Phenotype Prediction of Pathogenic Nonsynonymous Single Nucleotide Polymorphisms in WFS1

Abstract

Wolfram syndrome (WS) is a rare, progressive, neurodegenerative disorder that has an autosomal recessive pattern of inheritance. The gene for WS, wolfram syndrome 1 gene (WFS1), is located on human chromosome 4p16.1 and encodes a transmembrane protein. To date, approximately 230 mutations in WFS1 have been confirmed, in which nonsynonymous single nucleotide polymorphisms (nsSNPs) are the most common forms of genetic variation. Nonetheless, there is poor knowledge on the relationship between SNP genotype and phenotype in other nsSNPs of the WFS1 gene. Here, we analysed 395 nsSNPs associated with the WFS1 gene using different computational methods and identified 20 nsSNPs to be potentially pathogenic. Furthermore, to identify the amino acid distributions and significances of pathogenic nsSNPs in the protein of WFS1, its transmembrane domain was constructed by the TMHMM server, which suggested that mutations outside of the TMhelix could have more effects on protein function. The predicted pathogenic mutations for the nsSNPs of the WFS1 gene provide an excellent guide for screening pathogenic mutations.

Variants in WFS1 and Other Mendelian Deafness Genes Are Associated with Cisplatin-Associated Ototoxicity

“…Dominant mutations that cause low-frequency hearing loss are nearly always found in the 3′ end of WFS1 and are usually non-inactivating (34). On the other hand, WFS1 mutations causing the recessive Wolfram syndrome are numerous, usually loss-of-function, and distributed along the entire gene (34,39). Hearing impairment in patients with Wolfram syndrome is progressive and largely affects the high frequencies (34,40), as is also true for CAO, with hearing loss presenting in the 4–12 kHz range, which is critical for speech perception (1).…”

Functional Innovation in the Evolution of the Calcium-Dependent System of the Eukaryotic Endoplasmic Reticulum

“…As noted above, one of the uniquely metazoan proteins in the Ca 2+ -stores system is wolframin, a transmembrane protein localized to the ER membrane (Hildebrand et al, 2008;Rigoli et al, 2011;Qian et al, 2015) (Figure 2A, Supplementary Data). Wolframin, along with the structurally-unrelated and more widely phyletically distributed (Figure 2A) Wolfram syndrome 2 (WFS2) protein, is implicated in Wolfram syndrome (Inoue et al, 1998;Strom et al, 1998;Amr et al, 2007;Urano, 2016).…”

“…The wolframin TM region, located in the central region of the protein ( Figure 4A), consists of nine transmembrane helices (Hofmann et al, 2003;Rigoli et al, 2011;Qian et al, 2015). Despite extensive studies on the TM region, its precise role in affecting Ca 2+ flow across the ER membrane remains the subject of some debate (Osman et al, 2003;Aloi et al, 2012;Zatyka et al, 2015;Cagalinec et al, 2016).…”

Monogenic diabetes—diagnostic conundrums

“…Till date, there are around 230 WFS1 gene mutations that have been reported; however, there is a poor understanding of the relationship between the non-synonymous coding variants and the phenotype. Therefore, studies looking at short fragments or partial gene require extensive bioinformatics predication and careful interpretation of the novel variants identified [16].…”