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Sub-cellular localization analysis of MSH6 missense mutations does not reveal an overt MSH6 nuclear transport impairment

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Abstract

Nearly one-third of the identified MSH6 germline mutations deal with single amino acid substitutions. For an effective genetic counselling it is necessary to clearly elucidate by functional tools the specific sub-processes underlying the mismatch repair (MMR) misfunctioning in MSH6 non-truncating mutants. Since the MMR repair pathway occurs in the nucleus, we suppose the impairment of MutSα nuclear trafficking to be a possible Lynch syndrome susceptibility causative mechanism. In the present study the MMR status of the tumour, the main clinical features of mutation carriers and population data associated to the MSH6 missense variants, were complemented with computational data about tolerability predictions and amino acid substitution conservation. The selected panel of ten potentially pathogenic MSH6 mutations was analyzed in a homologous expression system for possible deleterious effects on nucleo-cytoplasmic shuttling through the assessment of the sub-cellular localization of the corresponding mutated proteins. Localization analysis results do not reveal an apparent role of MSH6 missense mutations in nuclear import impairment and provide the first hint to exclude the MSH6 nuclear translocation sub-process as a possible causative mechanisms of MMR misfunctioning.

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Acknowledgments

The authors thank Dr. Santarelli and all the Scientists of the Clinic of Occupational Medicine, Polytechnic University of Marche, Ancona, Italy, for providing helpful support and technical assistance in fluorescence microscopy analysis.

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Authors and Affiliations

  1. Dipartimento di Scienze Cliniche e Molecolari, Centro Regionale di Genetica Oncologica, Ospedali Riuniti, Università Politecnica delle Marche, Ancona, Italy

    Laura Belvederesi, Francesca Bianchi, Cristian Loretelli, Raffaella Bracci, Stefano Cascinu & Riccardo Cellerino

  2. Centro Regionale di Genetica Oncologica, Oncologia Medica, Ospedali Riuniti, Università Politecnica delle Marche, Via Tronto 10, 60126, Ancona, Italy

    Laura Belvederesi

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  1. Laura Belvederesi
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  2. Francesca Bianchi
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Correspondence to Laura Belvederesi.

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Belvederesi, L., Bianchi, F., Loretelli, C. et al. Sub-cellular localization analysis of MSH6 missense mutations does not reveal an overt MSH6 nuclear transport impairment. Familial Cancer 11, 675–680 (2012). https://doi.org/10.1007/s10689-012-9558-y

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