Molecular cloning and nucleotide sequence of complementary DNAs encoding human short chain acyl-coenzyme A dehydrogenase and the study of the molecular basis of human short chain acyl-coenzyme A dehydrogenase deficiency.

Naito, Etsuo; Ozasa, Hisashi; Ikeda, Yasuyuki; Tanaka, Kay

doi:10.1172/jci114058

Cited by 76 publications

(42 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This suggested that the defect of SCAD in these patients is caused by a point mutation in the SCAD gene (3). Furthermore, using immunoblot analysis and pulse-chase experiment, we showed that variant SCAD synthesized by the cells from one of the patients, reported by Amendt et al as L.N.…”

Section: Introductionsupporting

confidence: 62%

See 1 more Smart Citation

Identification of two variant short chain acyl-coenzyme A dehydrogenase alleles, each containing a different point mutation in a patient with short chain acyl-coenzyme A dehydrogenase deficiency.

Naito¹,

Indo²,

Tanaka³

1990

J. Clin. Invest.

Self Cite

View full text Add to dashboard Cite

Two distinct mutant alleles of the precursor (p) short chain acyl-CoA dehydrogenase (SCAD) gene were identified in a SCAD-deficient patient (YH2065) using the polymerase chain reaction to amplify cDNA synthesized from total RNA from her fibroblasts. Cells from this patient had previously been shown to synthesize a labile variant SCAD in contrast to the normal stability of variant SCADs in two other SCAD-deficient cell lines (Naito, E., Y. Indo, and K.

show abstract

Section: Introductionsupporting

confidence: 62%

“…our previous studies (3,4), we have shown that the cells from all three patients synthesized a variant SCAD protein of normal size. This suggested that the defect of SCAD in these patients is caused by a point mutation in the SCAD gene (3).…”

Section: Introductionmentioning

confidence: 54%

Identification of two variant short chain acyl-coenzyme A dehydrogenase alleles, each containing a different point mutation in a patient with short chain acyl-coenzyme A dehydrogenase deficiency.

Naito¹,

Indo²,

Tanaka³

1990

J. Clin. Invest.

Self Cite

View full text Add to dashboard Cite

show abstract

“…In humans, loss of function mutations have been identified in genes encoding SCAD (ACADS [37]), MCAD (ACADM [38]. ), VLCAD (ACADVL [39]), and CPT-1A [40], but not CPT-1B or LCAD [41].…”

Section: Discussionmentioning

confidence: 99%

Homozygous carnitine palmitoyltransferase 1b (muscle isoform) deficiency is lethal in the mouse

You

Kerner

et al. 2008

Molecular Genetics and Metabolism

View full text Add to dashboard Cite

Carnitine palmitoyltransferase-1 (CPT-1) catalyzes the rate-limiting step of mitochondrial β-oxidation of long chain fatty acids (LCFA), the most abundant fatty acids in mammalian membranes and in energy metabolism. Human deficiency of the muscle isoform CPT-1b is poorly understood. In the current study, embryos with a homozygous knockout of Cpt-1b were lost before embryonic day 9.5 − 11.5. Also, while there were normal percentages of CPT-1b+/−pups born from both male and female CPT-1b+/− mice crossed with wild-type mates, the number of CPT-1b+/− pups from CPT-1b+/− breeding pairs was under-represented (63% of the expected number). Northern blot analysis demonstrated ∼50% Cpt-1b mRNA expression in brown adipose tissue (BAT), heart and skeletal muscles in the CPT-1b+/− male mice. Consistent with tissue-specific expression of Cpt-1b mRNA in muscle but not liver, CPT-1+/− mice had ∼60% CPT-1 activity in skeletal muscle and no change in total liver CPT-1 activity. CPT-1b+/− mice had normal fasting blood glucose concentration. Consistent with expression of CPT-1b in BAT and muscle, ∼7% CPT-1b+/− mice (n=30) developed fatal hypothermia following a 3 hr cold challenge, while none of the CPT-1b+/+ mice (n=30) did. With a prolonged cold challenge (6 hr), significantly more CPT-1b+/− mice developed fatal hypothermia (52% CPT-1b+/− mice vs. 21% CPT-1b+/+ mice), with increased frequency in females of both genotypes (67% female vs. 38% male CPT-1b+/− mice, and 33% female vs. 8% male CPT-1b+/+ mice). Therefore, lethality of homozygous CPT-1b deficiency in the mice is consistent with paucity of human cases.

show abstract

“…Subunits of the SCAD enzyme are nuclear encoded and synthesized in the cytosol as precursor proteins that are imported into the mitochondrial matrix. Newly imported SCAD proteins are proteolytically processed, folded, and assembled into the biologically active homotetrameric form (168 kDa) containing one molecule of FAD per subunit (2). Hereditary deficiency of SCAD has been reported in 20 patients world-wide with a variety of clinical symptoms (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13).…”

mentioning

confidence: 99%

“…This agrees with the mutation spectrum observed in a larger group of SCAD patients. 2 Because the common SCAD variants are detected in 14% of the general population, they cannot be sufficient to cause SCAD deficiency. The role of 625GϾA and 511CϾT in the pathogenesis of SCAD deficiency, therefore, is not clear.…”

mentioning

confidence: 99%

Misfolding, Degradation, and Aggregation of Variant Proteins

Pedersen

Bross

Winter

et al. 2003

Journal of Biological Chemistry

View full text Add to dashboard Cite

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.

show abstract

Molecular cloning and nucleotide sequence of complementary DNAs encoding human short chain acyl-coenzyme A dehydrogenase and the study of the molecular basis of human short chain acyl-coenzyme A dehydrogenase deficiency.

Cited by 76 publications

References 25 publications

Identification of two variant short chain acyl-coenzyme A dehydrogenase alleles, each containing a different point mutation in a patient with short chain acyl-coenzyme A dehydrogenase deficiency.

Identification of two variant short chain acyl-coenzyme A dehydrogenase alleles, each containing a different point mutation in a patient with short chain acyl-coenzyme A dehydrogenase deficiency.

Homozygous carnitine palmitoyltransferase 1b (muscle isoform) deficiency is lethal in the mouse

Misfolding, Degradation, and Aggregation of Variant Proteins

Contact Info

Product

Resources

About