Gain of function variations may lead to enhancement of existing protein function (hyper- morph) or to acquisition of novel and possibly abnormal biological activities (neomorph). Point mutations, chromosomal rearrangements and copy number amplifcations are common mechanisms that exert a gain of function effect in several human diseases, such as cancer or rare developmental syndromes. Traditionally, “gain of function” and “loss of function” are considered as the antithetical functional effects of a particular genetic variation. Accordingly, gain of function mutations may be associated with highly heterogeneous phenotypical manifestations of the disease or even completely distinct clinical conditions when compared to loss of function variations in the same gene. However, this dichotomic scenario has become less cogent in the last decade with the evidence that both mutation types, when present in the same gene, may result in strikingly similar phenotypic outcomes. Such is the paradigmatic case of TP53, which may promote tumourigenesis after accumulation of both hypomorph and neomorph mutations. Importantly, many other factors, such as tissue type and genetic background, may also influence the phenotype. In the last few years, novel pathogenic mechanisms associated with gain of function variations have emerged, including the formation of new chromatin domains, also known as neo-TADs (Topologically Associated Domains), as a result of genomic duplications. Importantly, many innovative personalised therapies take advantage of the specifc targeting of gain of function variations through different strategies, such as enzymatic inhibition, RNA interference or targeted genome editing, suggesting the implementation of these therapeutic approaches in the near future

Patologia ereditaria da gain of function

Errichiello E
;
CASATI, BEATRICE;Zuffardi O
2017

Abstract

Gain of function variations may lead to enhancement of existing protein function (hyper- morph) or to acquisition of novel and possibly abnormal biological activities (neomorph). Point mutations, chromosomal rearrangements and copy number amplifcations are common mechanisms that exert a gain of function effect in several human diseases, such as cancer or rare developmental syndromes. Traditionally, “gain of function” and “loss of function” are considered as the antithetical functional effects of a particular genetic variation. Accordingly, gain of function mutations may be associated with highly heterogeneous phenotypical manifestations of the disease or even completely distinct clinical conditions when compared to loss of function variations in the same gene. However, this dichotomic scenario has become less cogent in the last decade with the evidence that both mutation types, when present in the same gene, may result in strikingly similar phenotypic outcomes. Such is the paradigmatic case of TP53, which may promote tumourigenesis after accumulation of both hypomorph and neomorph mutations. Importantly, many other factors, such as tissue type and genetic background, may also influence the phenotype. In the last few years, novel pathogenic mechanisms associated with gain of function variations have emerged, including the formation of new chromatin domains, also known as neo-TADs (Topologically Associated Domains), as a result of genomic duplications. Importantly, many innovative personalised therapies take advantage of the specifc targeting of gain of function variations through different strategies, such as enzymatic inhibition, RNA interference or targeted genome editing, suggesting the implementation of these therapeutic approaches in the near future
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11571/1217953
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