LAUSR

Wolfram-like syndrome (OMIM #614296) is a rare autosomal dominant disease caused by heterozygous mutations in the WFS1 gene [1]. Its clinical manifestations are highly variable, including sensorineural hearing loss, deafness, optic atrophy and/or diabetes mellitus (DM) [1]. The WFS1 gene (MIM# 606201) maps to chromosome 4p16, contains eight exons, and encodes wolframin, which is an 890-amino acid transmembrane protein. Wolframin is believed to be an integral, endoglycosidase H-sensitive membrane glycoprotein predominantly located in the endoplasmic reticulum (ER) [1]. Biochemical studies suggest that wolframin plays a role in membrane trafficking, protein processing, and/or regulation of endoplasmic reticulum calcium homeostasis. In addition, it has been suggested that wolframin preserves normal pancreatic beta-cell physiology by promoting insulin biosynthesis and negatively regulating ER stress [2]. Mutations in the WFS1 gene are not only implicated in the pathogenesis of Wolfram-like syndrome but are also involved in the development of other WFS1-related disorders such as Wolfram syndrome, DFNA6/14/38 nonsyndromic low-frequency sensorineural hearing loss, and nonsyndromic autosomal dominant diabetes [1]. In addition, several studies have shown a significant association between WFS1 sequence variants and type 1 and type 2 diabetes mellitus [1]. Over 90 different WFS1 gene mutations have been identified in Wolfram syndrome and low-frequency sensorineural hearing impairment [1]. Mutations associated with the Wolfram syndrome phenotype are distributed along the entire gene and are typically inactivating, with homozygous and compound heterozygous mutations being described. Previously reported mutations associated with Wolfram-like syndrome are located in exon 8 of the WFS1 gene, including p.Glu809Lys, p.Lys836Asn, p.Glu864Lys, p.Ala684Val, p.Tyr650His, and p.Asn682Asp [1–3]. However, to date, there are only five publications reporting Wolfram-like syndrome in the PubMed database. Wolfram-like syndrome is still largely a mystery. Here, we report the first case that describes a Chinese pedigree with progressive sensorineural hearing loss with variable diabetes consistent with Wolfram-like syndrome wherein affected individuals harbor a paternally inherited rare p.Val803Met variant in WFS1.