Low-Frequency Hearing Loss

WFS1 Gene Mutation and Polymorphism Database

Non-syndromic low frequency sensorineural hearing loss (LFSNHL) is an unusual type of hearing loss affecting the low frequencies, 2000 Hz and below. Many patients with LFSNHL have tinnitus which is not particularly bothersome, but there are otherwise no associated features such as vertigo. Because high frequency hearing is generally preserved, LFSNHL patients retain excellent understanding of speech, although presbysusis or noise exposure may cause high frequency loss later in life. Consequently, LFSNHL is often asymptomatic, and many patients choose not to wear hearing aids. Although over 70 loci have been mapped for non-syndromic sensorineural hearing loss, only two chromosomal locations, 5q31 (DFNA1) and 4p16 (DFNA6/14/38) are associated with LFSNHL. In contrast to LFSNHL associated with DFNA6/14, all affected individuals in the DFNA1 family become profoundly deaf by the fourth decade of life. LFSNHL linked to DFNA1 is caused by mutations in DIAPH1, the homolog of Drosophila diaphanous, whereas the mutations in the Wolfram syndrome gene (WFS1), which is mutated in the recessive Wolfram syndrome, were found in families with LFSNHL linked to DFNA6/14/38.

Wolfram syndrome is also known as DIDMOAD to denote the association of Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy and Deafness. Juvenile-onset diabetes mellitus and bilateral progressive optic atrophy are the minimal diagnostic criteria for Wolfram syndrome. Other features include renal tract abnormalities, ataxia, peripheral neuropathy, mental retardation and psychiatric illness.

The WFS1 gene consists of 8 exons and spans about 33.4 kb of genomic DNA. The smallest exon is exon 6, which is 61 bp in long, and largest is exon 8, which is about 2.6 kb long. Exon 1 is noncoding, while exons 2-7 and the major portion of exon 8 are coding. The WFS1 gene transcribes an mRNA of 3.6 kb and codes for a polypeptide of 890 amino acids, with a molecular mass of 100.29 kD and 9-11 possible transmembrane domains. The wolframin protein lacks homology to other known proteins, and its function is not known. A role of protein sorting or trafficking is hypothesized, as wolframin has been localized to the endoplasmic reticulum in cultured cells. WFS1 is ubiquitously expressed, but brain expression is concentrated in certain populations of neurons, including the ventral cochlear nucleus and inferior colliculus.

Several mutations are found in the WFS1 gene in patients with Wolfram syndrome, LFSNHL, psychiatric disorders, such as schizophrenia, bipolar disorder, etc and are distributed across the coding sequences. These mutations are heterozygous in the LFSNHL families, homozygous mutations results in Wolfram syndrome. In addition to the disease causing mutations, many sequence variations/polymorphisms are found in the coding as well as in the noncoding regions. The goal of this database is to facilitate the classification of sequence variations, either as disease causing (especially hearing loss) or polymorphisms.