April 2011
Volume 52, Issue 14
Free
ARVO Annual Meeting Abstract  |   April 2011
Differential Expression Of Cis-acting Genes As A Possible Mechanism To Explain Partial Penetrance Of PRPF31 Mutations
Author Affiliations & Notes
  • Giulia Venturini
    Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
  • Amna Shah
    Department of Molecular Genetics, University College London, London, United Kingdom
  • Shomi S. Bhattacharya
    Department of Molecular Genetics, University College London, London, United Kingdom
  • Carlo Rivolta
    Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
  • Footnotes
    Commercial Relationships  Giulia Venturini, None; Amna Shah, None; Shomi S. Bhattacharya, None; Carlo Rivolta, None
  • Footnotes
    Support  Swiss National Science Foundation (320030-121929)
Investigative Ophthalmology & Visual Science April 2011, Vol.52, 3309. doi:
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      Giulia Venturini, Amna Shah, Shomi S. Bhattacharya, Carlo Rivolta; Differential Expression Of Cis-acting Genes As A Possible Mechanism To Explain Partial Penetrance Of PRPF31 Mutations. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3309.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : Penetrance of PRPF31 mutations, causing autosomal dominant retinitis pigmentosa (adRP), is determined by at least 2 unidentified genetic elements. One of these maps to a linkage interval on chromosome 19q13.4, where PRPF31 lies as well. Isoalleles from this locus, inherited by the patients from the parent who does not carry the mutation, determine the raised level of wild-type PRPF31 mRNA expression, which in turn prevents the clinical manifestation of the disease. Our aim is to identify the molecular nature of such isoalleles.

Methods: : RNA was obtained from lymphoblastoid cell lines derived from a large family with adRP (RP856/AD5) that segregated with a 11-bp deletion in exon 11 of PRPF31. Real-time RT-PCRs were performed to assess the mRNA levels of all genes located in the linkage interval on chromosome 19.

Results: : It has previously been shown that penetrance factors for PRPF31 mutations act via diffusible factors (e.g. transcription factors or regulatory RNA or proteins) and hence their expression level should correlate with that of PRPF31. Nineteen out of the 47 genes comprised within the mapped chromosomal region were highly expressed in lymphoblastoid cell lines. Among them, 3 were selected as likely candidates: CNOT3, TFPT, and LOC100288135. TFPT was excluded as possible modulator of PRPF31 mRNA expression because it was equally expressed in all family members. Conversely, LOC100288135 and CNOT3 were differentially expressed and showed a positive correlation with the production of PRPF31 mRNA.

Conclusions: : Specific LOC100288135 and/or CNOT3 alleles could be the molecular determinant of penetrance of PRPF31 mutations. Silencing of these candidate modulators and other validation experiments, prior to direct DNA sequencing, are currently underway.

Keywords: retinal degenerations: hereditary • gene modifiers • gene/expression 
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