Severe Wolfram Syndrome Caused by a Novel Frameshift Mutation in WFS1 Gene: Effect on the WFS1/CaM Interaction and Phenotype-Genotype Correlation ()
Affiliation(s)
1Laboratory of Molecular and Functional Genetics, Faculty of Science, University of Sfax, Tunisia.
2Laboratory of Human Molecular Genetics, Faculty of Medicine, University of Sfax, Tunisia.
3Department of Endocrinology, Tahar Sfar Hospital, Mahdia, Tunisia.
4Department of Endocrinology, Hedi Chaker Hospital, Sfax, Tunisia.
ABSTRACT
Mutations in the WFS1 gene have been reported in Wolfram syndrome (WFS),
a rare and autosomal recessive disorder defined by early
onset of diabetes mellitus and progressive optic and hearing impairment. Only few data are available concerning the association between clinical and
molecular aspects of the WFS. We present a consanguineous family with a patient
presenting an early onset of WFS and severe manifestations. Sequencing of WFS1 gene was performed for all the family members to search for responsible mutation
and bioinformatics tools were conducted to predict its effect on structure and function of the protein.
We have detected a novel frameshift mutation in the proband at homozygous state
and at the heterozygous state in the parents who have no WFS manifestations. In
silico analysis predicted the pathogenicity of the mutation and could lead to a
complete loss of its function. Thus, 3D modeling showed that the mutation
abolishes the interaction of the CaM binding region to the N-terminal of WFS1
and then impairs the WFS1-CaM complex
formation. Genotype-phenotype correlation study shows that the novel
mutation predisposes to early onset of diabetes and severe symptoms observed in
the proband. We also report the effect of the frameshift mutation on the CaM-WFS1
impaired binding, and we discuss its possible consequence in pancreatic β-cells dysfunction and its role in the
early onset of diabetes. In conclusion, the combination of impaired functions
of WFS1 including unproper interaction of the CaM, Ca2+ uptake,
mitochondrial dysfunction, and apoptosis under the ER stress could be involved
in the severe phenotype and early onset of WFS of our patient.
Share and Cite:
Tabebi, M. , Felhi, R. , Mrabet, H. , Safi, W. , Zantour, B. , Sfar, M. , Abid, M. , Feki, M. and Fakhfakh, F. (2021) Severe Wolfram Syndrome Caused by a Novel Frameshift Mutation in
WFS1 Gene: Effect on the WFS1/CaM Interaction and Phenotype-Genotype Correlation.
Open Journal of Genetics,
11, 77-92. doi:
10.4236/ojgen.2021.114008.
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