PRPF31
Encyclopedia
PRP31 pre-mRNA processing factor 31 homolog (S. cerevisiae), also known as PRPF31, is a protein
which in humans is encoded by the PRPF31 gene
.
hPRP31. It is essential for the formation of the spliceosome
hPRP31 is associated with the U4
/U4
di-snRNP and interacts with another splicing factor, hPRP6
, to form the U4/U6-U5
tri-snRNP. It has been shown that when hPRP31 is knocked down by RNAi
, U4/U6 di-snPRNPs accumulate in the Cajal bodies
and the U4/U6-U5 tri-snRNP cannot form.
PRPF31 is recruited to intron
s following the attachment of U4 and U6 RNAs and the 15.5K protein NHP2L1
. The addition of PRPF31 is crucial for the transition of the spliceosomal complex to the activated state.
. The first mutation in PRPF31 was discovered by Vithana et al. in 2001. Retinitis pigmentosa (RP) is a clinically and genetically heterogeneous group of retinal dystrophies characterized by a progressive degeneration of photoreceptors, eventually resulting in severe visual impairment.
(adRP) in a mixed UK population. However, the inheritance pattern of PRPF31 mutations is atypical of dominant inheritance, showing the phenomenon of partial penetrance, whereby a dominant mutations appear to "skip" generations. This is thought to be due to the presence of two wild type
alleles, a high-expressivity allele
and a low-expressivity allele. If a patient has a mutant allele and a high-expressivity allele, they do not show disease phenotype. If a patient has a mutant allele and a low-expressivity allele, the residual level of protein falls beneath the threahold for normal function, and so they do show disease phenotype. The inheritance pattern of PRPF31 can therefore be thought of as a variation of haploinsufficiency
. This variant of haploinsufficiency is only seen in two other human diseases: Erythropoietic protoporphyria
, caused by mutations in the FECH gene; and hereditary elliptocytosis
, caused by mutations in the spectrin
gene.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
which in humans is encoded by the PRPF31 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
Function
PRPF31 is the gene coding for the splicing factorSplicing factor
A splicing factor is a protein involved in the removal of introns and exons from strings of messenger RNA; the process takes place in particles known as spliceosomes....
hPRP31. It is essential for the formation of the spliceosome
Spliceosome
A spliceosome is a complex of snRNA and protein subunits that removes introns from a transcribed pre-mRNA segment. This process is generally referred to as splicing.-Composition:...
hPRP31 is associated with the U4
U4 spliceosomal RNA
The U4 small nuclear Ribo-Nucleic Acid is a non-coding RNA component of the major or U2-dependent spliceosome – a eukaryotic molecular machine involved in the splicing of pre-messenger RNA...
/U4
U6 spliceosomal RNA
U6 snRNA is the non-coding small nuclear RNA component of U6 snRNP , an RNA-protein complex that combines with other snRNPs, unmodified pre-mRNA, and various other proteins to assemble a spliceosome, a large RNA-protein molecular complex upon which splicing of pre-mRNA occurs...
di-snRNP and interacts with another splicing factor, hPRP6
PRPF6
Pre-mRNA-processing factor 6 is a protein that in humans is encoded by the PRPF6 gene.-Interactions:PRPF6 has been shown to interact with TXNL4B, ARAF and Androgen receptor.-External links:*...
, to form the U4/U6-U5
U5 spliceosomal RNA
U5 RNA is a non-coding RNA that is a component of both types of known spliceosome. The precise function of this molecule is unknown, though it is known that the 5' loop is required for splice site selection and p220 binding, and that both the 3' stem-loop and the Sm site are important for Sm...
tri-snRNP. It has been shown that when hPRP31 is knocked down by RNAi
RNA interference
RNA interference is a process within living cells that moderates the activity of their genes. Historically, it was known by other names, including co-suppression, post transcriptional gene silencing , and quelling. Only after these apparently unrelated processes were fully understood did it become...
, U4/U6 di-snPRNPs accumulate in the Cajal bodies
Cajal body
Cajal bodies are spherical sub-organelles of 0.3-1.0 µm in diameter found in the nucleus of proliferative cells like embryonic cells and tumor cells, or metabolically active cells like neurons. In contrast to cytoplasmic organelles, CBs lack any phospholipid membrane which would separate their...
and the U4/U6-U5 tri-snRNP cannot form.
PRPF31 is recruited to intron
Intron
An intron is any nucleotide sequence within a gene that is removed by RNA splicing to generate the final mature RNA product of a gene. The term intron refers to both the DNA sequence within a gene, and the corresponding sequence in RNA transcripts. Sequences that are joined together in the final...
s following the attachment of U4 and U6 RNAs and the 15.5K protein NHP2L1
NHP2L1
NHP2-like protein 1 is a protein that in humans is encoded by the NHP2L1 gene.-Further reading:...
. The addition of PRPF31 is crucial for the transition of the spliceosomal complex to the activated state.
Clinical significance
A mutation in PRPF31 is one of 4 known mutations in splicing factors which are known to cause retinitis pigmentosaRetinitis pigmentosa
Retinitis pigmentosa is a group of genetic eye conditions that leads to incurable blindness. In the progression of symptoms for RP, night blindness generally precedes tunnel vision by years or even decades. Many people with RP do not become legally blind until their 40s or 50s and retain some...
. The first mutation in PRPF31 was discovered by Vithana et al. in 2001. Retinitis pigmentosa (RP) is a clinically and genetically heterogeneous group of retinal dystrophies characterized by a progressive degeneration of photoreceptors, eventually resulting in severe visual impairment.
Inheritance
Mutations in PRPF31 are inherited in an autosomal dominant manner, accounting for 2.5% of cases of autosomal dominant retinitis pigmentosaRetinitis pigmentosa
Retinitis pigmentosa is a group of genetic eye conditions that leads to incurable blindness. In the progression of symptoms for RP, night blindness generally precedes tunnel vision by years or even decades. Many people with RP do not become legally blind until their 40s or 50s and retain some...
(adRP) in a mixed UK population. However, the inheritance pattern of PRPF31 mutations is atypical of dominant inheritance, showing the phenomenon of partial penetrance, whereby a dominant mutations appear to "skip" generations. This is thought to be due to the presence of two wild type
Wild type
Wild type refers to the phenotype of the typical form of a species as it occurs in nature. Originally, the wild type was conceptualized as a product of the standard, "normal" allele at a locus, in contrast to that produced by a non-standard, "mutant" allele...
alleles, a high-expressivity allele
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
and a low-expressivity allele. If a patient has a mutant allele and a high-expressivity allele, they do not show disease phenotype. If a patient has a mutant allele and a low-expressivity allele, the residual level of protein falls beneath the threahold for normal function, and so they do show disease phenotype. The inheritance pattern of PRPF31 can therefore be thought of as a variation of haploinsufficiency
Haploinsufficiency
Haploinsufficiency occurs when a diploid organism only has a single functional copy of a gene and the single functional copy of the gene does not produce enough of a gene product to bring about a wild-type condition, leading to an abnormal or diseased state...
. This variant of haploinsufficiency is only seen in two other human diseases: Erythropoietic protoporphyria
Erythropoietic protoporphyria
Erythropoietic protoporphyria is a relatively mild form of porphyria, although very painful, which arises from a deficiency in the enzyme ferrochelatase, leading to abnormally high levels of protoporphyrin in the tissue...
, caused by mutations in the FECH gene; and hereditary elliptocytosis
Hereditary elliptocytosis
Hereditary elliptocytosis, also known as ovalocytosis, is an inherited blood disorder in which an abnormally large number of the sufferer's erythrocytes are elliptical rather than the typical biconcave disc shape. It is one of many red-cell membrane defects. In its severe forms, this disorder...
, caused by mutations in the spectrin
Spectrin
Spectrin is a cytoskeletal protein that lines the intracellular side of the plasma membrane of many cell types in pentagonal or hexagonal arrangements, forming a scaffolding and playing an important role in maintenance of plasma membrane integrity and cytoskeletal structure...
gene.