eprintid: 1412371 rev_number: 29 eprint_status: archive userid: 608 dir: disk0/01/41/23/71 datestamp: 2013-11-01 19:36:16 lastmod: 2021-10-10 23:03:31 status_changed: 2013-11-01 19:36:16 type: article metadata_visibility: show item_issues_count: 0 creators_name: Rose, AM creators_name: Shah, AZ creators_name: Venturini, G creators_name: Rivolta, C creators_name: Rose, GE creators_name: Bhattacharya, SS title: Dominant PRPF31 Mutations Are Hypostatic to a Recessive CNOT3 Polymorphism in Retinitis Pigmentosa: A Novel Phenomenon of "Linked Trans-Acting Epistasis" ispublished: pub divisions: UCL divisions: B02 divisions: C07 divisions: D08 keywords: CNOT3, PRPF31, epistasis, retinitis pigmentosa note: �© 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. 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." date: 2014-01 official_url: http://dx.doi.org/10.1111/ahg.12042 oa_status: green full_text_type: pub primo: open primo_central: open_green article_type_text: JOURNAL ARTICLE verified: verified_manual elements_source: PubMed elements_id: 911214 doi: 10.1111/ahg.12042 language_elements: ENG lyricists_name: Bhattacharya, Shom lyricists_name: Shah, Amna lyricists_id: SSBHA56 lyricists_id: AZSHA52 full_text_status: public publication: Ann Hum Genet volume: 78 number: 1 pagerange: 62-71 citation: Rose, AM; Shah, AZ; Venturini, G; Rivolta, C; Rose, GE; Bhattacharya, SS; (2014) Dominant PRPF31 Mutations Are Hypostatic to a Recessive CNOT3 Polymorphism in Retinitis Pigmentosa: A Novel Phenomenon of "Linked Trans-Acting Epistasis". Ann Hum Genet , 78 (1) pp. 62-71. 10.1111/ahg.12042 <https://doi.org/10.1111/ahg.12042>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/1412371/1/ahg12042.pdf