Retinitis pigmentosa-linked mutation in DHX38 modulates its splicing activity

Abstract

Retinitis pigmentosa (RP) is a hereditary disease affecting tens of thousands of people world-wide. Here we analyzed the effect of an amino acid substitution in the RNA helicase DHX38 (Prp16) causing RP. DHX38 has been proposed as the helicase important for the 2nd step of splicing. We showed that DHX38 associates with key splicing factors involved in both splicing steps but did not find any evidence that the RP mutations changes DHX38 interaction profile with the spliceosome. We further downregulated DHX38 and monitored changes in splicing. We observed only minor perturbations of general splicing but detected modulation of ~70 alternative splicing events. Next, we probed DHX38 function in splicing of retina specific genes and found that FSCN2 splicing is dependent on DHX38. In addition, RHO splicing was inhibited specifically by expression of DHX38 RP variant. Finally, we showed that overexpression of DHX38 promotes usage of canonical as well as cryptic 5’ splice sites in HBB splicing reporter. Together, our data show that DHX38 is a splicing factor that promotes splicing of cryptic splice sites and regulate alternative splicing. We further provide evidence that the RP-linked substitution G332D modulates DHX38 splicing activity.

Novel frameshift Variant c.3056delA of the DHX38 Gene in a Chinese Family With Retinitis Pigmentosa

“…Therefore, it seems that this heterozygous mutation, as a loss of function mutation, leads to elimination of DEAH box function. Mina Obuća proved that Meanwhile, DHX38 is well-connected with the spilcing of RHO which could product Rhodopsin [15]. Based on structure prediction results, the mutant protein is partially missing and its 3D structure is obviously different from wild-type protein.…”

Identification of hub genes associated with spermatogenesis by bioinformatics analysis

“…The expression of miR-145 in breast and ovarian cancer cells affects cell migration and inhibits EMT by targeting FSCN1 44 . FSCN2 has been found in retinal photoreceptor cells and its splicing variants might be related to retinitis pigmentosa and hearing loss 45 , 46 . While FSCN3 is a testis-specific expressed gene, mainly expressed in elongated spermatids during late spermiogenesis 47 .…”