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The Impact of Mutations in Wolframin on Psychiatric Disorders

ABSTRACT: Wolfram Syndrome is a rare autosomal recessive disease characterized by early-onset diabetes mellitus, neurodegeneration, and psychological disorders. Mutations in the gene WFS1, coding for the protein wolframin, cause Wolfram Syndrome and are associated with bipolar disorder and schizophrenia. This report aims to connect WFS1 mutations to their impact on protein expression and structure, which ultimately translates to altered cell function and behavioral alterations of an individual. Methods: Published data were used to compile WFS1 mutations associated with psychiatric symptoms, both in homozygous patients and heterozygous carriers of WFS1 mutations. These mutations were evaluated in silico using SNAP2, PolyPhen-2, and PROVEAN to predict the effects of sequence variants. Statistical analysis was performed to assess the correlation between the locations of the mutations and the damage prediction scores. Results: Several mutations, clustering in the center and C-terminus of the WFS1 polypeptide, such as A559T and R558C, are found in individuals with psychiatric diseases and appear particularly impactful on protein structure. Our analysis showed that mutations in all regions of wolframin were present in patients with schizophrenia whereas only cytoplasmic and ER luminal mutations were reported in patients with manic episodes and bipolar disorders. According to Poly-Phen-2 predictions, 82.4% of the ER lumen mutations and 85.7% of the membrane mutations are damaging. Conclusion: We propose mood disorders in Wolfram Syndrome and heterozygous carriers of WFS1 mutations are the consequence of specific mutations in WFS1 that alter the structure of wolframin, resulting in intracellular calcium dysregulations and impaired cell signaling, Understanding the effect of WFS1 mutations on bipolar disorder and schizoprenia is integral to designing clinically targeted treatments for both diseases, which need more specialized treatments.

SUBMITTER: Munshani S

PROVIDER: S-EPMC8567103 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundPsychiatric disorders are common in patients with cancer. The impact of both psychiatric disorders and psychiatric treatment on mortality in patients with cancer needs to be established.Materials and methodsNationwide claims data were analyzed. To investigate the association between psychiatric disorders and mortality, 6,292 male and 4,455 female patients with cancer who did not have a record of psychiatric disorders before cancer onset were included. To examine the association between psychiatric treatment and mortality, 1,467 male and 1,364 female patients with cancer were included. Incident psychiatric disorder and receipt of psychiatric treatment within 30 days from the onset of a psychiatric disorder were the main independent variables. Dependent variables were all-cause and cancer-related mortality. Cox proportional hazards regression with time-dependent covariates was used.ResultsThe onset of psychiatric disorders was associated with a significantly increased risk of mortality in both male (all-cause hazard ratio [HR]: 1.55; cancer-related HR: 1.47) and female patients with cancer (all-cause HR: 1.50; cancer-related HR: 1.44) compared with patients with cancer without psychiatric disorders. Both male and female patients who received psychiatric treatment within 30 days of diagnosis of a psychiatric disorder had a lower risk of cancer-related mortality (males, HR: 0.73; females, HR: 0.71) compared with patients with cancer with psychiatric disorders who did not receive psychiatric treatment.ConclusionPatients with cancer with newly diagnosed psychiatric disorders had a higher mortality rate. Among these, those who received psychiatric treatment showed lower rates of mortality. Thus, early detection and early treatment of psychiatric disorders in patients with cancer is needed.Implications for practiceThe current study supplements the body of evidence supporting the association of psychiatric disorders onset and treatment with cancer outcomes. Patients with cancer showed an increased risk of both all-cause and cancer-related mortality upon psychiatric disorder onset. Among patients with newly diagnosed psychiatric disorders, those who received psychiatric treatment showed lower cancer-related mortality. Thus, raising awareness of both the risk of psychiatric disorders and the positive effects of psychiatric treatment on cancer outcomes is necessary among patients with cancer, caregivers, and oncologists. Furthermore, it is necessary to adopt a multidisciplinary approach, encouraging patients with cancer to undergo a neuropsychological assessment of their mental health status and receive appropriate and timely psychological interventions.

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The Impact of Mutations in Wolframin on Psychiatric Disorders

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