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 subprocesses 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 MutSa 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.
Sub-cellular localization analysis of MSH6 missense mutations does not reveal an overt MSH6 nuclear transport impairment / L. Belvederesi, F. Bianchi, C. Loretelli, R. Bracci, S. Cascinu, R. Cellerino. - In: FAMILIAL CANCER. - ISSN 1389-9600. - 11:4(2012), pp. 675-680.
Sub-cellular localization analysis of MSH6 missense mutations does not reveal an overt MSH6 nuclear transport impairment
C. Loretelli;
2012
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 subprocesses 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 MutSa 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.File | Dimensione | Formato | |
---|---|---|---|
Sub-cellular localization analysis of MSH6 missense mutations does not reveal an overt MSH6 nuclear transport impairment.pdf
accesso riservato
Tipologia:
Publisher's version/PDF
Dimensione
401.88 kB
Formato
Adobe PDF
|
401.88 kB | Adobe PDF | Visualizza/Apri Richiedi una copia |
Pubblicazioni consigliate
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.