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GPATCH11 variants cause mis-splicing and early onset retinal dystrophy with neurological impairment

ABSTRACT: G-patch domain-containing proteins have emerged as pivotal regulators of RNA metabolism, dysfunctions of which have been linked to a large range of phenotypic traits. This study provides compelling evidence that biallelic mutations in GPATCH11 lead to severe early-onset photoreceptor degeneration, neurological issues, and skeletal abnormalities. Using engineered disease variants in mice, we show abnormal levels of spliceosome components in mutant retina, together with significant splicing deregulation, indicating a role for GPATCH11 in spliceosome homeostasis and splicing. Additionally, we identified deregulated gene expression, partly independent of splicing abnormalities, suggesting GPATCH11 involvement in transcriptional regulation. The affected genes were related to phototransduction and transmission of visual message, protein homeostasis, RNA homeostasis, and cilia metabolism. GPATCH11 presence in cilia basal bodies further supports its potential role in cilia functions. Studying GPATCH11 dysfunctions sheds light on the complex roles of this protein in RNA metabolism, highlighting GPATCH11's significance in maintaining proper gene expression and its contributions to various aspects of retinal, neurological, and skeletal function or development.

ORGANISM(S): Mus musculus (mouse)

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PROVIDER: S-BSST1157 | biostudies-other |

REPOSITORIES: biostudies-other

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