title: Dominant PRPF31 mutations are hypostatic to a recessive CNOT3 polymorphism in retinitis pigmentosa: a novel phenomenon of "linked trans-acting epistasis".
abstract: Mutations in PRPF31 are responsible for autosomal dominant retinitis pigmentosa (adRP, RP11 form) and affected families show nonpenetrance. Differential expression of the wildtype PRPF31 allele is responsible for this phenomenon: coinheritance of a mutation and a higher expressing wildtype allele provide protection against development of disease. It has been suggested that a major modulating factor lies in close proximity to the wildtype PRPF31 gene on Chromosome 19, implying that a cis-acting factor directly alters PRPF31 expression. Variable expression of CNOT3 is one determinant of PRPF31 expression. This study explored the relationship between CNOT3 (a trans-acting factor) and its paradoxical cis-acting nature in relation to RP11. Linkage analysis on Chromosome 19 was performed in mutation-carrying families, and the inheritance of the wildtype PRPF31 allele in symptomatic-asymptomatic sibships was assessed-confirming that differential inheritance of wildtype chromosome 19q13 determines the clinical phenotype (P < 2.6 × 10(-7) ). A theoretical model was constructed that explains the apparent conflict between the linkage data and the recent demonstration that a trans-acting factor (CNOT3) is a major nonpenetrance factor: we propose that this apparently cis-acting effect arises due to the intimate linkage of CNOT3 and PRPF31 on Chromosome 19q13-a novel mechanism that we have termed "linked trans-acting epistasis."
authors.affiliation: Department of Genetics, UCL Institute of Ophthalmology, London, United Kingdom.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Rose
authors.forename: Amna Z
authors.initials: AZ
authors.lastname: Shah
authors.forename: Giulia
authors.initials: G
authors.lastname: Venturini
authors.forename: Carlo
authors.initials: C
authors.lastname: Rivolta
authors.forename: Geoffrey E
authors.initials: GE
authors.lastname: Rose
authors.forename: Shomi S
authors.initials: SS
authors.lastname: Bhattacharya
mesh_terms: D000483:Alleles; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics; D019295:Computational Biology; D004843:Epistasis, Genetic; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005799:Genes, Dominant; D005808:Genes, Recessive; D008040:Genetic Linkage; D056426:Genetic Loci; D006579:Heterozygote; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D009154:Mutation; D010375:Pedigree; D011015:Pneumonia, Aspiration / Q000235:genetics; D011110:Polymorphism, Genetic; D012174:Retinitis Pigmentosa / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: C466622:CNOT3 protein, human; D005136:Eye Proteins; C454222:PRPF31 protein, human; D014157:Transcription Factors
keywords: CNOT3; PRPF31; epistasis; retinitis pigmentosa