DHX38 – Retinitis Pigmentosa

The association between DHX38 and retinitis pigmentosa is supported by robust genetic and experimental evidence. Initial studies identified a novel missense mutation, c.995G>A (p.Gly332Asp), in a consanguineous Pakistani family, where four affected individuals were found to be homozygous for this variant while unaffected relatives were heterozygous (PMID:24737827). Homozygosity mapping and exome sequencing were instrumental in localizing the disease signal to this mutation, with a LOD score of 3.25 further supporting linkage in this single-family report.

Subsequent multi-patient studies have confirmed the contribution of DHX38 in the etiology of early-onset autosomal recessive retinitis pigmentosa by identifying additional deleterious missense variants. In two independent Pakistani families, the variant c.971G>A (p.Arg324Gln) was shown to segregate with the arRP phenotype, yielding LOD scores of 5.0 and 4.3 in the respective families (PMID:30208423). These findings across multiple families reinforce the genetic association and the recessive mode of inheritance.

Detailed genetic evidence demonstrates that the two identified missense variants disrupt the function of the DHX38 protein, a critical pre-mRNA splicing factor. The variant c.995G>A (p.Gly332Asp), chosen here as the representative allele, has been shown to be absent in extensive control populations, further increasing the specificity of this association (PMID:24737827; PMID:30208423). Together, these data indicate that the pathogenic variants are rare, co-segregate with the disease phenotype, and meet rigorous variant classification criteria.

Functional studies add a complementary layer of evidence. Experimental assessments using yeast models and in vitro splicing assays have demonstrated that DHX38, which encodes a protein homologous to the splicing factor PRP16, plays an essential role in pre-mRNA splicing. Mutations affecting conserved amino acids in DHX38 result in aberrant splicing, a mechanism that is highly consistent with the observed retinal degeneration phenotype (PMID:9611193; PMID:24848011).

The integrated evidence from both case reports and multi-patient studies, as well as functional assays, clearly supports a strong gene-disease relationship. This coherent narrative highlights that DHX38 contributes to retinal health by ensuring proper mRNA splicing, and its disruption leads to the degeneration characteristic of retinitis pigmentosa. The degree of genetic segregation and the concordant functional data substantiate this association well beyond anecdotal reports.

Key take‑home sentence: The robust genetic and experimental evidence confirms that DHX38 mutations are a strong, clinically actionable contributor to early-onset autosomal recessive retinitis pigmentosa, supporting its use in diagnostic decision‑making and targeted therapeutic development.

References

• Journal of Medical Genetics • 2014 • A missense mutation in the splicing factor gene DHX38 is associated with early‑onset retinitis pigmentosa with macular coloboma PMID:24737827
• Investigative Ophthalmology & Visual Science • 2018 • Confirmation of the Role of DHX38 in the Etiology of Early‑Onset Retinitis Pigmentosa PMID:30208423
• Genetics • 1998 • Mutational analysis of the yeast DEAH‑box splicing factor Prp16 PMID:9611193
• Nucleic Acids Research • 2014 • Remodeling of U2‑U6 snRNA helix I during pre‑mRNA splicing by Prp16 and the NineTeen Complex protein Cwc2 PMID:24848011

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