TY  - JOUR
AV  - public
VL  - 78
Y1  - 2014/01//
SP  - 62
EP  - 71
TI  - Dominant PRPF31 Mutations Are Hypostatic to a Recessive CNOT3 Polymorphism in Retinitis Pigmentosa: A Novel Phenomenon of "Linked Trans-Acting Epistasis"
IS  - 1
N1  - ?© 2013 The Authors.
Annals of Human Genetics published by John Wiley & Sons Ltd/University College London.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution
in any medium, provided the original work is properly cited, the use is non-commercial and no modification or adaptations are made.
UR  - http://dx.doi.org/10.1111/ahg.12042
N2  - 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."
ID  - discovery1412371
A1  - Rose, AM
A1  - Shah, AZ
A1  - Venturini, G
A1  - Rivolta, C
A1  - Rose, GE
A1  - Bhattacharya, SS
KW  - CNOT3
KW  -  PRPF31
KW  -  epistasis
KW  -  retinitis pigmentosa
JF  - Ann Hum Genet
ER  -