Dataset Information

Christianson syndrome: A novel splicing variant of SLC9A6 causes exon skipping in a Chinese boy and a literature review.

ABSTRACT:

Background

Variants in the endosomal solute carrier family 9 member A6 (SLC9A6)/(Na⁺ ,K⁺ )/H⁺ exchanger 6 (NHE6) gene have been linked to epilepsy, speech loss, truncal ataxia, hyperkinesia, and postnatal microcephaly.

Methods

In the present study, we evaluated genetic alterations in a 3-year-old Chinese boy displayed features of epilepsy, psychomotor retardation, microcephaly, low body weight, difficulty in feeding, excessive movement, attention loss, ataxia, and cerebellar atrophy and his healthy family using WES method. The identified variant was further confirmed by Sanger sequencing method. Finally, minigene assays were used to verify whether the novel SLC9A6 intronic variant influenced the normal splicing of mRNA.

Results

We identified a novel hemizygous splicing variant [NM_001042537.1: c.1463-1G>A] in SLC9A6 by trio-based exome sequencing. The minigene expression in vitro confirmed the splicing variant altered a consensus splice acceptor site of SLC9A6 intron 11, resulting in skipping over exon 12.

Conclusions

Our finding extends the catalog of pathogenic intronic variants affecting SLC9A6 pre-mRNA splicing and provides a basis for the genetic diagnosis of CS.

SUBMITTER: Zhang X

PROVIDER: S-EPMC8761434 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Publications

Christianson syndrome: A novel splicing variant of SLC9A6 causes exon skipping in a Chinese boy and a literature review.

Zhang Xiaoge X Wu Xiaofang X Liu Hongli H Song Tingting T Jiang Yongsheng Y He Hanhan H Yang Shaoqing S Xie Yun Y

Journal of clinical laboratory analysis 20211117 1

<h4>Background</h4>Variants in the endosomal solute carrier family 9 member A6 (SLC9A6)/(Na<sup>+</sup> ,K<sup>+</sup> )/H<sup>+</sup> exchanger 6 (NHE6) gene have been linked to epilepsy, speech loss, truncal ataxia, hyperkinesia, and postnatal microcephaly.<h4>Methods</h4>In the present study, we evaluated genetic alterations in a 3-year-old Chinese boy displayed features of epilepsy, psychomotor retardation, microcephaly, low body weight, difficulty in feeding, excessive movement, attention l ...[more]

PMID: 34791706

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Project description: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.

Dataset Information

Christianson syndrome: A novel splicing variant of SLC9A6 causes exon skipping in a Chinese boy and a literature review.

Background

Methods

Results

Conclusions

Publications

Christianson syndrome: A novel splicing variant of SLC9A6 causes exon skipping in a Chinese boy and a literature review.

Similar Datasets

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