A rare coding variant within the wolframin gene in bipolar and unipolar affective disorder cases

doi:10.1016/S0304-3940(99)00865-4

Neuroscience Letters

Volume 277, Issue 2, 24 December 1999, Pages 123-126

https://doi.org/10.1016/S0304-3940(99)00865-4 Get rights and content

Abstract

A recent report has shown that Wolfram syndrome carriers (heterozygotes) are 26-fold more likely to require psychiatric hospitalization compared with non-carriers, and that Wolfram syndrome heterozygotes may constitute approximately 25% of individuals hospitalized with depression and suicide attempts. We analyzed a His611Arg polymorphism of the wolframin gene by the polymerase chain reaction (PCR) and HhaI restriction digestion, in 158 bipolar I and 163 unipolar major affective disorder cases, and 316 controls. Statistical analyses of allele or genotype frequencies do not support a major role for wolframin in affective disorder. HhaI restriction digestion and sequencing of PCR products from four affective disorder cases showed a heterozygous Ala559Thr change. The Ala559Thr variant was not detectable in 382 controls tested. Thus, the rare wolframin 559Thr allele deserves consideration as a risk allele for affective disorder.

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Acknowledgements

We thank Elizabeth Buckeridge and Caroline Crane for technical support and Dr. Sanjeev Jain for the collection of some bipolar samples. Drs. John Old, Kimmo Kontula and Katsushi Tokunaga for the Nigerian, Finnish and Japanese DNAs, respectively. R.A.F. is a Peterhouse Senior Research Associate in Neuroscience, J.S.R. is a Betty Behrens Research Fellow at Clare Hall, Cambridge in receipt of a Sackler studentship, and D.C.R. is a Glaxo Wellcome Research Fellow. The collection of unipolar samples

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Cited by (45)

Wolframin gene H611R polymorphism: No direct association with suicidal behavior but possible link to mood disorders
2009, Progress in Neuro-Psychopharmacology and Biological Psychiatry
Wolframin gene polymorphisms, including the H611R polymorphism, are reportedly associated with mood disorders and psychiatric hospitalization, but there is disagreement about the association of this specific variant with suicidality and impulsive traits. This study tested the association of the H611R polymorphism with mood disorders, suicidal behavior, and aggressive–impulsive traits. Two hundred and one subjects with mood disorders and 113 healthy volunteers were genotyped for the H611R polymorphism and underwent structured interviews for diagnosis and clinical ratings. All were Caucasians. The H611R polymorphism was associated with mood disorders but not suicidal behavior, aggressive/impulsive traits or suicidality in first-degree relatives. The HR heterozygote genotype was more frequent in mood disorder (χ² = 7.505; df = 2; p = .023). If this finding will be replicated, the H611R polymorphism may be a possible marker for mood disorders in a psychiatric population, and not just in relatives of Wolfram syndrome probands.
Wolfram syndrome 1 (Wfs1) mRNA expression in the normal mouse brain during postnatal development
2009, Neuroscience Research
Citation Excerpt :
In addition, the Wfs1 gene was suggested to be a putative biomarker for post-traumatic stress disorder by a behavioral study using rats (Kesner et al., 2007), and the Wfs1 knockout mouse showed bipolar disorder-like behavioral phenotypes, such as retardation in emotionally triggered behavior, decreased social interaction, and altered behavioral despair depending on experimental conditions (Kato et al., 2008). Conversely, several molecular neuropsychiatric studies have found no evidence of a supporting role for the WFS1 gene in psychiatric disorders, particularly major depression and bipolar disorder (Furlong et al., 1999; Evans et al., 2000; Middle et al., 2000; Ohtsuki et al., 2000; Kato et al., 2003; Kawamoto et al., 2004). As described here, it is not known whether mutations of the WFS1 gene contribute significantly to the incidence of psychiatric illness.
Wolfram syndrome is a rare genetic disorder accompanying diabetes insipidus, sensorineural hearing loss, neurological complications, and psychiatric illness. This syndrome has been attributed to mutations in the WFS1 gene. In this study, we made a detailed histochemical analysis of the distribution of Wfs1 mRNA in the brain of developing mice. There were three patterns of change in the strength of Wfs1 mRNA signals from birth to early adulthood. In type 1, the signals were weak or absent in neonates but strong or moderate in young adults. This pattern was observed in the CA1 field, parasubiculum, and entorhinal cortex. In type 2, the signals were of a relatively constant strength during development. This pattern was seen in limbic structures (e.g. subiculum and central amygdaloid nucleus) and brainstem nuclei (e.g. facial and chochlear nuclei). In type 3, the signals peaked in the second week of age. This pattern was observed in the thalamic reticular nucleus. Thus, Wfs1 mRNA was widely distributed in the normal mouse brain during postnatal development. This evidence may provide clues as to the physiological role of the Wfs1 gene in the central nervous system, and help to explain endocrinological, otological, neurological, and psychiatric symptoms in Wolfram syndrome patients.
The wolframin His611Arg polymorphism influences medication overuse headache
2007, Neuroscience Letters
Homozygosis for wolframin (WFS1) mutations determines Wolfram syndrome (WS), and common polymorphisms of WFS1 are associated with psychiatric illnesses and dependence behaviour. To test the influence of WFS1 polymorphisms on medication overuse headache (MOH), a chronic headache condition related to symptomatic drugs overuse, we analyzed 82 MOH patients for the WFS1 His611Arg polymorphism, and performed a comparison between clinical features of Arg/Arg (R/R) and non-R/R individuals. Individuals harbouring the R/R genotype showed significantly higher monthly drug consumption (t = −3.504; p = 0.00075) and more severe depressive symptoms on the BDI questionnaire (t = −3.048; p = 0.003) than non-R/R. WFS1 polymorphism emerged as the only significant predictor of drug consumption, at the multivariate regression analysis (F = 12.277; d.f. = 1,80; p = 0.00075, adjusted R² = 0.122). These results implicate WFS1 in the clinical picture of MOH, may be through an influence on need for drugs as in other conditions of abuse behaviour.
Wolfram's syndrome presenting as a cerebellar ataxia
2007, Revue Neurologique
Le syndrome de Wolfram est une maladie génétique, à transmission autosomique récessive, associant un diabète sucré juvénile et une atrophie optique bilatérale.
Nous rapportons le cas d’un patient âgé de 47 ans pour lequel nous avons porté le diagnostic de syndrome de Wolfram devant l’apparition d’un tableau neurologique tardif associant ataxie et nystagmus horizontal bilatéral. L’IRM encéphalique révélait une atrophie majeure du tronc cérébral et du cervelet.
Le syndrome de Wolfram est une pathologie rare, dont l’issue est fatale avant l’âge de 50 ans dont le diagnostic doit être évoqué devant l’association d’un diabète sucré juvénile et d’une atrophie optique, en particulier en présence d’autres symptômes tels qu’ataxie, hypoacousie, diabète insipide, troubles neuro-psychiatriques ou troubles vésico-rénaux.
Wolfram syndrome is a genetic disease with recessive autosomic transmission, associating early-onset diabetes mellitus and bilateral optical atrophy.
We report the case of a 47-year-old patient for whom we diagnosed a Wolfram syndrome in view of a late neurological syndrome in association with ataxia and bilateral horizontal nystagmus. The brain resonance magnetic imaging revealed a major atrophy of the brainstem and cerebellum.
Wolfram syndrome is a rare pathology, with fatal consequences before the age of 50. The association of diabetes mellitus and optical atrophy, especially when there are other symptoms (ataxia, deafness, diabetes insipidus, neuropsychiatric manifestations or urinary tract disorders) should lead to this diagnosis and to carry out a genetic confirmation.
Mitochondrial Dysfunction in Bipolar Disorder: from <sup>31</sup>P-Magnetic Resonance Spectroscopic Findings to their Molecular Mechanisms
2005, International Review of Neurobiology
Citation Excerpt :
These findings suggest that multiple deletions due to mutations of nuclear genes can cause mitochondrial diseases, and one of their characteristic symptoms is mood disorder. Many studies of mutation screening of WFS1 in bipolar disorder have been reported, but the hypothesis that a significant portion of patients with bipolar disorder are heterozygous carriers of the WFS1 mutation was not supported (Evans et al., 2000; Furlong et al., 1999; Kato et al., 2003b; Middle et al., 2000; Ohtsuki et al., 2000; Serretti et al., 2003; Torres et al., 2001). There is no report of mutation screening of the other three genes causing multiple deletions of mtDNA.
This chapter provides the evidence for mitochondrial dysfunction in bipolar disorder and presents a hypothesis that alters mitochondrial calcium regulation and causes impaired neural plasticity that results in bipolar disorder. Bipolar disorder is a major mental disorder characterized by recurrent manic and depressive episodes. The alteration of monoaminergic neurotransmission was postulated in the pathophysiology of bipolar disorder based on the mechanism of action of antidepressants and antipsychotics. Because these agents are symptomatic treatment for depressive or manic episodes, monoaminergic dysfunction represents the pathophysiology of these episodes rather than the etiological basis of recurrence of these episodes. Thus, the neurobiological basis of bipolar disorder needs to be studied independently to monoamine theory. In the ³¹P-magnetic resonance spectra of the brain, seven major peaks can be resolved: phosphomonoester (PME), inorganic phosphate (P_i), phosphodiester (PDE), phosphocreatine (PCr), and three phosphate residues from adenosine triphosphate (α, β, and γ-ATP). Near-infrared spectroscopy (NIRS) mainly measures the blood volume in microvessels, rather than larger vessels. The neuroimaging and molecular genetic studies suggest possible roles of mitochondrial dysfunction in bipolar disorder. Mitochondrial calcium regulation is important for neural plasticity. The role of neuroplasticity has been postulated in bipolar disorder. Further studies will clarify the role of mitochondrial dysfunction in bipolar disorder.
Proposed multigenic Composite Inheritance in major depression
2005, Medical Hypotheses
Various rationale have been considered in the familial inheritance pattern of major depression ranging from simple one-gene Mendelian inheritance to pseudo-additive gene action. We instead predict broad genetic expressivity patterns in the progeny of parents where at least one parent has recurrent major depression. In keeping with this idea, we feel that recurrent major depression could involve an expression imbalance of “normal” genes either exclusively or along with allelic variation(s). The patterns of pathology are theoretically conceptualized as qualitative and quantitative, meaning that expressivity of the genetic pattern in these children may range from minimal to complete even among siblings. Thus, prediction of the particular genetic pattern expressed by a particular child might prove difficult. The complex inheritance pattern that we propose is referred to as Composite Inheritance. Composite Inheritance considers that both the up- and down-regulation of luxury genes and housekeeping genes are involved in this dichotomous qualitative inheritance pattern and also the wide quantitative expressivity. The luxury genes include such genes as those coding for the neurotransmitter transporters and receptors. The housekeeping genes found to date include those that code for proteins involved in gene transcription, secondary signaling systems, fatty acid metabolism and transport, and intracellular calcium homeostasis. Other luxury and housekeeping genes no doubt remain to be discovered. Our current research utilizes an empirical approach involving advanced genomics and specialized pattern recognition mathematics in families having at least one parent with recurrent major depression. The goal of our research is to develop a pattern recognition system of genetic expressivity in major depression to which prevention and early intervention may be tailored.

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A rare coding variant within the wolframin gene in bipolar and unipolar affective disorder cases

Abstract

Section snippets

Acknowledgements

Lancet

Nature Genet

Lancet

A locus for bipolar affective disorder on chromosome 4p

Nat. Genet.

‘Statistical Methods in Core Research Vol. I: The Design and Analysis of Case-control Studies’

Prediction of transmembrane α -helices in prokariotic membrane proteins: the dense alignment surface method

Proc. Eng.

A diagnostic interview: the schedule for affective disorders and schizophrenia

Arch. Gen. Psychiatry