Universität zu Köln

Linder, Bastian ORCID: 0000-0003-1203-3136, Hirmer, Anja, Gal, Andreas, Ruether, Klaus, Bolz, Hanno Joern, Winkler, Christoph ORCID: 0000-0003-4688-6241, Laggerbauer, Bernhard and Fischer, Utz ORCID: 0000-0002-1465-6591 (2014). Identification of a PRPF4 Loss-of-Function Variant That Abrogates U4/U6.U5 Tri-snRNP Integration and Is Associated with Retinitis Pigmentosa. PLoS One, 9 (11). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1932-6203

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Abstract

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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Linder, Bastian UNSPECIFIED orcid.org/0000-0003-1203-3136 UNSPECIFIED Hirmer, Anja UNSPECIFIED UNSPECIFIED UNSPECIFIED Gal, Andreas UNSPECIFIED UNSPECIFIED UNSPECIFIED Ruether, Klaus UNSPECIFIED UNSPECIFIED UNSPECIFIED Bolz, Hanno Joern UNSPECIFIED UNSPECIFIED UNSPECIFIED Winkler, Christoph UNSPECIFIED orcid.org/0000-0003-4688-6241 UNSPECIFIED Laggerbauer, Bernhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Fischer, Utz UNSPECIFIED orcid.org/0000-0002-1465-6591 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-423477
DOI:	10.1371/journal.pone.0111754
Journal or Publication Title:	PLoS One
Volume:	9
Number:	11
Date:	2014
Publisher:	PUBLIC LIBRARY SCIENCE
Place of Publication:	SAN FRANCISCO
ISSN:	1932-6203
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language SPLICING FACTOR GENES; RECYCLING FACTOR; DEVELOPMENTAL DISORDER; U4ATAC SNRNA; MUTATIONS; RNA; PROTEIN; SPLICEOSOME; CYCLOPHILIN; EXPRESSIVITY Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/42347