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Revealing the complexity of a monogenic disease: rett syndrome exome sequencing.

Grillo E, Lo Rizzo C, Bianciardi L, Bizzarri V, Baldassarri M, Spiga O, Furini S, De Felice C, Signorini C, Leoncini S, Pecorelli A, Ciccoli L, Mencarelli MA, Hayek J, Meloni I, Ariani F, Mari F, Renieri A - PLoS ONE (2013)

Bottom Line: On the other hand, a subgroup of variants related to modulation of immune system, exclusive to the Zappella Rett patients are driving toward a milder phenotype.Combinations of mutations that affect speaking, walking and intellectual capabilities may represent targets for new therapeutic approaches.Most importantly, we demonstrated that monogenic diseases may be more complex than previously thought.

View Article: PubMed Central - PubMed

Affiliation: Medical Genetics, University of Siena, Siena, Italy.

ABSTRACT
Rett syndrome (OMIM#312750) is a monogenic disorder that may manifest as a large variety of phenotypes ranging from very severe to mild disease. Since there is a weak correlation between the mutation type in the Xq28 disease-gene MECP2/X-inactivation status and phenotypic variability, we used this disease as a model to unveil the complex nature of a monogenic disorder. Whole exome sequencing was used to analyze the functional portion of the genome of two pairs of sisters with Rett syndrome. Although each pair of sisters had the same MECP2 (OMIM*300005) mutation and balanced X-inactivation, one individual from each pair could not speak or walk, and had a profound intellectual deficit (classical Rett syndrome), while the other individual could speak and walk, and had a moderate intellectual disability (Zappella variant). In addition to the MECP2 mutation, each patient has a group of variants predicted to impair protein function. The classical Rett girls, but not their milder affected sisters, have an enrichment of variants in genes related to oxidative stress, muscle impairment and intellectual disability and/or autism. On the other hand, a subgroup of variants related to modulation of immune system, exclusive to the Zappella Rett patients are driving toward a milder phenotype. We demonstrate that genome analysis has the potential to identify genetic modifiers of Rett syndrome, providing insight into disease pathophysiology. Combinations of mutations that affect speaking, walking and intellectual capabilities may represent targets for new therapeutic approaches. Most importantly, we demonstrated that monogenic diseases may be more complex than previously thought.

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Relevant pathways of altered genes in classical Rett (a) and Zappella Rett variant girls (b).Only pathways in which at least two altered genes were included, or where one gene was mutated in either both classical Rett (RTT) (a) or both Zappella Rett variant (Z-RTT) (b) patients have been included. Genes that are involved in only one pathway are in white. Genes that are involved in more than one pathway are indicated with the same color. For each pathway the code assigned in the Kyoto Encyclopedia of Genes and Genomes (KEGG) database is indicated (see File S1). For each gene the mutation type is indicated.
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pone-0056599-g002: Relevant pathways of altered genes in classical Rett (a) and Zappella Rett variant girls (b).Only pathways in which at least two altered genes were included, or where one gene was mutated in either both classical Rett (RTT) (a) or both Zappella Rett variant (Z-RTT) (b) patients have been included. Genes that are involved in only one pathway are in white. Genes that are involved in more than one pathway are indicated with the same color. For each pathway the code assigned in the Kyoto Encyclopedia of Genes and Genomes (KEGG) database is indicated (see File S1). For each gene the mutation type is indicated.

Mentions: The first group includes 112 variants belonging to 108 genes (Table S1 in File S1). Three genes, CNTNAP2 (OMIM*604569), GFPT2 (OMIM*603865) and RYR1 (OMIM*180901) had variations predicted to impair the protein function in both the unrelated classical RTT girls. These genes are involved in cell adhesion, oxidative stress and calcium signaling. Each classical RTT patient has in addition about 50 mutated genes among which we selected 21 potentially relevant genes through a meticulous analysis of the literature on Pubmed and taking into account if the genes where listed in OMIM and known to be associated with a neurological or neuromuscular phenotype (10 genes) (Table 2) and if the related protein was involved in a particular pathway (13 genes, 2 of which were already selected using the above mentioned criteria) (Fig. 2a). Interestingly, the two classical RTT patients shared alterations in pathways of steroid biosynthesis, dopaminergic synapses, mRNA surveillance and purine metabolism (Fig. 2a). Additional genes are associated with muscle impairment and intellectual disability and/or autism (Table 2).


Revealing the complexity of a monogenic disease: rett syndrome exome sequencing.

Grillo E, Lo Rizzo C, Bianciardi L, Bizzarri V, Baldassarri M, Spiga O, Furini S, De Felice C, Signorini C, Leoncini S, Pecorelli A, Ciccoli L, Mencarelli MA, Hayek J, Meloni I, Ariani F, Mari F, Renieri A - PLoS ONE (2013)

Relevant pathways of altered genes in classical Rett (a) and Zappella Rett variant girls (b).Only pathways in which at least two altered genes were included, or where one gene was mutated in either both classical Rett (RTT) (a) or both Zappella Rett variant (Z-RTT) (b) patients have been included. Genes that are involved in only one pathway are in white. Genes that are involved in more than one pathway are indicated with the same color. For each pathway the code assigned in the Kyoto Encyclopedia of Genes and Genomes (KEGG) database is indicated (see File S1). For each gene the mutation type is indicated.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585308&req=5

pone-0056599-g002: Relevant pathways of altered genes in classical Rett (a) and Zappella Rett variant girls (b).Only pathways in which at least two altered genes were included, or where one gene was mutated in either both classical Rett (RTT) (a) or both Zappella Rett variant (Z-RTT) (b) patients have been included. Genes that are involved in only one pathway are in white. Genes that are involved in more than one pathway are indicated with the same color. For each pathway the code assigned in the Kyoto Encyclopedia of Genes and Genomes (KEGG) database is indicated (see File S1). For each gene the mutation type is indicated.
Mentions: The first group includes 112 variants belonging to 108 genes (Table S1 in File S1). Three genes, CNTNAP2 (OMIM*604569), GFPT2 (OMIM*603865) and RYR1 (OMIM*180901) had variations predicted to impair the protein function in both the unrelated classical RTT girls. These genes are involved in cell adhesion, oxidative stress and calcium signaling. Each classical RTT patient has in addition about 50 mutated genes among which we selected 21 potentially relevant genes through a meticulous analysis of the literature on Pubmed and taking into account if the genes where listed in OMIM and known to be associated with a neurological or neuromuscular phenotype (10 genes) (Table 2) and if the related protein was involved in a particular pathway (13 genes, 2 of which were already selected using the above mentioned criteria) (Fig. 2a). Interestingly, the two classical RTT patients shared alterations in pathways of steroid biosynthesis, dopaminergic synapses, mRNA surveillance and purine metabolism (Fig. 2a). Additional genes are associated with muscle impairment and intellectual disability and/or autism (Table 2).

Bottom Line: On the other hand, a subgroup of variants related to modulation of immune system, exclusive to the Zappella Rett patients are driving toward a milder phenotype.Combinations of mutations that affect speaking, walking and intellectual capabilities may represent targets for new therapeutic approaches.Most importantly, we demonstrated that monogenic diseases may be more complex than previously thought.

View Article: PubMed Central - PubMed

Affiliation: Medical Genetics, University of Siena, Siena, Italy.

ABSTRACT
Rett syndrome (OMIM#312750) is a monogenic disorder that may manifest as a large variety of phenotypes ranging from very severe to mild disease. Since there is a weak correlation between the mutation type in the Xq28 disease-gene MECP2/X-inactivation status and phenotypic variability, we used this disease as a model to unveil the complex nature of a monogenic disorder. Whole exome sequencing was used to analyze the functional portion of the genome of two pairs of sisters with Rett syndrome. Although each pair of sisters had the same MECP2 (OMIM*300005) mutation and balanced X-inactivation, one individual from each pair could not speak or walk, and had a profound intellectual deficit (classical Rett syndrome), while the other individual could speak and walk, and had a moderate intellectual disability (Zappella variant). In addition to the MECP2 mutation, each patient has a group of variants predicted to impair protein function. The classical Rett girls, but not their milder affected sisters, have an enrichment of variants in genes related to oxidative stress, muscle impairment and intellectual disability and/or autism. On the other hand, a subgroup of variants related to modulation of immune system, exclusive to the Zappella Rett patients are driving toward a milder phenotype. We demonstrate that genome analysis has the potential to identify genetic modifiers of Rett syndrome, providing insight into disease pathophysiology. Combinations of mutations that affect speaking, walking and intellectual capabilities may represent targets for new therapeutic approaches. Most importantly, we demonstrated that monogenic diseases may be more complex than previously thought.

Show MeSH
Related in: MedlinePlus