Wolframin mutations and hospitalization for psychiatric illness

Abstract

Genetic predisposition plays an important role in most common psychiatric disorders. The identification of a specific gene associated with a psychiatric illness can lead to improved management of the gene-associated disorder. Mutations in the wolframin gene are associated with mental illness. Many patients with the Wolfram syndrome (WS), who are homozygous or compound heterozygous for wolframin mutations, have severe psychiatric symptoms. In WS families, close blood relatives, who have a high probability of carrying a single wolframin mutation, had a statistically significant excess, over spouse controls, of psychiatric hospitalizations, attempted and completed suicides, and self-reports of mental illness. Since heterozygous carriers of wolframin mutations are relatively frequent in the population according to the general Hardy-Weinberg principle, such mutations might be responsible for the illnesses of many psychiatric patients. The hypothesis that heterozygous carriers of a wolframin mutation are predisposed to psychiatric illness was tested in subjects from 25 WS families. In all, 11 relatives who had psychiatric hospitalizations could be genotyped through mutation analysis. Eight of these carried the wolframin mutation transmitted in their family, significantly (one-sided P ¼ 0.0022) more than the 3.0 expected if there were no association between psychiatric hospitalizations and mutations at this locus. All eight mutation-positive subjects had been hospitalized for a major depression. This confirmation of the association is not influenced by confounders, undetected stratification, or genetic heterogeneity. The relative risk of psychiatric hospitalization for depression was estimated to be 7.1 (95% CI 1.9-26.6) for carriers of a single wolframin mutation compared to noncarriers. Molecular Psychiatry (2005) 10, 799-803.

Wolfram syndrome 1 gene negatively regulates ER stress signaling in rodent and human cells

“…The heterozygotes who do not have Wolfram syndrome are 26-fold more likely than noncarriers to have a psychiatric hospitalization (43). The relative risk of psychiatric hospitalization for depression was estimated to be 7.1 in these heterozygotes (44). Therefore, it is possible that dysregulation of a negative feedback loop of ER stress signaling may have a pathological role in psychiatric illness.…”

Distribution of Wfs1 protein in the central nervous system of the mouse and its relation to clinical symptoms of the Wolfram syndrome

“…An implication of Wfs1 dysfunction in psychiatric disorders has been previously suggested by frequent diagnosis of psychiatric disorders in Wolfram syndrome patients. Furthermore, Wolfram syndrome carriers have increased susceptibility to affective and anxiety disorders, and a possible association of Wfs1 haplotypes with major depressive disorder has been reported (Swift et al, 1990;Koido et al, 2005;Swift and Swift, 2005). We have previously identified an upregulation of Wfs1 mRNA in the amygdaloid area of rats in response to cat odor-induced fear response (Koks et al, 2002).…”

Identification of novel mutations in WFS1 and genotype–phenotype correlation in Wolfram syndrome

“…On the contrary, only non-inactivating mutations, that is missense mutations, have been identified in autosomal dominant low frequency sensorineural hearing impairment (LFSNHI; OMIM# 600965), a non-syndromic hearing loss also linked to WFS1 [Young et al, 2001;Gurtler et al, 2005;Toth et al, 2006]. Several WFS1 polymorphisms have also been found associated with insulin-dependent diabetes mellitus (IDDM) [Awata et al, 2000], non-insulin-dependent diabetes mellitus (NIDDM) [Domenech et al, 2002;Minton et al, 2002], combination of DM and deafness [Domenech et al, 2002], or psychiatric disorders [Swift et al, 1991[Swift et al, , 1998Furlong et al, 1999;Sequeira et al, 2003;Koido et al, 2005;Swift and Swift, 2005].…”