observation that low vitamin D levels might play a role in VKH pathogenesis and mutations in genes involved in vitamin D anabolism and catabolism might be of importance in VKH pathobiology.
authors.affiliation: College of Medicine, Taibah University Almadinah Almunawarah, Medina, Kingdom of Saudi Arabia.|Magribi Hospital, Almadinah Almunawarah, Medina, Kingdom of Saudi Arabia.
authors.forename: Ma'an Abdullah
authors.initials: MA
authors.lastname: Al-Barry
authors.affiliation: Center for Genetics and Inherited Diseases, Taibah University Almadinah Almunawarah, Medina, 30001, Kingdom of Saudi Arabia.
authors.forename: Alia M
authors.initials: AM
authors.lastname: Albalawi
authors.affiliation: College of Medicine, Taibah University Almadinah Almunawarah, Medina, Kingdom of Saudi Arabia.
authors.forename: Mohammed Abu
authors.initials: MA
authors.lastname: Sayf
authors.affiliation: College of Medicine, Taibah University Almadinah Almunawarah, Medina, Kingdom of Saudi Arabia.
authors.forename: Abdulrahman
authors.initials: A
authors.lastname: Badawi
authors.affiliation: Prince Naif Center for Immunology Research, College of Medicine, King Saud University, Riyadh, 11472, Saudi Arabia.
authors.forename: Sibtain
authors.initials: S
authors.lastname: Afzal
authors.affiliation: Center for Genetics and Inherited Diseases, Taibah University Almadinah Almunawarah, Medina, 30001, Kingdom of Saudi Arabia.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Latif
authors.affiliation: Center for Genetics and Inherited Diseases, Taibah University Almadinah Almunawarah, Medina, 30001, Kingdom of Saudi Arabia.
authors.forename: Mohammed I
authors.initials: MI
authors.lastname: Samman
authors.affiliation: Center for Genetics and Inherited Diseases, Taibah University Almadinah Almunawarah, Medina, 30001, Kingdom of Saudi Arabia. sbasit.phd@gmail.com.
authors.forename: Sulman
authors.initials: S
authors.lastname: Basit
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D002648:Child; D053493:Cholestanetriol 26-Monooxygenase; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D000072467:Cytochrome P450 Family 2; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D018167:Receptors, Calcitriol / Q000235:genetics*; D017422:Sequence Analysis, DNA; D014607:Uveomeningoencephalitic Syndrome / Q000097:blood / Q000235:genetics*; D014807:Vitamin D / Q000097:blood; D065668:Vitamin D3 24-Hydroxylase; D055815:Young Adult
chemical_list: D018167:Receptors, Calcitriol; C579457:VDR protein, human; D014807:Vitamin D; D003577:Cytochrome P-450 Enzyme System; D000072467:Cytochrome P450 Family 2; C506833:CYP2R1 protein, human; D053493:Cholestanetriol 26-Monooxygenase; C585549:CYP24A1 protein, human; D065668:Vitamin D3 24-Hydroxylase; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; C000600378:CYP27B1 protein, human
keywords: Genes; Mutations; Vitamin D; Vogt-Koyanagi-Harada