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Homozygosity Mapping and Direct Sequencing Identify a Novel Pathogenic Variant in the Cisd2 Gene in an Iranian Wolfram Syndrome Family Publisher Pubmed



Pourreza MR1 ; Sobhani M2 ; Rahimi A1 ; Aramideh M3 ; Kajbafzadeh AM4 ; Nooridaloii MR2, 5 ; Tabatabaiefar MA1, 6
Authors
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Authors Affiliations
  1. 1. Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, 81746-73461, Iran
  2. 2. Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran
  3. 3. Department of Medicinal Chemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
  4. 4. Pediatric Urology Research Center, Department of Pediatric Urology, Children’s Hospital Medical Center, Tehran University of Medical Sciences, Tehran, Iran
  5. 5. Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
  6. 6. Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran

Source: Acta Diabetologica Published:2020


Abstract

Aims: Wolfram syndrome (WS) is a rare recessive neurodegenerative disorder characterized by diabetes mellitus and optic atrophy. Mortality and morbidity rate of the disease is high in adulthood due to neurological and respiratory defects. So far, two WS genes, WFS1 (more than 90% of cases) and CISD2, have been identified. In the present study, we aimed to determine the role of WFS2 in a group of Iranian WS families. Methods: We recruited 27 families with the clinical diagnosis of WS. Homozygosity mapping was implemented using short tandem repeat polymorphic markers and bi-directional sequencing of the CISD2 gene in families negative for WFS1 mutations. The candidate variant was checked among family members. In silico analysis and protein modeling were applied to assess the pathogenic effect of the variant. Tetra-primers ARMS PCR was set up for checking the variant in 50 ethnic-matched controls. Results: One family showed homozygosity by descent at WFS2. A novel missense variant, c.310T > C (p.S104P), was found in exon 2 of the CISD2 gene. Computational predictions revealed its pathogenic effect on protein structure, function, and stability. Parents and his healthy brother were heterozygous for the variant. The variant was not observed in the control group. Conclusions: This is the first study that elucidates the role of the CISD2 gene among Iranian WS families with a novel disease-causing missense variant. Next-generation sequencing could unravel disease-causing genes in remained families to expand genetic heterogeneity of WS. © 2019, Springer-Verlag Italia S.r.l., part of Springer Nature.
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