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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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Comparison of oxidative stress markers in classical Rett versus Zappella Rett variant.In classical Rett (RTT) patients (N = 2), all the examined oxidative stress (OS) markers were significantly increased compared to healthy controls (N = 15, all females, mean age 36.5±4.2), whereas Zappella Rett variant (Z-RTT) patients (N = 2) behave as controls subjects except for plasma 4-HNE-PAs. Intra-erythrocyte and plasma non-protein bound iron (NPBI) are markers of hypoxia with hemoglobin oxidation and subsequent heme iron release. Plasma 4-HNE PAs is a marker of protein oxidation due to aldehyde binding from lipid peroxidation sources. F(2)-isoprostanes (F2-IsoPs) are the end-products of arachidonic acid oxidation, a polyunsaturated fatty acid that is abundant in both brain grey and white matter. F(2)-dihomo-isoprostanes (F2-dihomo-IsoPs) derive from oxidation of adrenic acid, a fatty acid abundant in white matter, specifically myelin. F(4)-neuroprostanes (F4-NeuroPs) are the end-products of docosahexanoic acid, abundant in neuronal membranes. Statistical differences were evaluated using Mann-Whitney sum rank test, Kruskal-Wallis analysis of variance (ANOVA) Two-tailed P-values are shown. Values are expressed as means ± standard error means (SEM); intra-erythrocyte NPBI is reported as nmol/ml erythrocytes suspension; plasma 4-HNE-PAs are expressed as arbitrary units (AU), while isoprostanes (IsoPs) are expressed as pg/ml.
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pone-0056599-g003: Comparison of oxidative stress markers in classical Rett versus Zappella Rett variant.In classical Rett (RTT) patients (N = 2), all the examined oxidative stress (OS) markers were significantly increased compared to healthy controls (N = 15, all females, mean age 36.5±4.2), whereas Zappella Rett variant (Z-RTT) patients (N = 2) behave as controls subjects except for plasma 4-HNE-PAs. Intra-erythrocyte and plasma non-protein bound iron (NPBI) are markers of hypoxia with hemoglobin oxidation and subsequent heme iron release. Plasma 4-HNE PAs is a marker of protein oxidation due to aldehyde binding from lipid peroxidation sources. F(2)-isoprostanes (F2-IsoPs) are the end-products of arachidonic acid oxidation, a polyunsaturated fatty acid that is abundant in both brain grey and white matter. F(2)-dihomo-isoprostanes (F2-dihomo-IsoPs) derive from oxidation of adrenic acid, a fatty acid abundant in white matter, specifically myelin. F(4)-neuroprostanes (F4-NeuroPs) are the end-products of docosahexanoic acid, abundant in neuronal membranes. Statistical differences were evaluated using Mann-Whitney sum rank test, Kruskal-Wallis analysis of variance (ANOVA) Two-tailed P-values are shown. Values are expressed as means ± standard error means (SEM); intra-erythrocyte NPBI is reported as nmol/ml erythrocytes suspension; plasma 4-HNE-PAs are expressed as arbitrary units (AU), while isoprostanes (IsoPs) are expressed as pg/ml.

Mentions: Given the difference in the number of metabolic pathway genes related to oxidative stress (OS) in classical versus Z-RTT patients, we decided to test whether there was a difference in the OS phenotype. Interestingly, for five out of six OS markers (non-protein bound iron (NPBI), F(2)-dihomo-isoprostanes (F2-dihomo-IsoPs), F(3)-isoprostanes, F(4)-neuroprostanes (F4-NeuroPs), and F(2)-isoprostanes (F2-IsoPs)) there was not a statistically significant difference between Z-RTT and controls, while in classical RTT OS markers were significantly increased (Fig. 3).


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)

Comparison of oxidative stress markers in classical Rett versus Zappella Rett variant.In classical Rett (RTT) patients (N = 2), all the examined oxidative stress (OS) markers were significantly increased compared to healthy controls (N = 15, all females, mean age 36.5±4.2), whereas Zappella Rett variant (Z-RTT) patients (N = 2) behave as controls subjects except for plasma 4-HNE-PAs. Intra-erythrocyte and plasma non-protein bound iron (NPBI) are markers of hypoxia with hemoglobin oxidation and subsequent heme iron release. Plasma 4-HNE PAs is a marker of protein oxidation due to aldehyde binding from lipid peroxidation sources. F(2)-isoprostanes (F2-IsoPs) are the end-products of arachidonic acid oxidation, a polyunsaturated fatty acid that is abundant in both brain grey and white matter. F(2)-dihomo-isoprostanes (F2-dihomo-IsoPs) derive from oxidation of adrenic acid, a fatty acid abundant in white matter, specifically myelin. F(4)-neuroprostanes (F4-NeuroPs) are the end-products of docosahexanoic acid, abundant in neuronal membranes. Statistical differences were evaluated using Mann-Whitney sum rank test, Kruskal-Wallis analysis of variance (ANOVA) Two-tailed P-values are shown. Values are expressed as means ± standard error means (SEM); intra-erythrocyte NPBI is reported as nmol/ml erythrocytes suspension; plasma 4-HNE-PAs are expressed as arbitrary units (AU), while isoprostanes (IsoPs) are expressed as pg/ml.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3585308&req=5

pone-0056599-g003: Comparison of oxidative stress markers in classical Rett versus Zappella Rett variant.In classical Rett (RTT) patients (N = 2), all the examined oxidative stress (OS) markers were significantly increased compared to healthy controls (N = 15, all females, mean age 36.5±4.2), whereas Zappella Rett variant (Z-RTT) patients (N = 2) behave as controls subjects except for plasma 4-HNE-PAs. Intra-erythrocyte and plasma non-protein bound iron (NPBI) are markers of hypoxia with hemoglobin oxidation and subsequent heme iron release. Plasma 4-HNE PAs is a marker of protein oxidation due to aldehyde binding from lipid peroxidation sources. F(2)-isoprostanes (F2-IsoPs) are the end-products of arachidonic acid oxidation, a polyunsaturated fatty acid that is abundant in both brain grey and white matter. F(2)-dihomo-isoprostanes (F2-dihomo-IsoPs) derive from oxidation of adrenic acid, a fatty acid abundant in white matter, specifically myelin. F(4)-neuroprostanes (F4-NeuroPs) are the end-products of docosahexanoic acid, abundant in neuronal membranes. Statistical differences were evaluated using Mann-Whitney sum rank test, Kruskal-Wallis analysis of variance (ANOVA) Two-tailed P-values are shown. Values are expressed as means ± standard error means (SEM); intra-erythrocyte NPBI is reported as nmol/ml erythrocytes suspension; plasma 4-HNE-PAs are expressed as arbitrary units (AU), while isoprostanes (IsoPs) are expressed as pg/ml.
Mentions: Given the difference in the number of metabolic pathway genes related to oxidative stress (OS) in classical versus Z-RTT patients, we decided to test whether there was a difference in the OS phenotype. Interestingly, for five out of six OS markers (non-protein bound iron (NPBI), F(2)-dihomo-isoprostanes (F2-dihomo-IsoPs), F(3)-isoprostanes, F(4)-neuroprostanes (F4-NeuroPs), and F(2)-isoprostanes (F2-IsoPs)) there was not a statistically significant difference between Z-RTT and controls, while in classical RTT OS markers were significantly increased (Fig. 3).

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