title: Molecular pathogenesis of a novel mutation, G108D, in short-chain acyl-CoA dehydrogenase identified in subjects with short-chain acyl-CoA dehydrogenase deficiency.
abstract: Short-chain acyl-CoA dehydrogenase (SCAD) is a mitochondrial enzyme involved in the beta-oxidation of fatty acids. Genetic defect of SCAD was documented to cause clinical symptoms such as progressive psychomotor retardation, muscle hypotonia, and myopathy in early reports. However, clinical significance of SCAD deficiency (SCADD) has been getting ambiguous, for some variants in the ACADS gene, which encodes the SCAD protein, has turned out to be widely prevailed among general populations. Accordingly, the pathophysiology of SCADD has not been clarified thus far. The present report focuses on two suspected cases of SCADD detected through the screening of newborns by tandem mass spectrometry. In both subjects, compound heterozygous mutations in ACADS were detected. The mutated genes were expressed in a transient gene expression system, and the enzymatic activities of the obtained mutant SCAD proteins were measured. The activities of the mutant SCAD proteins were significantly lower than that of the wild-type enzyme, confirming the mechanism underlying the diagnosis of SCADD in both subjects. Moreover, the mutant SCAD proteins gave rise to mitochondrial fragmentation and autophagy, both of which were proportional to the decrease in SCAD activities. The association of autophagy with programmed cell death suggests that the mutant SCAD proteins are toxic to mitochondria and to the cells in which they are expressed. The expression of recombinant ACADS-encoded mutant proteins offers a technique to evaluate both the nature of the defective SCAD proteins and their toxicity. Moreover, our results provide insight into possible molecular pathophysiology of SCADD.
authors.affiliation: Department of Pediatrics, Hiroshima University Graduate School of Biomedical Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Shirao
authors.forename: Satoshi
authors.initials: S
authors.lastname: Okada
authors.forename: Go
authors.initials: G
authors.lastname: Tajima
authors.forename: Miyuki
authors.initials: M
authors.lastname: Tsumura
authors.forename: Keiichi
authors.initials: K
authors.lastname: Hara
authors.forename: Shin'ichiro
authors.initials: S
authors.lastname: Yasunaga
authors.forename: Motoaki
authors.initials: M
authors.lastname: Ohtsubo
authors.forename: Ikue
authors.initials: I
authors.lastname: Hata
authors.forename: Nobuo
authors.initials: N
authors.lastname: Sakura
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Shigematsu
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Takihara
authors.forename: Masao
authors.initials: M
authors.lastname: Kobayashi
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D044926:Butyryl-CoA Dehydrogenase / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D005796:Genes; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D007231:Infant, Newborn; D052439:Lipid Metabolism Disorders / Q000235:genetics* / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D010084:Oxidation-Reduction; D017433:Protein Structure, Secondary / Q000235:genetics; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D011994:Recombinant Proteins; D044926:Butyryl-CoA Dehydrogenase