Wfs1- deficient rats develop primary symptoms of Wolfram syndrome: insulin-dependent diabetes, optic nerve atrophy and medullary degeneration

Wolfram syndrome (WS) is a rare autosomal-recessive disorder that is caused by mutations in the WFS1 gene and is characterized by juvenile-onset diabetes, optic atrophy, hearing loss and a number of other complications. Here, we describe the creation and phenotype of Wfs1 mutant rats, in which exon...

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Bibliographic Details
Published in:Scientific reports 2017-08, Vol.7 (1), p.10220-10220, Article 10220
Main Authors: Plaas, Mario, Seppa, Kadri, Reimets, Riin, Jagomäe, Toomas, Toots, Maarja, Koppel, Tuuliki, Vallisoo, Tuuli, Nigul, Mait, Heinla, Indrek, Meier, Riho, Kaasik, Allen, Piirsoo, Andres, Hickey, Miriam A., Terasmaa, Anton, Vasar, Eero
Format: Article
Language:English
Subjects:
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Age
Amino acid sequence
Amino acids
Atrophy
Beta cells
Body weight
Body weight loss
Diabetes
Diabetes mellitus
Electron microscopy
Gliosis
Glucose
Glucose tolerance
Hearing loss
Hereditary diseases
Humanities and Social Sciences
Hyperglycemia
Insulin
Insulin secretion
Intolerance
multidisciplinary
Myelin
Neurodegeneration
Optic atrophy
Optic nerve
Retina
Rodents
Science
Science (multidisciplinary)
Secretion
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Summary:Wolfram syndrome (WS) is a rare autosomal-recessive disorder that is caused by mutations in the WFS1 gene and is characterized by juvenile-onset diabetes, optic atrophy, hearing loss and a number of other complications. Here, we describe the creation and phenotype of Wfs1 mutant rats, in which exon 5 of the Wfs1 gene is deleted, resulting in a loss of 27 amino acids from the WFS1 protein sequence. These Wfs1-ex5-KO232 rats show progressive glucose intolerance, which culminates in the development of diabetes mellitus, glycosuria, hyperglycaemia and severe body weight loss by 12 months of age. Beta cell mass is reduced in older mutant rats, which is accompanied by decreased glucose-stimulated insulin secretion from 3 months of age. Medullary volume is decreased in older Wfs1-ex5-KO232 rats, with the largest decreases at the level of the inferior olive. Finally, older Wfs1-ex5-KO232 rats show retinal gliosis and optic nerve atrophy at 15 months of age. Electron microscopy revealed axonal degeneration and disorganization of the myelin in the optic nerves of older Wfs1-ex5-KO232 rats. The phenotype of Wfs1-ex5-KO232 rats indicates that they have the core symptoms of WS. Therefore, we present a novel rat model of WS.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-017-09392-x