A P2RX2 exon-2 complex indel disrupts splicing and reduces P2X2 output: implications for DFNA41 and variable…

Abstract

Background

P2RX2 encodes the ATP-gated P2X2 receptor associated with autosomal dominant non-syndromic hearing loss 41 (DFNA41). DFNA41 is characterized by progressive sensorineural hearing loss and an increased susceptibility to acoustic trauma. However, the specific phenotypic consequences of truncating or splice-altering variants within this gene remain poorly understood.Methods

We evaluated a Han Chinese family using a targeted hearing-loss gene panel with segregation analysis. Splicing consequences of a complex indel in P2RX2 exon 2 (NM_174873: c.278_288delinsACGTGAAGCCCCC) were assessed using a pcMINI-C minigene assay, followed by RT-qPCR and Western blotting after expression of the reconstructed aberrant isoforms in heterologous cells.Results

The proband had early-onset severe-to-profound sensorineural hearing loss and carried a heterozygous P2RX2 complex indel inherited from the father, together with a maternally inherited pathogenic GJB2 frameshift. Minigene assays revealed cryptic splice usage that generated two frameshifted isoforms with premature termination codons. Both mutant isoforms showed reduced steady-state mRNA and markedly reduced P2X2 protein output, consistent with decreased overall P2X2 expression.Conclusion

We functionally establish that this exon-2 complex indel disrupts splicing and markedly reduces P2X2 output. These findings support a mechanism of loss-of-function and haploinsufficiency. The pronounced intrafamilial variability-manifesting as profound early-onset hearing loss in the proband compared to a milder phenotype in the heterozygous father-underscores the variable expressivity and incomplete penetrance characteristic of P2RX2-linked DFNA41. Although oligogenic modulation is a plausible conceptual framework, it requires cautious interpretation and independent future validation.

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BibTeX RIS

BibTeX

@article{tao2026p2rx2,
  title = {{A P2RX2 exon-2 complex indel disrupts splicing and reduces P2X2 output: implications for DFNA41 and variable expressivity}},
  author = {Yilun Tao and Wenxia Song and Lihong Wang and Tongli Han and Dong Han and Luna Hao and Chen Zhao and Jiangyuan Ping and Xiaoze Li},
  journal = {Frontiers in genetics},
  year = {2026},
  month = oct,
  doi = {10.3389/fgene.2026.1934538},
  url = {https://europepmc.org/article/PMC/PMC13727070},
  note = {CC BY},
}

RIS

TY  - JOUR
TI  - A P2RX2 exon-2 complex indel disrupts splicing and reduces P2X2 output: implications for DFNA41 and variable expressivity
AU  - Yilun Tao
AU  - Wenxia Song
AU  - Lihong Wang
AU  - Tongli Han
AU  - Dong Han
AU  - Luna Hao
AU  - Chen Zhao
AU  - Jiangyuan Ping
AU  - Xiaoze Li
PY  - 2026
DA  - 2026/10/20
JO  - Frontiers in genetics
DO  - 10.3389/fgene.2026.1934538
UR  - https://europepmc.org/article/PMC/PMC13727070
AB  - Background  P2RX2 encodes the ATP-gated P2X2 receptor associated with autosomal dominant non-syndromic hearing loss 41 (DFNA41). DFNA41 is characterized by progressive sensorineural hearing loss and an increased susceptibility to acoustic trauma. However, the specific phenotypic consequences of truncating or splice-altering variants within this gene remain poorly understood.Methods  We evaluated a Han Chinese family using a targeted hearing-loss gene panel with segregation analysis. Splicing consequences of a complex indel in P2RX2 exon 2 (NM_174873: c.278_288delinsACGTGAAGCCCCC) were assessed using a pcMINI-C minigene assay, followed by RT-qPCR and Western blotting after expression of the reconstructed aberrant isoforms in heterologous cells.Results  The proband had early-onset severe-to-profound sensorineural hearing loss and carried a heterozygous P2RX2 complex indel inherited from the father, together with a maternally inherited pathogenic GJB2 frameshift. Minigene assays revealed cryptic splice usage that generated two frameshifted isoforms with premature termination codons. Both mutant isoforms showed reduced steady-state mRNA and markedly reduced P2X2 protein output, consistent with decreased overall P2X2 expression.Conclusion  We functionally establish that this exon-2 complex indel disrupts splicing and markedly reduces P2X2 output. These findings support a mechanism of loss-of-function and haploinsufficiency. The pronounced intrafamilial variability-manifesting as profound early-onset hearing loss in the proband compared to a milder phenotype in the heterozygous father-underscores the variable expressivity and incomplete penetrance characteristic of P2RX2-linked DFNA41. Although oligogenic modulation is a plausible conceptual framework, it requires cautious interpretation and independent future validation.
SN  - 1664-8021
ER  -

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