Ethylmalonic Aciduria Is Associated with an Amino Acid Variant of Short Chain Acyl-Coenzyme A Dehydrogenase

Corydon, Morten J.; Gregersen, Niels; Lehnert, W.; Ribes, Antònia; Rinaldo, Piero; Kmoch, Stanislav; Christensen, Ernst; Kristensen, T.J.; Andresen, Brage S.; Bross, Peter; Winter, Vibeke; Martínez, Gemma; Neve, Søren; Jensen, Thomas G.; Bolund, Lars; Kølvraa, Steen

doi:10.1203/00006450-199606000-00021

Cited by 96 publications

(69 citation statements)

References 38 publications

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“…For the SCAD/EMA patient group, a modifying effect of variations in the chaperonin genes on SCAD enzyme folding was suggested by the observation that the two non-synonymous polymorphic ACADS gene variants c.511T and c.625A, which are strongly overrepresented in the patient group compared to controls (Corydon et al 1996;Corydon et al 2001), cause prolonged interaction of their encoded SCAD variant proteins with the Hsp60 chaperone and delayed folding and assembly to the active tetramer (Pedersen et al 2003). Variations in the chaperonin genes that compromise their function or affect their expression could possibly exacerbate this mild effect and trigger disease.…”

Section: Discussionmentioning

confidence: 99%

Single-nucleotide variations in the genes encoding the mitochondrial Hsp60/Hsp10 chaperone system and their disease-causing potential

Bross

Hansen

et al. 2006

J Hum Genet

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Molecular chaperones assist protein folding, and variations in their encoding genes may be disease-causing in themselves or influence the phenotypic expression of disease-associated or susceptibility-conferring variations in many different genes. We have screened three candidate patient groups for variations in the HSPD1 and HSPE1 genes encoding the mitochondrial Hsp60/Hsp10 chaperone complex: two patients with multiple mitochondrial enzyme deficiency, 61 sudden infant death syndrome cases (MIM: #272120), and 60 patients presenting with ethylmalonic aciduria carrying non-synonymous susceptibility variations in the ACADS gene (MIM: *606885 and #201470). Besides previously reported variations we detected six novel variations: two in the bidirectional promoter region, and one synonymous and three non-synonymous variations in the HSPD1 coding region. One of the non-synonymous variations was polymorphic in patient and control samples, and the rare variations were each only found in single patients and absent in 100 control chromosomes. Functional investigation of the effects of the variations in the promoter region and the non-synonymous variations in the coding region indicated that none of them had a significant impact. Taken together, our data argue against the notion that the chaperonin genes play a major role in the investigated diseases. However, the described variations may represent genetic modifiers with subtle effects.

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Section: Discussionmentioning

confidence: 99%

Single-nucleotide variations in the genes encoding the mitochondrial Hsp60/Hsp10 chaperone system and their disease-causing potential

Bross

Hansen

et al. 2006

J Hum Genet

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“…Less than half of the 19 reported cases fit these criteria, and could be considered classic SCAD deficiency such as the first of two cases reported by Amendt et al (4). The second, larger group may have intermittent ethylmalonic aciduria, variably decreased SCAD activity, and an SCAD gene susceptibility variation (625 G3 A/G3 A or 511 C3 T/C3 T) in both alleles, sometimes accompanied by a heterozygous inactivating mutation in one SCAD allele (2,5,6). Biochemical abnormalities may be less pronounced in this second group, and clinical abnormalities show marked heterogeneity (1)(2)(3)(4)7).…”

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confidence: 99%

Rare Disorders of Metabolism with Elevated Butyryl- and Isobutyryl-Carnitine Detected by Tandem Mass Spectrometry Newborn Screening

et al. 2003

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“…The R147W and G185S variant proteins were produced at lower levels in Escherichia coli, but could be partly rescued and subsequently purified by co-expression of the bacterial GroEL/ES chaperonin-system (bacterial homologue to hsp60/ hsp10) (18,19). Purified G185S SCAD showed impaired catalytic efficiency with butyryl-CoA as substrate (10 M Ϫ1 s Ϫ1 versus 33 M Ϫ1 s Ϫ1 ), whereas the catalytic efficiency (30 M Ϫ1 s Ϫ1 ) and thermostability of the R147W variant enzyme were similar to that of wild type SCAD (33 M Ϫ1 s Ϫ1 ) (19).…”

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confidence: 99%

“…At present, 14 disease-causing variations have been reported in the SCAD gene, all of which are of the missense type except one (a 3-bp deletion) (4,12,(15)(16)(17). Besides the rare pathogenic variations in the SCAD gene leading to a complete deficiency of SCAD activity, two common SCAD variations have been identified in Western European populations that encode proteins with reduced catalytic activity and/or thermostability: 625GϾA (G185S) and 511CϾT (R147W) (12,17,18). The 625A and 511T alleles are overrepresented in homozygous or in compound heterozygous form in patients with elevated ethylmalonic acid levels (Ͼ18 mmol/mol creatinine) in the urine (69 versus 14% in the general population) (17,18).…”

mentioning

confidence: 99%

“…Besides the rare pathogenic variations in the SCAD gene leading to a complete deficiency of SCAD activity, two common SCAD variations have been identified in Western European populations that encode proteins with reduced catalytic activity and/or thermostability: 625GϾA (G185S) and 511CϾT (R147W) (12,17,18). The 625A and 511T alleles are overrepresented in homozygous or in compound heterozygous form in patients with elevated ethylmalonic acid levels (Ͼ18 mmol/mol creatinine) in the urine (69 versus 14% in the general population) (17,18). The majority of patients reported with apparent SCAD deficiency carry only the common variant genotypes (625A/ 625A, 511T/511T, and 625A/511T) or a genotype defined by common variations in one allele and rare variations in the other (12,17).…”

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confidence: 99%

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Misfolding, Degradation, and Aggregation of Variant Proteins

Pedersen

Bross

Winter

et al. 2003

Journal of Biological Chemistry

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Short chain acyl-CoA dehydrogenase (SCAD) deficiency is an inborn error of the mitochondrial fatty acid metabolism caused by rare variations as well as common susceptibility variations in the SCAD gene. Earlier studies have shown that a common variant SCAD protein (R147W) was impaired in folding, and preliminary experiments suggested that the variant protein displayed prolonged association with chaperonins and delayed formation of active enzyme. Accordingly, the molecular pathogenesis of SCAD deficiency may rely on intramitochondrial protein quality control mechanisms, including degradation and aggregation of variant SCAD proteins. In this study we investigated the processing of a set of disease-causing variant SCAD proteins (R22W, G68C, W153R, R359C, and Q341H) and two common variant proteins (R147W and G185S) that lead to reduced SCAD activity. All SCAD proteins, including the wild type, associate with mitochondrial hsp60 chaperonins; however, the variant SCAD proteins remained associated with hsp60 for prolonged periods of time. Biogenesis experiments at two temperatures revealed that some of the variant proteins (R22W, G68C, W153R, and R359C) caused severe misfolding, whereas others (R147W, G185S, and Q341H) exhibited a less severe temperaturesensitive folding defect. Based on the magnitude of in vitro defects, these SCAD proteins are characterized as folding-defective variants and mild folding variants, respectively. Pulse-chase experiments demonstrated that the variant SCAD proteins either triggered proteolytic degradation by mitochondrial proteases or, especially at elevated temperature, aggregation of non-native conformers. The latter finding may indicate that accumulation of aggregated SCAD proteins may play a role in the pathogenesis of SCAD deficiency.

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Ethylmalonic Aciduria Is Associated with an Amino Acid Variant of Short Chain Acyl-Coenzyme A Dehydrogenase

Cited by 96 publications

References 38 publications

Single-nucleotide variations in the genes encoding the mitochondrial Hsp60/Hsp10 chaperone system and their disease-causing potential

Single-nucleotide variations in the genes encoding the mitochondrial Hsp60/Hsp10 chaperone system and their disease-causing potential

Rare Disorders of Metabolism with Elevated Butyryl- and Isobutyryl-Carnitine Detected by Tandem Mass Spectrometry Newborn Screening

Misfolding, Degradation, and Aggregation of Variant Proteins

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