June 2013
Volume 54, Issue 15
Free
ARVO Annual Meeting Abstract  |   June 2013
Linkage analysis in Leber’s hereditary optic neuropathy (LHON): failure to locate significant loci in a very large family indicates a polygenic/environmental complex contribution to penetrance
Author Affiliations & Notes
  • Valerio Carelli
    Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna, Italy
    IRCCS Institute of Neurological Sciences, Bologna, Italy
  • Leonardo Caporali
    Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna, Italy
    IRCCS Institute of Neurological Sciences, Bologna, Italy
  • Alessandra Maresca
    Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna, Italy
    IRCCS Institute of Neurological Sciences, Bologna, Italy
  • Maria Valentino
    Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna, Italy
    IRCCS Institute of Neurological Sciences, Bologna, Italy
  • Solange Salomao
    Department of Ophthalmology, Federal University of São Paulo (UNIFESP), São Paulo, Brazil
  • Alfredo Sadun
    Departments of Ophthalmology and Neurosurgery, Keck School of Medicine at University of Southern California, Los Angeles, CA
  • Pio d'Adamo
    Medical Genetics, University of Trieste, Trieste, Italy
    IRCCS-Burlo Garofolo Children Hospital, Trieste, Italy
  • Footnotes
    Commercial Relationships Valerio Carelli, None; Leonardo Caporali, None; Alessandra Maresca, None; Maria Valentino, None; Solange Salomao, None; Alfredo Sadun, None; Pio d'Adamo, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2013, Vol.54, 1208. doi:
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      Valerio Carelli, Leonardo Caporali, Alessandra Maresca, Maria Valentino, Solange Salomao, Alfredo Sadun, Pio d'Adamo; Linkage analysis in Leber’s hereditary optic neuropathy (LHON): failure to locate significant loci in a very large family indicates a polygenic/environmental complex contribution to penetrance. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1208.

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

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Abstract

Purpose: Leber’s hereditary optic neuropathy (LHON) is due to homoplasmic mtDNA missense mutations affecting complex I, but penetrance is largely incomplete. The existence of nuclear modifying genetic variants is hypothesized.

Methods: We carried out linkage analysis in a very large LHON pedigree (SOA-BR family, 354 subjects) carrying the 11778/ND4 mutation on a haplogroup J background. In total we genotyped 43 subjects with HumanCytoSNP-12 arrays (~300.000 molecular markers). The weight of age, gender, smoke, alcohol and other toxins as covariates was determined in affected subjects and unaffected mutation carriers. In order to perform the linkage analysis, we splitted the big pedigree in 3 smallest ones using PEDCUT. The 3 selected pedigrees are the ones with the maximum numbers of genotyped and phenotyped individuals (the most informative). After the splitting, we performed both parametric and non-parametric linkage analysis on autosomes and X chromosome with MERLIN.

Results: Despite the informativeness of the families, genome wide analysis produced very low LOD scores with both parametric and non-parametric linkage. As possible explanations for this failure we considered the existence of covariates not included in the analysis and/or the involvement of more genes as modifying factors. The covariates of gender and smoke were clearly associated with the affected status in the SOA-BR family, as largely expected from the literature data and previous studies conducted in this family.

Conclusions: Failure to locate any significant loci under the assumption of a monogenic modifier strongly suggests that incomplete penetrance in LHON is a polygenic trait. Interestingly, the previously reported identification of significant loci in the X-chromosome in this family is not confirmed by the current analysis. Furthermore, important covariates like gender and smoke has to be taken into account for future analysis. Some of these covariates may be correlated.

Keywords: 536 gene modifiers • 613 neuro-ophthalmology: optic nerve • 600 mitochondria  
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