AKR1A1 Variant Associated With Schizophrenia Causes Exon Skipping, Leading to Loss of Enzymatic Activity

Kyoka Iino, Kazuya Toriumi, Riko Agarie, Mitsuhiro Miyashita, Kazuhiro Suzuki, Yasue Horiuchi, Kazuhiro Niizato, Kenichi Oshima, Atsushi Imai, Yukihiro Nagase, Itaru Kushima, Shinsuke Koike, Tempei Ikegame, Seiichiro Jinde, Eiichiro Nagata, Shinsuke Washizuka, Toshio Miyata, Shunya Takizawa, Ryota Hashimoto, Kiyoto KasaiNorio Ozaki, Masanari Itokawa, Makoto Arai*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Schizophrenia is a heterogeneous psychiatric disorder characterized by positive symptoms such as hallucinations and delusions, negative symptoms such as anhedonia and flat affect, and cognitive impairment. Recently, glucuronate (GlucA) levels were reported to be significantly higher in serum of patients with schizophrenia than those in healthy controls. The accumulation of GlucA is known to be related to treatment-resistant schizophrenia, since GlucA is known to promote drug excretion by forming conjugates with drugs. However, the cause of GlucA accumulation remains unclear. Aldo-keto reductase family one member A1 (AKR1A1) is an oxidoreductase that catalyzes the reduction of GlucA. Genetic loss of AKR1A1 function is known to result in the accumulation of GlucA in rodents. Here, we aimed to explore genetic defects in AKR1A1 in patients with schizophrenia, which may result in the accumulation of GlucA. We identified 28 variants of AKR1A1 in patients with schizophrenia and control subjects. In particular, we identified a silent c.753G > A (rs745484618, p. Arg251Arg) variant located at the first position of exon 8 to be associated with schizophrenia. Using a minigene assay, we found that the c.753G > A variant induced exon 8 skipping in AKR1A1, resulting in a frameshift mutation, which in turn led to truncation of the AKR1A1 protein. Using the recombinant protein, we demonstrated that the truncated AKR1A1 completely lost its activity. Furthermore, we showed that AKR1A1 mRNA expression in the whole blood cells of individuals with the c.753G > A variant tended to be lower than that in those without the variants, leading to lower AKR activity. Our findings suggest that AKR1A1 carrying the c.753G > A variant induces exon skipping, leading to a loss of gene expression and enzymatic activity. Thus, GlucA patients with schizophrenia with the c.753G > A variant may show higher GlucA levels, leading to drug-resistant schizophrenia, since drug excretion by GlucA is enhanced.

Original languageEnglish
Article number762999
JournalFrontiers in Genetics
Volume12
DOIs
Publication statusPublished - 2021 Dec 6
Externally publishedYes

Keywords

  • aldo-keto reductase family 1 member A1
  • exon skipping
  • frameshift mutation
  • glucuronate
  • single nucleotide variant (SNV)
  • treatment-resistant schizophrenia

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Genetics(clinical)

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