Study of gene-targeted mouse models of splicing factor gene Prpf31 implicated in human autosomal dominant retinitis pigmentosa (RP).
OBJECTIVE
Pre-mRNA processing factor 31 (PRPF31) is a ubiquitous protein needed for the assembly of the pre-mRNA splicing machinery. It has been shown that mutations in this gene cause autosomal dominant retinitis pigmentosa 11 (RP11), which is characterized by rod-cell degeneration. Interestingly, mutations in this ubiquitously expressed gene do not lead to phenotypes other than retinal malfunction. Furthermore, the dominant inheritance pattern has shown incomplete penetrance, which poses interesting questions about the disease mechanism of RP11.


METHODS
To characterize PRPF31 function in the rod cells, two animal models have been generated. One was a heterozygous knock-in mouse (Prpf31(A216P/+)) carrying a point mutation p.A216P, which has previously been identified in RP11 patients. The second was a heterozygous knockout mouse (Prpf31(+/-)). Retinal degeneration in RP11 mouse models was monitored by electroretinography and histology.


RESULTS
Generation of the mouse models is presented, as are results of ERGs and retinal morphology. No degenerative phenotype on fundus examination was found in Prpf31(A216P/+) and Prpf31(+/-) mice. Prpf31(A216P/A216P) and Prpf31(-/-) genotypes were embryonic lethal.


CONCLUSIONS
The results imply that Prpf31 is necessary for survival, and there is no compensation mechanism in mouse for the lack of this splicing factor. The authors suggest that p.A216P mutation in Prpf31 does not exert a dominant negative effect and that one Prpf31 wild-type allele is sufficient for maintenance of the healthy retina in mice.
Bujakowska
Kinga
K
Institute of Ophthalmology, University College London, London, United Kingdom.
Maubaret
Cecilia
C
Chakarova
Christina F
CF
Tanimoto
Naoyuki
N
Beck
Susanne C
SC
Fahl
Edda
E
Humphries
Marian M
MM
Kenna
Paul F
PF
Makarov
Evgeny
E
Makarova
Olga
O
Paquet-Durand
François
F
Ekström
Per A
PA
van Veen
Theo
T
Leveillard
Thierry
T
Humphries
Peter
P
Seeliger
Mathias W
MW
Bhattacharya
Shomi S
SS
D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D004591:Electrophoresis, Polyacrylamide Gel; D004596:Electroretinography; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D055879:Gene Knock-In Techniques; D055786:Gene Knockout Techniques; D018390:Gene Targeting; D005799:Genes, Dominant; D005838:Genotype; D006801:Humans; D020287:In Situ Nick-End Labeling; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009887:Ophthalmoscopy; D017354:Point Mutation; D012160:Retina / Q000503:physiopathology; D012174:Retinitis Pigmentosa / Q000235:genetics* / Q000503:physiopathology
D005136:Eye Proteins; C454222:PRPF31 protein, human