Abstract
Aims
Wolfram syndrome is a rare neurodegenerative disorder with an autosomal recessive pattern of inheritance characterized by various clinical manifestations. The related gene, WFS1, encodes a transmembrane glycoprotein, named wolframin. Genetic analyses demonstrated that mutations in this gene are associated with WS type 1. Our aim in this study was to sequence WFS1 coding region in Iranian Wolfram syndrome pedigrees.
Methods
Genomic DNA was extracted from peripheral blood of 12 WS patients and their healthy parents. Exons 2–8 and the exon–intron junctions of WFS1 were sequenced. DNA sequences were compared to the reference using Sequencher software.
Results
Molecular analysis of WFS1 revealed six different mutations. Four novel and two previously reported mutations were identified. One novel mutation, c.1379_1381del, is predicted to produce an aberrant protein. A second novel mutation, c.1384G > T, encodes a truncated protein. Novel mutation, c.1097-1107dup (11 bp), causes a frameshift which results in a premature stop codon. We screened for the novel missense mutation, c.1010C > T, in 100 control alleles. This mutation was not found in any of the healthy controls.
Conclusion
Our study increased the spectrum of WFS1 mutations and supported the role of WFS1 in susceptibility to WS. We hope that these findings open new horizons to future molecular investigations which may help to prevent and treat this devastating disease.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Barrett T, Bundey S, Macleod A (1995) Neurodegeneration and diabetes: UK nationwide study of Wolfram (DIDMOAD) syndrome. Lancet 346(8988):1458–1463
Hofmann S et al (1997) Wolfram (DIDMOAD) syndrome and Leber hereditary optic neuropathy (LHON) are associated with distinct mitochondrial DNA haplotypes. Genomics 39(1):8–18
Scolding NJ et al (1996) Wolfram syndrome: hereditary diabetes mellitus with brainstem and optic atrophy. Ann Neurol 39(3):352–360
Gómez-Zaera M et al (2001) Presence of a major WFS1 mutation in Spanish Wolfram syndrome pedigrees. Mol Genet Metab 72(1):72–81
Inoue H et al (1998) A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome). Nat Genet 20(2):143–148
Tessa A et al (2001) Identification of novel WFS1 mutations in Italian children with Wolfram syndrome. Hum Mutat 17(4):348–349
Takeda K et al (2001) WFS1 (Wolfram syndrome 1) gene product: predominant subcellular localization to endoplasmic reticulum in cultured cells and neuronal expression in rat brain. Hum Mol Genet 10(5):477–484
Urano F (2014) Diabetes: targeting endoplasmic reticulum to combat juvenile diabetes. Nat Rev Endocrinol 10(3):129–130
Berry V et al (2013) Wolfram gene (WFS1) mutation causes autosomal dominant congenital nuclear cataract in humans. Eur J Hum Genet 21(12):1356–1360
Rigoli L, Lombardo F, Di Bella C (2011) Wolfram syndrome and WFS1 gene. Clin Genet 79(2):103–117
Hardy C et al (1999) Clinical and molecular genetic analysis of 19 Wolfram syndrome kindreds demonstrating a wide spectrum of mutations in WFS1. Am J Hum Genet 65(5):1279–1290
Collier DA et al (1996) Linkage of Wolfram syndrome to chromosome 4p16. 1 and evidence for heterogeneity. Am J Hum Genet 59(4):855
Bucca BC, Klingensmith G, Bennett JL (2011) Wolfram syndrome: a rare optic neuropathy in youth with type 1 diabetes. Optom Vis Sci 88(11):E1383–E1390
Rigoli L, Di Bella C (2012) Wolfram syndrome 1 and Wolfram syndrome 2. Curr Opin Pediatr 24(4):512–517
Sobhani M et al (2013) Molecular characterization of WFS1 in an Iranian family with Wolfram syndrome reveals a novel frameshift mutation associated with early symptoms. Gene 528(2):309–313
Yuca SA et al (2012) Rapidly progressive renal disease as part of Wolfram syndrome in a large inbred Turkish family due to a novel WFS1 mutation (p. Leu511Pro). Eur J Med Genet 55(1):37–42
Sobhani M et al (2014) Significant expressivity of Wolfram syndrome: phenotypic assessment of two known and one novel mutation in the WFS1 gene in three Iranian families. Mol Biol Rep 41(11):7499–7505
Aloi C et al (2012) Wolfram syndrome: new mutations, different phenotype. PLoS One 7(1):e29150
Piccinno E et al (2014) Novel homozygous mutation in exon 5 of WFS1 gene in an Apulian family with mild phenotypic expression of Wolfram syndrome. Clin Genet 86(2):197–198
Bonnycastle LL et al (2013) Autosomal dominant diabetes arising from a Wolfram syndrome 1 mutation. Diabetes 62(11):3943–3950
Gasparin MRR et al (2009) Identification of novel mutations of the WFS1 gene in Brazilian patients with Wolfram syndrome. Eur J Endocrinol 160(2):309–316
Hansen L et al (2005) Mutation analysis of the WFS1 gene in seven Danish Wolfram syndrome families; four new mutations identified. Eur J Hum Genet 13(12):1275–1284
Elli FM et al (2012) A new structural rearrangement associated to Wolfram syndrome in a child with a partial phenotype. Gene 509(1):168–172
Pitt K et al (2011) A single base-pair deletion in the WFS1 gene causes Wolfram syndrome. J Pediatr Endocrinol Metab 24(5–6):389–391
Amr S et al (2007) A homozygous mutation in a novel zinc-finger protein, ERIS, is responsible for Wolfram syndrome 2. Am J Hum Genet 81(4):673–683
Acknowledgments
We gratefully acknowledge the contribution of the scientific collaborators of Human Genetics Department of Bu-Ali Research Institute of Mashhad University of Medical Sciences.
Authors’ contributions
MGh and SH carried out the molecular genetic studies and drafted the manuscript. FFG participated in molecular studied. NGh and RV contributed in clinical diagnosis of samples for study. MRA and RV designed and supervised the study. MMF revised the manuscript. All authors read and approved the final manuscript.
Funding
This study was supported by grants to RV from Mashhad University of Medical Sciences (No. 86526).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare no potential conflicts of interest.
Ethical standard
All procedures were in accordance with the ethical standards of institutional research committee and with the Helsinky declaration.
Human and animal rights
All procedures performed in studies involving human participants were in accordance with the Ethical Standards of the Mashhad University of Medical Sciences and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Informed consent
Informed consent was obtained from all individual participants included in the study.
Additional information
Managed by Massimo Federici.
Rights and permissions
About this article
Cite this article
Ghahraman, M., Abbaszadegan, M.R., Vakili, R. et al. Identification of four novel mutations of the WFS1 gene in Iranian Wolfram syndrome pedigrees. Acta Diabetol 53, 899–904 (2016). https://doi.org/10.1007/s00592-016-0884-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00592-016-0884-7