CLINT1 – Schizophrenia

The association between CLINT1 and schizophrenia has been evaluated in several studies with conflicting results, resulting in a disputed ClinGen gene–disease classification. One family‐based association study in a Latin American cohort identified a statistically significant association between genetic variation in CLINT1 and psychosis among 337 families comprising 1,423 subjects (PMID:18929466). This study provided initial support by demonstrating that haplotypes spanning the gene were significantly associated with psychotic manifestations, including schizophrenia and related phenotypes.

Genetic evidence further includes analyses of single nucleotide polymorphisms across CLINT1. However, despite the encouraging findings in the Latin American study, two subsequent investigations—a case–control analysis in a Japanese population of 354 patients and 365 controls (PMID:18696005) and a family‐based study in Han Chinese subjects with 269 patients and 236 controls (PMID:16616458)—failed to replicate the association. These studies, which considered multiple variant classes, underscore the inconsistency in the genetic evidence supporting CLINT1 as a risk factor for schizophrenia.

Segregation data from the initial study did not explicitly enumerate affected relatives with segregating variants, and thus the observed family-based association has not been bolstered by clear segregation counts. In addition, while a specific variant such as c.123A>T (p.Lys41Asn) can be noted from the available variant data, the overall variant spectrum remains limited in providing conclusive mechanistic insight, especially when compared across studies.

On the experimental front, a functional assessment study in zebrafish demonstrated that mutation of clint1 leads to epidermal defects and inflammation resembling psoriasis (PMID:19570844). Although these studies are robust in the context of skin biology and epidermal homeostasis, their findings do not provide direct evidence for a neuronal mechanism in schizophrenia. This divergence between the functional context and the neuropsychiatric phenotype further weakens the overall support for CLINT1’s role in schizophrenia pathogenesis.

In summary, the genetic evidence for CLINT1 in schizophrenia is contradictory: a single positive association study in a large family cohort is counterbalanced by two independent negative replication studies, and the only available functional evidence is derived from a model of skin pathology rather than a neurobiological system. Overall, the integration of these findings leaves the gene–disease association in a disputed state, cautioning against its immediate diagnostic or commercial use without further confirmatory research.

Key take‑home sentence: Although initial findings suggested a link between CLINT1 and schizophrenia, conflicting genetic replication and non‑corroborative functional data highlight the need for additional studies to establish clinical utility.

References

• Schizophrenia research | 2008 | The epsin 4 gene is associated with psychotic disorders in families of Latin American origin PMID:18929466
• Journal of neural transmission | 2008 | Failure to confirm an association between Epsin 4 and schizophrenia in a Japanese population PMID:18696005
• Schizophrenia research | 2006 | Genetic analysis of the human ENTH (Epsin 4) gene and schizophrenia PMID:16616458
• Development (Cambridge, England) | 2009 | The ENTH domain protein Clint1 is required for epidermal homeostasis in zebrafish PMID:19570844

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