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Dominant PRPF31 Mutations Are Hypostatic to a Recessive CNOT3 Polymorphism in Retinitis Pigmentosa: A Novel Phenomenon of “Linked Trans-Acting Epistasis”

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 pr...

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Autores principales: Rose, Anna M, Shah, Amna Z, Venturini, Giulia, Rivolta, Carlo, Rose, Geoffrey E, Bhattacharya, Shomi S
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BlackWell Publishing Ltd 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4240469/
https://www.ncbi.nlm.nih.gov/pubmed/24116917
http://dx.doi.org/10.1111/ahg.12042
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author Rose, Anna M
Shah, Amna Z
Venturini, Giulia
Rivolta, Carlo
Rose, Geoffrey E
Bhattacharya, Shomi S
author_facet Rose, Anna M
Shah, Amna Z
Venturini, Giulia
Rivolta, Carlo
Rose, Geoffrey E
Bhattacharya, Shomi S
author_sort Rose, Anna M
collection PubMed
description 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.”
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spelling pubmed-42404692014-12-22 Dominant PRPF31 Mutations Are Hypostatic to a Recessive CNOT3 Polymorphism in Retinitis Pigmentosa: A Novel Phenomenon of “Linked Trans-Acting Epistasis” Rose, Anna M Shah, Amna Z Venturini, Giulia Rivolta, Carlo Rose, Geoffrey E Bhattacharya, Shomi S Ann Hum Genet Short Communication 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.” BlackWell Publishing Ltd 2013-01 2013-01-01 /pmc/articles/PMC4240469/ /pubmed/24116917 http://dx.doi.org/10.1111/ahg.12042 Text en © 2013 The Authors. Annals of Human Genetics published by John Wiley & Sons Ltd/University College London. http://creativecommons.org/licenses/by-nc-nd/3.0/ 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 modifications or adaptations are made.
spellingShingle Short Communication
Rose, Anna M
Shah, Amna Z
Venturini, Giulia
Rivolta, Carlo
Rose, Geoffrey E
Bhattacharya, Shomi S
Dominant PRPF31 Mutations Are Hypostatic to a Recessive CNOT3 Polymorphism in Retinitis Pigmentosa: A Novel Phenomenon of “Linked Trans-Acting Epistasis”
title Dominant PRPF31 Mutations Are Hypostatic to a Recessive CNOT3 Polymorphism in Retinitis Pigmentosa: A Novel Phenomenon of “Linked Trans-Acting Epistasis”
title_full Dominant PRPF31 Mutations Are Hypostatic to a Recessive CNOT3 Polymorphism in Retinitis Pigmentosa: A Novel Phenomenon of “Linked Trans-Acting Epistasis”
title_fullStr Dominant PRPF31 Mutations Are Hypostatic to a Recessive CNOT3 Polymorphism in Retinitis Pigmentosa: A Novel Phenomenon of “Linked Trans-Acting Epistasis”
title_full_unstemmed Dominant PRPF31 Mutations Are Hypostatic to a Recessive CNOT3 Polymorphism in Retinitis Pigmentosa: A Novel Phenomenon of “Linked Trans-Acting Epistasis”
title_short Dominant PRPF31 Mutations Are Hypostatic to a Recessive CNOT3 Polymorphism in Retinitis Pigmentosa: A Novel Phenomenon of “Linked Trans-Acting Epistasis”
title_sort dominant prpf31 mutations are hypostatic to a recessive cnot3 polymorphism in retinitis pigmentosa: a novel phenomenon of “linked trans-acting epistasis”
topic Short Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4240469/
https://www.ncbi.nlm.nih.gov/pubmed/24116917
http://dx.doi.org/10.1111/ahg.12042
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