A universal mechanism ties genotype to phenotype in trinucleotide diseases.

Trinucleotide hereditary diseases such as Huntington disease and Friedreich ataxia are cureless diseases associated with inheriting an abnormally large number of DNA trinucleotide repeats in a gene. The genes associated with different diseases are unrelated and harbor a trinucleotide repeat in diffe...

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Autores principales:	Shai Kaplan, Shalev Itzkovitz, Ehud Shapiro
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2007
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/2dd5700087dc47ba8d533e8291fe36c7
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spelling	oai:doaj.org-article:2dd5700087dc47ba8d533e8291fe36c72021-11-25T05:41:31ZA universal mechanism ties genotype to phenotype in trinucleotide diseases.1553-734X1553-735810.1371/journal.pcbi.0030235https://doaj.org/article/2dd5700087dc47ba8d533e8291fe36c72007-11-01T00:00:00Zhttps://doi.org/10.1371/journal.pcbi.0030235https://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358Trinucleotide hereditary diseases such as Huntington disease and Friedreich ataxia are cureless diseases associated with inheriting an abnormally large number of DNA trinucleotide repeats in a gene. The genes associated with different diseases are unrelated and harbor a trinucleotide repeat in different functional regions; therefore, it is striking that many of these diseases have similar correlations between their genotype, namely the number of inherited repeats and age of onset and progression phenotype. These correlations remain unexplained despite more than a decade of research. Although mechanisms have been proposed for several trinucleotide diseases, none of the proposals, being disease-specific, can account for the commonalities among these diseases. Here, we propose a universal mechanism in which length-dependent somatic repeat expansion occurs during the patient's lifetime toward a pathological threshold. Our mechanism uniformly explains for the first time to our knowledge the genotype-phenotype correlations common to trinucleotide disease and is well-supported by both experimental and clinical data. In addition, mathematical analysis of the mechanism provides simple explanations to a wide range of phenomena such as the exponential decrease of the age-of-onset curve, similar onset but faster progression in patients with Huntington disease with homozygous versus heterozygous mutation, and correlation of age of onset with length of the short allele but not with the long allele in Friedreich ataxia. If our proposed universal mechanism proves to be the core component of the actual mechanisms of specific trinucleotide diseases, it would open the search for a uniform treatment for all these diseases, possibly by delaying the somatic expansion process.Shai KaplanShalev ItzkovitzEhud ShapiroPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 3, Iss 11, p e235 (2007)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Shai Kaplan Shalev Itzkovitz Ehud Shapiro A universal mechanism ties genotype to phenotype in trinucleotide diseases.
description	Trinucleotide hereditary diseases such as Huntington disease and Friedreich ataxia are cureless diseases associated with inheriting an abnormally large number of DNA trinucleotide repeats in a gene. The genes associated with different diseases are unrelated and harbor a trinucleotide repeat in different functional regions; therefore, it is striking that many of these diseases have similar correlations between their genotype, namely the number of inherited repeats and age of onset and progression phenotype. These correlations remain unexplained despite more than a decade of research. Although mechanisms have been proposed for several trinucleotide diseases, none of the proposals, being disease-specific, can account for the commonalities among these diseases. Here, we propose a universal mechanism in which length-dependent somatic repeat expansion occurs during the patient's lifetime toward a pathological threshold. Our mechanism uniformly explains for the first time to our knowledge the genotype-phenotype correlations common to trinucleotide disease and is well-supported by both experimental and clinical data. In addition, mathematical analysis of the mechanism provides simple explanations to a wide range of phenomena such as the exponential decrease of the age-of-onset curve, similar onset but faster progression in patients with Huntington disease with homozygous versus heterozygous mutation, and correlation of age of onset with length of the short allele but not with the long allele in Friedreich ataxia. If our proposed universal mechanism proves to be the core component of the actual mechanisms of specific trinucleotide diseases, it would open the search for a uniform treatment for all these diseases, possibly by delaying the somatic expansion process.
format	article
author	Shai Kaplan Shalev Itzkovitz Ehud Shapiro
author_facet	Shai Kaplan Shalev Itzkovitz Ehud Shapiro
author_sort	Shai Kaplan
title	A universal mechanism ties genotype to phenotype in trinucleotide diseases.
title_short	A universal mechanism ties genotype to phenotype in trinucleotide diseases.
title_full	A universal mechanism ties genotype to phenotype in trinucleotide diseases.
title_fullStr	A universal mechanism ties genotype to phenotype in trinucleotide diseases.
title_full_unstemmed	A universal mechanism ties genotype to phenotype in trinucleotide diseases.
title_sort	universal mechanism ties genotype to phenotype in trinucleotide diseases.
publisher	Public Library of Science (PLoS)
publishDate	2007
url	https://doaj.org/article/2dd5700087dc47ba8d533e8291fe36c7
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A universal mechanism ties genotype to phenotype in trinucleotide diseases.

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