Metabolism as a complex genetic trait, a systems biology approach: Implications for inborn errors of metabolism and clinical diseases

Vockley, Jerry

doi:10.1007/s10545-008-1005-8

Cited by 42 publications

(29 citation statements)

References 65 publications

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“…It is important to note that the three-allele system outlined for EPP refers to the presence of three different allele types in the same gene in the general population and should not be confused with triallelic inheritance of disorders caused by a combination of three mutations in two different genes, as in Bardet-Biedl syndrome. Triallelic inheritance has not yet been reported for metabolic disorders, although clinical manifestation of some disorders may be influenced by genetic variants in other pathways (Vockley 2008). This, however, is not a focus of the present article.…”

Section: Pseudodominant Inheritance Caused By Prevalent Loss-of-functmentioning

confidence: 90%

Dominant versus recessive: Molecular mechanisms in metabolic disease

Zschocke

2008

J of Inher Metab Disea

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Inborn errors of metabolism used to be regarded as simple monogenic traits, but a closer look at how different alleles of a gene determine different phenotypes shows that the molecular mechanisms in the individual case are often complicated. Most metabolic disorders represent a spectrum of phenotypes from normal via attenuated to severe (and sometimes prenatally fatal), and disease manifestation is often influenced by other specific genetic or exogenous factors. The terms 'dominant' or 'recessive' relate to the functional consequences of differing alleles in the (compound) heterozygous individual; the terms are irrelevant for homozygous individuals and inappropriate for X-linked disorders. Mutations affecting the same amino acid residue may be associated with different inheritance patterns. True dominant inheritance in metabolism is rare; it may be found e.g. in tightly regulated biosynthetic pathways or when minor changes in metabolite concentrations have a functional effect. Some disorders such as erythropoietic protoporphyria show pseudodominant inheritance due to prevalent loss-of-function polymorphisms in the general population and are better acknowledged as recessive traits. The term 'variable expressivity' is not helpful with regard to autosomal recessive disorders when variable phenotypes are explained by different mutations in the respective gene. Clonal unmasking of a heterozygous mutation through somatic loss of the second allele, the main pathomechanism in inherited tumour predisposition syndromes, is rare in metabolic disorders, but focal congenital hyperinsulinism is a notable exception. Somatic mosaicism for an OTC gene mutation is given as an example of an apparently heterozygous mutation pattern in a boy with an X-linked disease.

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Section: Pseudodominant Inheritance Caused By Prevalent Loss-of-functmentioning

confidence: 90%

Dominant versus recessive: Molecular mechanisms in metabolic disease

Zschocke

2008

J of Inher Metab Disea

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“…Estimates suggest that ~15--20% of RCD are due to mtDNA mutations, while the rest are likely caused by nuclear defects ( 18, 26 ). Due to their clinical and genetic heterogeneity, and the pleoitropy of known disease loci, RCD diagnosis is extremely difficult ( 11, 76, 115 ).…”

Section: Mendelian Mitochondrial Diseasesmentioning

confidence: 99%

The Mitochondrial Proteome and Human Disease

Calvo

Mootha

2010

Annu. Rev. Genom. Hum. Genet.

524

404

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For nearly three decades, the sequence of the human mitochondrial genome (mtDNA) has provided a molecular framework for understanding maternally inherited diseases. However, the vast majority of human mitochondrial disorders are caused by nuclear defects, which is not surprising since the mtDNA encodes only 13 proteins. Advances in genomics, mass spectrometry, and computation have only recently made it possible to systematically identify the complement of over 1,000 proteins that comprise the mammalian mitochondrial proteome. Here, we review recent progress in characterizing the mitochondrial proteome and highlight insights into its complexity, tissue heterogeneity, evolutionary origins, and biochemical versatility. We then discuss how this proteome is being used to discover the genetic basis of respiratory chain disorders as well as to expand our definition of mitochondrial disease. Finally, we explore future prospects and challenges for using the mitochondrial proteome as a foundation for systems analysis of the organelle.

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“…Although we know many important molecular factors, yet the complexity of the metabolic and regulatory network hampers elucidating the relation between the primary disease factors and their systemic effects [1], [2]. Moreover, the experimental accessibility of large parts of the metabolic networks is limited.…”

Section: Introductionmentioning

confidence: 99%

Biochemical Competition Makes Fatty-Acid β-Oxidation Vulnerable to Substrate Overload

et al. 2013

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Fatty-acid metabolism plays a key role in acquired and inborn metabolic diseases. To obtain insight into the network dynamics of fatty-acid β-oxidation, we constructed a detailed computational model of the pathway and subjected it to a fat overload condition. The model contains reversible and saturable enzyme-kinetic equations and experimentally determined parameters for rat-liver enzymes. It was validated by adding palmitoyl CoA or palmitoyl carnitine to isolated rat-liver mitochondria: without refitting of measured parameters, the model correctly predicted the β-oxidation flux as well as the time profiles of most acyl-carnitine concentrations. Subsequently, we simulated the condition of obesity by increasing the palmitoyl-CoA concentration. At a high concentration of palmitoyl CoA the β-oxidation became overloaded: the flux dropped and metabolites accumulated. This behavior originated from the competition between acyl CoAs of different chain lengths for a set of acyl-CoA dehydrogenases with overlapping substrate specificity. This effectively induced competitive feedforward inhibition and thereby led to accumulation of CoA-ester intermediates and depletion of free CoA (CoASH). The mitochondrial [NAD+]/[NADH] ratio modulated the sensitivity to substrate overload, revealing a tight interplay between regulation of β-oxidation and mitochondrial respiration.

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Metabolism as a complex genetic trait, a systems biology approach: Implications for inborn errors of metabolism and clinical diseases

Cited by 42 publications

References 65 publications

Dominant versus recessive: Molecular mechanisms in metabolic disease

Dominant versus recessive: Molecular mechanisms in metabolic disease

The Mitochondrial Proteome and Human Disease

Biochemical Competition Makes Fatty-Acid β-Oxidation Vulnerable to Substrate Overload

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