Mutations in spliceosomal proteins and retina degeneration

Abstract

A majority of human genes contain non-coding intervening sequences – introns that must be precisely excised from the pre-mRNA molecule. This event requires the coordinated action of five major small nuclear ribonucleoprotein particles (snRNPs) along with additional non-snRNP splicing proteins. Introns must be removed with nucleotidal precision, since even a single nucleotide mistake would result in a reading frame shift and production of a non-functional protein. Numerous human inherited diseases are caused by mutations that affect splicing, including mutations in proteins which are directly involved in splicing catalysis. One of the most common hereditary diseases associated with mutations in core splicing proteins is retinitis pigmentosa (RP). So far, mutations in more than 70 genes have been connected to RP. While the majority of mutated genes are expressed specifically in the retina, eight target genes encode for ubiquitous core snRNP proteins (Prpf3, Prpf4, Prpf6, Prpf8, Prpf31, and SNRNP200/Brr2) and splicing factors (RP9 and DHX38). Why mutations in spliceosomal proteins, which are essential in nearly every cell in the body, causes a disease that displays such a tissue-specific phenotype is currently a mystery. In this review, we recapitulate snRNP functions, summarize the missense mutations which are found in spliceosomal proteins as well as their impact on protein functions and discuss specific models which may explain why the retina is sensitive to these mutations.

Splicing-related Retinitis Pigmentosa mutations mimicked in C. elegans allow the identification of disease modifiers and drug screens

“…In humans, s-adRP mutations cause defects that provoke degeneration of photoreceptors in the retina through a very slow process (28). Such slowness is a handicap in the modeling of the disease and hampers the understanding of the molecular mechanisms of the pathology.…”

“…PRPF8 and SNRNP200 are two of the seven genes associated to autosomal dominant Retinitis Pigmentosa (adRP) (9). Several mutations in these two genes have been identified in distinct families at different countries (10)(11)(12)(13)(14)(15)(16).…”

High prevalence of mutations affecting the splicing process in a Spanish cohort with autosomal dominant retinitis pigmentosa

“…This gene encodes for the 200-kDa helicase hBrr2. During splicing, the spliceosome undergoes structural rearrangements that are mediated by several RNA helicases including hBrr2, which is essential for unwinding of the U4/U6 snRNP duplex, a key step in the catalytic activation of the spliceosome complex3536. hBrr2 comprises two helicase modules, one active and the other with regulatory activity.…”

“…All six mutations identified in SNRNP200 to date, including the Ser1087Leu mutation, are located in the hBrr2 protein region containing the first DExD-helicase module, a key component for the U4-U6 unwinding function in vivo and in vitro and for cell survival353637. The first of the two consecutive Hel308-like modules, which comprises a DExD/H domain and a Sec63 domain, shows the highest level of conservation among species, thus pointing to its functional relevance38.…”

Brr2 is a splicing fidelity factor

“…Brr2 is one of multiple spliceosomal proteins implicated in Retinitis Pigmentosa (RP), a hereditary form of blindness (Růžičková and Staněk 2017). Point mutations identified as causal in RP tend to map to highly conserved, and thus likely functionally important, amino acids.…”