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Abstract <p>Pathogenic variants in the <i>SLC26A4</i> gene (OMIM #605646, 21 exons), encoding the transmembrane protein pendrin, are one of the most significant genetic causes of hearing loss. It is known that approximately 25% of all pathogenic <i>SLC26A4</i> variants, located in both intronic and exonic regions of the gene (particularly near the exon–intron boundaries), lead to aberrant splicing. A detailed analysis of the <i>SLC26A4</i> gene in Tuvinian patients with hearing loss (from the Tyva Republic, Southern Siberia) revealed a specific spectrum of variations, including both previously identified pathogenic variants and novel variants with unclear clinical significance. One of the novel variants, c.1545T&gt;G, is located at a position potentially “sensitive” to splicing (the first nucleotide in exon 14). The segregation of c.1545T&gt;G with hearing loss in patient pedigrees and its significantly higher frequency in the patient sample compared to the control group suggest the pathogenic potential of this variant. The aim of this study was to analyze the effect of the novel c.1545T&gt;G variant of the <i>SLC26A4</i> gene on splicing using a minigene assay. A minigene system was constructed, including both the c.1545T&gt;G variant and the wild-type variant. The study was conducted in HEK293T cells and repeated in HeLa and SW480 cells. Comparative analysis of the splicing patterns in minigenes with the c.1545T&gt;G variant and the wild-type did not reveal any differences. Thus, the c.1545T&gt;G variant of the <i>SLC26A4</i> gene does not disrupt splicing, and its pathogenic effect may be attributed to the substitution of phenylalanine (Phe) with leucine (Leu) at amino acid position 515 (p.Phe515Leu) in the pendrin protein.</p>

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Analysis by Minigene Assay of the Splicing Effect of a Novel Variant c.1545T>G in the SLC26A4 Gene Associated with Hearing Loss

  • 期刊论文

  • 发表日期：

    2025年5月1日

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  • E. A. Panina,
  • V. Yu. Danilchenko,
  • M. V. Zytsar,
  • K. E. Orishchenko,
  • O. L. Posukh

摘要

Abstract

Pathogenic variants in the SLC26A4 gene (OMIM #605646, 21 exons), encoding the transmembrane protein pendrin, are one of the most significant genetic causes of hearing loss. It is known that approximately 25% of all pathogenic SLC26A4 variants, located in both intronic and exonic regions of the gene (particularly near the exon–intron boundaries), lead to aberrant splicing. A detailed analysis of the SLC26A4 gene in Tuvinian patients with hearing loss (from the Tyva Republic, Southern Siberia) revealed a specific spectrum of variations, including both previously identified pathogenic variants and novel variants with unclear clinical significance. One of the novel variants, c.1545T>G, is located at a position potentially “sensitive” to splicing (the first nucleotide in exon 14). The segregation of c.1545T>G with hearing loss in patient pedigrees and its significantly higher frequency in the patient sample compared to the control group suggest the pathogenic potential of this variant. The aim of this study was to analyze the effect of the novel c.1545T>G variant of the SLC26A4 gene on splicing using a minigene assay. A minigene system was constructed, including both the c.1545T>G variant and the wild-type variant. The study was conducted in HEK293T cells and repeated in HeLa and SW480 cells. Comparative analysis of the splicing patterns in minigenes with the c.1545T>G variant and the wild-type did not reveal any differences. Thus, the c.1545T>G variant of the SLC26A4 gene does not disrupt splicing, and its pathogenic effect may be attributed to the substitution of phenylalanine (Phe) with leucine (Leu) at amino acid position 515 (p.Phe515Leu) in the pendrin protein.