Hypoxia-regulated components of the U4/U6.U5 tri-small nuclear riboprotein complex: possible role in autosomal dominant retinitis pigmentosa
PMID: 18334927
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We detected novel missense changes in individual patients in the sequence of the genes PRPF4 and EFTUD2, but the role of these changes in relationship to disease could not be verified.
Case#: Benaglio_2014_Proband_001-417, sex not reported, age not reported, national origin German
CasePresentingHPOs: N/A
CaseHPOFreeText: The proband has been diagnosed with autosomal dominant retinitis pigmentosa.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Previous testing in the proband consisted of screening either by Sanger sequencing of 90% of known adRP genes, by genotyping microarray of known RP variants, or sequencing-based genotyping of RHO, RDS, PRPF31, RP1, PRPF8, IMPDH1, NRL, PRPF3, NR2E3, and SNRNP200.
CaseMethod1: next-generation sequencing of PRPF4 and EFTUD2 genes
CaseMethod2: Sanger sequencing of the coding regions of NHP2L1 and AAR2
CaseGenotypingMethod: Genotyping of the proband initially consisted of either Sanger sequencing of 90% of known adRP genes, genotyping microarray of known RP variants, or sequencing-based genotyping of RHO, RDS, PRPF31, RP1, PRPF8, IMPDH1, NRL, PRPF3, NR2E3, and SNRNP200. Subsequent genotyping was performed by next-generation sequencing of PRPF4 and EFTUD2 genes and Sanger sequencing of the coding regions of NHP2L1 and AAR2.
Variant: The proband harbors the NM_001244926.2(PRPF4):c.556C>G (p.Pro186Ala) variant in the heterozygous state.
ClinVar ID: 865751
gnomAD: The NM_001244926.2(PRPF4):c.556C>G (p.Pro186Ala) variant is found in gnomAD v4.1.0 at a frequency of 0.00006609 (90 alleles / 1180038 total alleles, with 0 homozygotes) in the European (non-Finnish) population https://gnomad.broadinstitute.org/variant/9-113283207-C-G?dataset=gnomad_r4
VariantEvidence: NM_001244926.2(PRPF4):c.556C>G (p.Pro186Ala) is a missense variant located 5 bp from the 3' end of exon 5 with no direct evidence of an abnormal impact on the PRPF4 protein.
CaseAddInfo: The proband has an affected sibling who also harbors the variant.
CasePMIDs: N/A
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The non-snRNP factors are also necessary for splicing, of which serine/arginine (SR)-rich proteins were considered as markers of splicing speckles (25). We determined whether p.Pro315Leu could affect the pattern of splicing speckles using SC-35, a non-snRNP component, as a marker (25). We performed immunofluorescence and Q-PCR on cells carrying either p.Pro315Leu or WT allele. By confocal microscopy, we found the level of endogenous SC-35 is dramatically increased with a diffused pattern in hPrp4Pro315Leu fibroblasts, whereas in control fibroblasts the SC-35 showed a distinctly speckled pattern (Fig. 4B and C). Consistently, Q-PCR revealed that the expression levels of SRSF1 (encoding SF2/ASF; NM_006924.4), another non-snRNP component and SRSF2 (encoding SC-35; NM_003016.4) were significantly increased in hPrp4Pro315Leu fibroblasts compared with WT fibroblasts (Fig. 4A). Similar changes in the levels and distribution of SC-35 were also observed in ARPE19 and 293T cells transfected with hPrp4Pro315Leu, but not in those transfected with hPrp4WT (Fig. 4D–G), indicating that the p.Pro315Leu variant of PRPF4 affected the splicing machinery.
ExperimentName: Altered pattern of splicing speckles in patient fibroblasts harboring a heterozygous p.Pro315Leu variant in PRPF4
PatientCell: CL:0000057 (fibroblast)
GeneFunction: GO:0000398 (mRNA splicing, via spliceosome)
GeneAlteration: Cells harbor a heterozygous p.Pro315Leu variant in PRPF4.
FunctionalEvidence: Patient cells harboring the variant exhibit a much higher level of endogenous marker of splicing speckles (SC-35) with a diffused distribution rather than a pattern of distinct speckles (Figures 4B and 4C). RT-PCR showed increased expression of SRSF1 and SRSF2 as well (Figure 4A). Collectively, the patient cells harboring the variant show molecular evidence of disrupted splicing.
FAVariants: The model harbors the NM_001244926.2(PRPF4):c.941C>T (p.Pro314Leu) variant in the heterozygous state (ClinVar ID: 143057).
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Identification of a PRPF4 loss-of-function variant that abrogates U4/U6.U5 tri-snRNP integration and is associated with retinitis pigmentosa
PMID: 25383878
Gene: PRPF4
HGNC: 17349
Disease: retinitis pigmentosa 70
MONDO: 0014400
InheritancePattern: autosomal dominant
Prevalence: The overall prevalence of retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of retinitis pigmentosa with a dominant mode of inheritance is estimated to be 15-35% (between 1 in 8,500 and 1 in 27,000). The proportion of that incidence made up by the specific form caused by variants in PRPF4 is not clear.
Penetrance: Known disease-causing alleles appear to be incompletely penetrant (PMID: 25383878).
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PRPF4
Case#: Dueñas Rey_2024_Proband_F11, sex and age not reported, part of cohort from Center for Medical Genetics Ghent
CasePresentingHPOs: Rod-cone dystrophy HP:0000510, Intellectual disability HP:0001249
CaseHPOFreeText: The proband has been diagnosed with rod-cone dystrophy and clinical signs of Bardet-Biedl syndrome. Intellectual disability may be part of the phenotype.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Previous testing in the proband consisted of whole exome sequencing with analysis focused on the 5' UTR regions of 378 genes highly expressed in the retina.
CaseMethod1: whole exome sequencing
CaseMethod2: Sanger sequencing of the coding regions of PRPF4
CaseGenotypingMethod: Genotyping of the proband initially consisted of whole exome sequencing, followed by Sanger sequencing of the coding regions of PRPF4.
Variant: The proband harbors the NM_001244926.2:c.-6C>T variant in the heterozygous state.
CAID: CA2579423618
gnomAD: The NM_001244926.2:c.-6C>T variant is found in gnomAD v4.1.0 at a frequency of 8.400e-7 (4 alleles / 1178930 total alleles, with 0 homozygotes) in the European (non-Finnish) population https://gnomad.broadinstitute.org/variant/9-113275738-C-T?dataset=gnomad_r4
VariantEvidence: NM_001244926.2:c.-6C>T is a 5' UTR variant located within the Kozak consensus sequence but has no direct evidence of an abnormal impact on PRPF4 expression.
CaseAddInfo: The proband has apparently unaffected parents.
CasePMIDs: N/A
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