A human derived SSADH coding variant is replacing the ancestral allele shared with primates

Leone, Ofelia; Blasi, Paola; Palmerio, Francesca; Козлов, А. И.; Malaspina, Patrizia; Novelletto, Andrea

doi:10.1080/03014460601035748

Cited by 7 publications

(4 citation statements)

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“…This suggests that a variety of enzymes with potentially varying levels of catalytic activity may function in human. Genotyping individuals from diverse populations and all continents revealed an interesting geographical pattern for the distribution of c.538 and c.545 variants (17,109). These studies confirmed only a limited number of haplotypes, with the c.538C>T polymorphism most common, and the c.538C allele demonstrating a range of frequency (0.50-1.0), as well as the lowest frequency in Africans and the highest in Chinese populations.…”

Section: Variation In the Ssadh Genementioning

confidence: 53%

Succinic Semialdehyde Dehydrogenase: Biochemical–Molecular–Clinical Disease Mechanisms, Redox Regulation, and Functional Significance

Kim

Pearl

Jensen

et al. 2011

Antioxidants & Redox Signaling

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Succinic semialdehyde dehydrogenase (SSADH; aldehyde dehydrogenase 5a1, ALDH5A1; E.C. 1.2.1.24; OMIM 610045, 271980) deficiency is a rare heritable disorder that disrupts the metabolism of the inhibitory neurotransmitter 4-aminobutyric acid (GABA). Identified in conjunction with increased urinary excretion of the GABA analog gamma-hydroxybutyric acid (GHB), numerous patients have been identified worldwide and the autosomal-recessive disorder has been modeled in mice. The phenotype is one of nonprogressive neurological dysfunction in which seizures may be prominently displayed. The murine model is a reasonable phenocopy of the human disorder, yet the severity of the seizure disorder in the mouse exceeds that observed in SSADHdeficient patients. Abnormalities in GABAergic and GHBergic neurotransmission, documented in patients and mice, form a component of disease pathophysiology, although numerous other disturbances (metabolite accumulations, myelin abnormalities, oxidant stress, neurosteroid depletion, altered bioenergetics, etc.) are also likely to be involved in developing the disease phenotype. Most recently, the demonstration of a redox control system in the SSADH protein active site has provided new insights into the regulation of SSADH by the cellular oxidation=reduction potential. The current review summarizes some 30 years of research on this protein and disease, addressing pathological mechanisms in human and mouse at the protein, metabolic, molecular, and whole-animal level. Antioxid. Redox Signal. 15, 691-718.

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Section: Variation In the Ssadh Genementioning

confidence: 53%

Succinic Semialdehyde Dehydrogenase: Biochemical–Molecular–Clinical Disease Mechanisms, Redox Regulation, and Functional Significance

Kim

Pearl

Jensen

et al. 2011

Antioxidants & Redox Signaling

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“…The gene SSADH (also known as ALDH5A1 ) codes for an enzyme that metabolizes GABA, the principal inhibitory neurotransmitter in the brain. This gene matters for cognition: It has been associated with general cognitive ability (IQ; Plomin et al 2004), it is related to the preservation of cognitive function in the elderly (De Rango et al 2008), and it may be undergoing recent natural selection (Leone et al 2006), as might be expected for a gene that has a large effect on a trait that could assist in survival and reproduction. Furthermore, rare mutations of SSADH are associated with mental retardation, and animals in which the gene is experimentally knocked out (i.e., rendered inoperative) are cognitively impaired and develop epileptic seizures (Buzzi et al 2006, Knerr et al 2008).…”

Section: Cautionary Tales and Constructive Responsesmentioning

confidence: 99%

The Promises and Pitfalls of Genoeconomics

et al. 2012

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This article reviews existing research at the intersection of genetics and economics, presents some new findings that illustrate the state of genoeconomics research, and surveys the prospects of this emerging field. Twin studies suggest that economic outcomes and preferences, once corrected for measurement error, appear to be about as heritable as many medical conditions and personality traits. Consistent with this pattern, we present new evidence on the heritability of permanent income and wealth. Turning to genetic association studies, we survey the main ways that the direct measurement of genetic variation across individuals is likely to contribute to economics, and we outline the challenges that have slowed progress in making these contributions. The most urgent problem facing researchers in this field is that most existing efforts to find associations between genetic variation and economic behavior are based on samples that are too small to ensure adequate statistical power. This has led to many false positives in the literature. We suggest a number of possible strategies to improve and remedy this problem: (a) pooling data sets, (b) using statistical techniques that exploit the greater information content of many genes considered jointly, and (c) focusing on economically relevant traits that are most proximate to known biological mechanisms.

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“…78 Therefore, the level of genotype diversity observed in humans predicted an array of enzymes, depending upon the subunit composition of the tetramer, with likely consequences on its overall catalytic activity. A more detailed view of the geographical pattern in the distribution of c.538 and c.545 coding variants was developed by genotyping subjects representing 60 populations from all continents 78,79. This analysis confirmed the presence of a restricted number of compound haplotypes and showed that the c.538C > T polymorphism is the most common: the c.538C allele shows a wide range of frequencies (from 0.50 to 1.0), with the lowest and highest extremes observed in African and Chinese populations, respectively.…”

Section: Common Polymorphic Variation In the Aldh5a1 Coding Regionmentioning

confidence: 99%

Comparative genomics of aldehyde dehydrogenase 5a1 (succinate semialdehyde dehydrogenase) and accumulation of gamma-hydroxybutyrate associated with its deficiency

et al. 2009

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Succinic semialdehyde dehydrogenase (SSADH; aldehyde dehydrogenase 5A1 [ALDH5A1]; locus 6p22) occupies a central position in central nervous system (CNS) neurotransmitter metabolism as one of two enzymes necessary for g-aminobutyric acid (GABA) recycling from the synaptic cleft. Its importance is highlighted by the neurometabolic disease associated with its inherited deficiency in humans, as well as the severe epileptic phenotype observed in Aldh5a1 -/-knockout mice. Expanding evidence now suggests, however, that even subtle decreases in human SSADH activity, associated with rare and common single nucleotide polymorphisms, may produce subclinical pathological effects. SSADH, in conjunction with aldo-keto reductase 7A2 (AKR7A2), represent two neural enzymes responsible for further catabolism of succinic semialdehyde, producing either succinate (SSADH) or g-hydroxybutyrate (GHB; AKR7A2). A GABA analogue, GHB is a short-chain fatty alcohol with unusual properties in the CNS and a long pharmacological history. Moreover, SSADH occupies a further role in the CNS as the enzyme responsible for further metabolism of the lipid peroxidation aldehyde 4-hydroxy-2-nonenal (4-HNE), an intermediate known to induce oxidant stress. Accordingly, subtle decreases in SSADH activity may have the capacity to lead to regional accumulation of neurotoxic intermediates (GHB,. Polymorphisms in SSADH gene structure may also associate with quantitative traits, including intelligence quotient and life expectancy. Further population-based studies of human SSADH activity promise to reveal additional properties of its function and additional roles in CNS tissue.

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A human derived SSADH coding variant is replacing the ancestral allele shared with primates

Abstract: The analysis of robust correlations based on a large panel of populations is potentially able to identify clusters of genomic regions or genes showing co-evolution of the frequencies of derived alleles.

Cited by 7 publications

References 25 publications

Succinic Semialdehyde Dehydrogenase: Biochemical–Molecular–Clinical Disease Mechanisms, Redox Regulation, and Functional Significance

Succinic Semialdehyde Dehydrogenase: Biochemical–Molecular–Clinical Disease Mechanisms, Redox Regulation, and Functional Significance

The Promises and Pitfalls of Genoeconomics

Comparative genomics of aldehyde dehydrogenase 5a1 (succinate semialdehyde dehydrogenase) and accumulation of gamma-hydroxybutyrate associated with its deficiency

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