A Polymorphic Variant in the Human Electron Transfer Flavoprotein α-Chain (α-T171) Displays Decreased Thermal Stability and Is Overrepresented in Very-Long-Chain acyl-CoA Dehydrogenase-Deficient Patients with Mild Childhood Presentation

Bross, Peter; Pedersen, Palle; Winter, Vibeke; Nyholm, M.; Johansen, Bent; Olsen, Rikke K.J.; Corydon, Thomas J.; Andresen, Brage S.; Eiberg, Hans; Kølvraa, Steen; Gregersen, Niels

doi:10.1006/mgme.1999.2856

Cited by 20 publications

(22 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Bross et al . [26] reported that βT154M of the ETFβ gene had no significant consequence on the stability of ETFβ. Electron transfer flavoprotein β probably could not link up with mutant αG267R, hence instability of the intramitochondrial ETFβ was observed.…”

Section: Discussionmentioning

confidence: 99%

Molecular study of electron transfer flavoprotein α‐subunit deficiency in two Japanese children with different phenotypes of glutaric acidemia type II

Purevjav

Kimura

Takusa

et al. 2002

Eur J Clin Investigation

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 99%

Molecular study of electron transfer flavoprotein α‐subunit deficiency in two Japanese children with different phenotypes of glutaric acidemia type II

Purevjav

Kimura

Takusa

et al. 2002

Eur J Clin Investigation

View full text Add to dashboard Cite

show abstract

“…The human DLD and DLST cDNAs (GenBank™ accession numbers NM_000108.3 and NM_001933.4, respectively) were isolated from total cDNA by PCR using Taq® polymerase (Amersham, Freiburg, Germany) and subcloned with a 3′ His 6 sequence into pcDNA3.1/V5-His-TOPO using the corresponding TOPO TA Expression Kit (Invitrogen). The human ETFA and ETFB cDNA (GenBank™ accession numbers NM_000126.3 and NM_001985.2, respectively) were kindly provided by Dr. P. Bross (Aarhus University, Denmark) and isolated from the pCRII-ETFA and -ETFB vectors [13] by PCR using Phusion® polymerase (Thermo Scientific, St. Leon-Rot, Germany) and subcloned with a 3′ His 6 sequence into the pcDNA3.1D/V5-His-TOPO vector using the corresponding Directional TOPO Expression Kit (Invitrogen). HMGCL cDNA was kindly provided by Dr. S. Gersting, (LMU Munich, Germany) and cloned into the pcDNA3.1D/V5-His-TOPO as described above.…”

Section: Methodsmentioning

confidence: 99%

Interaction of Glutaric Aciduria Type 1-Related glutaryl-CoA Dehydrogenase with Mitochondrial Matrix Proteins

et al. 2014

View full text Add to dashboard Cite

Glutaric aciduria type 1 (GA1) is an inherited neurometabolic disorder caused by mutations in the GCDH gene encoding glutaryl-CoA dehydrogenase (GCDH), which forms homo- and heteromeric complexes in the mitochondrial matrix. GA1 patients are prone to the development of encephalopathic crises which lead to an irreversible disabling dystonic movement disorder. The clinical and biochemical manifestations of GA1 vary considerably and lack correlations to the genotype. Using an affinity chromatography approach we report here for the first time on the identification of mitochondrial proteins interacting directly with GCDH. Among others, dihydrolipoamide S-succinyltransferase (DLST) involved in the formation of glutaryl-CoA, and the β-subunit of the electron transfer flavoprotein (ETFB) serving as electron acceptor, were identified as GCDH binding partners. We have adapted the yellow fluorescent protein-based fragment complementation assay and visualized the oligomerization of GCDH as well as its direct interaction with DLST and ETFB in mitochondria of living cells. These data suggest that GCDH is a constituent of multimeric mitochondrial dehydrogenase complexes, and the characterization of their interrelated functions may provide new insights into the regulation of lysine oxidation and the pathophysiology of GA1.

show abstract

“…The pK-lac-ETF-ab3 (C/T) plasmid (here named pWt) has been described previously [Bross et al, 1999b]. In order to introduce the G to A mutation at position 382 of ETFB cDNA into the pKlac-ETF-ab3 (C/T) plasmid, a fragment covering nucleotide position 235 through 811 of the ETFB cDNA sequence was PCR-amplified under standard conditions by means of Pfu Turbot DNA Polymerase (Stratagene) using Patient 7 cDNA as template.…”

Section: Expression and Analysis Of Wild-type And Mutant Etf In E Comentioning

confidence: 99%

Clear relationship betweenETF/ETFDH genotype and phenotype in patients with multiple acyl-CoA dehydrogenation deficiency

et al. 2003

Self Cite

View full text Add to dashboard Cite

Mutations in electron transfer flavoprotein (ETF) and its dehydrogenase (ETFDH) are the molecular basis of multiple acyl-CoA dehydrogenation deficiency (MADD), an autosomal recessively inherited and clinically heterogeneous disease that has been divided into three clinical forms: a neonatal-onset form with congenital anomalies (type I), a neonatal-onset form without congenital anomalies (type II), and a late-onset form (type III). To examine whether these different clinical forms could be explained by different ETF/ETFDH mutations that result in different levels of residual ETF/ETFDH enzyme activity, we have investigated the molecular genetic basis for disease development in nine patients representing the phenotypic spectrum of MADD. We report the genomic structures of the ETFA, ETFB, and ETFDH genes and the identification and characterization of seven novel and three previously reported disease-causing mutations. Our molecular genetic investigations of these nine patients are consistent with three clinical forms of MADD showing a clear relationship between the nature of the mutations and the severity of disease. Interestingly, our data suggest that homozygosity for two null mutations causes fetal development of congenital anomalies resulting in a type I disease phenotype. Even minute amounts of residual ETF/ETFDH activity seem to be sufficient to prevent embryonic development of congenital anomalies giving rise to type II disease. Overexpression studies of an ETFB-D128N missense mutation identified in a patient with type III disease showed that the residual activity of the mutant enzyme could be rescued up to 59% of that of wild-type activity when ETFB-D128N-transformed E. coli cells were grown at low temperature. This indicates that the effect of the ETF/ETFDH genotype in patients with milder forms of MADD, in whom residual enzyme activity allows modulation of the enzymatic phenotype, may be influenced by environmental factors like cellular temperature.

show abstract

A Polymorphic Variant in the Human Electron Transfer Flavoprotein α-Chain (α-T171) Displays Decreased Thermal Stability and Is Overrepresented in Very-Long-Chain acyl-CoA Dehydrogenase-Deficient Patients with Mild Childhood Presentation

Cited by 20 publications

References 21 publications

Molecular study of electron transfer flavoprotein α‐subunit deficiency in two Japanese children with different phenotypes of glutaric acidemia type II

Molecular study of electron transfer flavoprotein α‐subunit deficiency in two Japanese children with different phenotypes of glutaric acidemia type II

Interaction of Glutaric Aciduria Type 1-Related glutaryl-CoA Dehydrogenase with Mitochondrial Matrix Proteins

Clear relationship betweenETF/ETFDH genotype and phenotype in patients with multiple acyl-CoA dehydrogenation deficiency

Contact Info

Product

Resources

About