Identification of a PRPF4 loss-of-function variant that abrogates U4/U6.U5 tri-snRNP integration and is associated with retinitis pigmentosa
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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. / Linder, Bastian; Hirmer, Anja; Gal, Andreas; Rüther, Klaus; Bolz, Hanno Jörn; Winkler, Christoph; Laggerbauer, Bernhard; Fischer, Utz.
in: PLOS ONE, Jahrgang 9, Nr. 11, 2014, S. e111754.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Identification of a PRPF4 loss-of-function variant that abrogates U4/U6.U5 tri-snRNP integration and is associated with retinitis pigmentosa
AU - Linder, Bastian
AU - Hirmer, Anja
AU - Gal, Andreas
AU - Rüther, Klaus
AU - Bolz, Hanno Jörn
AU - Winkler, Christoph
AU - Laggerbauer, Bernhard
AU - Fischer, Utz
PY - 2014
Y1 - 2014
N2 - Pre-mRNA splicing by the spliceosome is an essential step in the maturation of nearly all human mRNAs. Mutations in six spliceosomal proteins, PRPF3, PRPF4, PRPF6, PRPF8, PRPF31 and SNRNP200, cause retinitis pigmentosa (RP), a disease characterized by progressive photoreceptor degeneration. All splicing factors linked to RP are constituents of the U4/U6.U5 tri-snRNP subunit of the spliceosome, suggesting that the compromised function of this particle may lead to RP. Here, we report the identification of the p.R192H variant of the tri-snRNP factor PRPF4 in a patient with RP. The mutation affects a highly conserved arginine residue that is crucial for PRPF4 function. Introduction of a corresponding mutation into the zebrafish homolog of PRPF4 resulted in a complete loss of function in vivo. A series of biochemical experiments suggested that p.R192H disrupts the binding interface between PRPF4 and its interactor PRPF3. This interferes with the ability of PRPF4 to integrate into the tri-snRNP, as shown in a human cell line and in zebrafish embryos. These data suggest that the p.R192H variant of PRPF4 represents a functional null allele. The resulting haploinsufficiency of PRPF4 compromises the function of the tri-snRNP, reinforcing the notion that this spliceosomal particle is of crucial importance in the physiology of the retina.
AB - Pre-mRNA splicing by the spliceosome is an essential step in the maturation of nearly all human mRNAs. Mutations in six spliceosomal proteins, PRPF3, PRPF4, PRPF6, PRPF8, PRPF31 and SNRNP200, cause retinitis pigmentosa (RP), a disease characterized by progressive photoreceptor degeneration. All splicing factors linked to RP are constituents of the U4/U6.U5 tri-snRNP subunit of the spliceosome, suggesting that the compromised function of this particle may lead to RP. Here, we report the identification of the p.R192H variant of the tri-snRNP factor PRPF4 in a patient with RP. The mutation affects a highly conserved arginine residue that is crucial for PRPF4 function. Introduction of a corresponding mutation into the zebrafish homolog of PRPF4 resulted in a complete loss of function in vivo. A series of biochemical experiments suggested that p.R192H disrupts the binding interface between PRPF4 and its interactor PRPF3. This interferes with the ability of PRPF4 to integrate into the tri-snRNP, as shown in a human cell line and in zebrafish embryos. These data suggest that the p.R192H variant of PRPF4 represents a functional null allele. The resulting haploinsufficiency of PRPF4 compromises the function of the tri-snRNP, reinforcing the notion that this spliceosomal particle is of crucial importance in the physiology of the retina.
KW - Amino Acid Sequence
KW - Animals
KW - Base Sequence
KW - Blotting, Western
KW - Embryo, Nonmammalian
KW - Gangliosides
KW - Gene Components
KW - HEK293 Cells
KW - Humans
KW - Molecular Sequence Data
KW - Mutation, Missense
KW - Nuclear Proteins
KW - Pedigree
KW - Retinitis Pigmentosa
KW - Ribonucleoprotein, U4-U6 Small Nuclear
KW - Sequence Analysis, DNA
KW - Spliceosomes
KW - Zebrafish
U2 - 10.1371/journal.pone.0111754
DO - 10.1371/journal.pone.0111754
M3 - SCORING: Journal article
C2 - 25383878
VL - 9
SP - e111754
JO - PLOS ONE
JF - PLOS ONE
SN - 1932-6203
IS - 11
ER -