Characterization of Novel WFS1 Variants in Three Diabetes Pedigrees

Area of Science:

• Genetics and Molecular Biology
• Endocrinology
• Human Disease Genetics

Background:

• Mutations in the Wolfram syndrome 1 (WFS1) gene are linked to Wolfram syndrome (WS), Wolfram-like syndrome (WFLS), and maturity-onset diabetes of the young (MODY).
• The WFS1 gene encodes wolframin, a protein crucial for endoplasmic reticulum function, but the precise genotype-phenotype correlations remain unclear.
• Further patient data is essential to elucidate the complex relationship between WFS1 mutations and associated clinical manifestations.

Purpose of the Study:

• To investigate genotype-phenotype correlations in WFS1-related diabetes.
• To identify and characterize novel mutations within the WFS1 gene.
• To analyze the distribution and impact of WFS1 mutations on WS, WFLS, and MODY phenotypes.

Main Methods:

• High-throughput sequencing was utilized to detect WFS1 gene mutations in three diabetes pedigrees.
• Bioinformatic analyses, including pathogenicity and conservation assessments, were performed.
• Three-dimensional protein structure modeling and database analysis (Human Gene Mutation Database) were employed to understand mutation effects and patterns.

Main Results:

• Four heterozygous WFS1 mutations were identified, including one novel benign missense mutation (c.766A>G/p.K256E) and a pathogenic frameshift mutation (c.1523_1524del/p.Y508Cfs*34).
• The mutation c.985T>A/p.F329I was confirmed as associated with MODY.
• WFS1 mutations linked to WS phenotypes were found to be significantly more frequent (18.7 times) than those linked to MODY, with missense mutations in exon 8 being most common.

Conclusions:

• A novel WFS1 mutation (c.766A>G/p.K256E) was identified, broadening the known spectrum of WFS1 genetic variations.
• Inactivating and benign missense WFS1 mutations appear to correlate with more severe WS phenotypes compared to pathogenic missense mutations.
• The WFS1 gene exhibits distinct genotype-phenotype associations with WS, WFLS, and MODY, underscoring the complexity of WFS1-related disorders.