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.
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ABSTRACT: The acyl-CoA dehydrogenase, C-2 to C-3 short chain (ACADS) gene is known to be related with fat metabolism, especially coverts the fat to the energy sources in cattle. In human, the mutations in this gene cause SCAD deficiency, which is one of the fatty acid metabolism disorders. The ACADS gene is located on bovine chromosome 17. The objective of this study was to identify SNPs in Hanwoo ACADS gene and identify the relationships with economic traits. In this study, two SNPs, T1570G SNP in exon 2 and G13917A SNP in exon 4, were observed. Moreover, in the coding region, 2 missense mutations, T (Cys) G (Trp) mutation at 1570 bp and G (Arg) A (Gln) mutation at 13917 bp, were observed. These mutations were subjected to the PCR-RFLP for typing 198 Hanwoo animals. The observed genotype frequency for T1570G was 0.135 (TT), 0.860 (TG) and 0.005 (GG), respectively. Also, 0.900 (GG) and 0.100 (GA) were observed for the G13917A mutation. The association of these SNPs with four economic traits, CW (Carcass Weight), BF (Backfat Thickness), LMA (Longissimus Muscle Area), MS (Marbling Score), were also observed. The results indicated that no significant results were observed in all four traits (P>0.05). This might indicate that further studies are ultimately needed to use the SNPs in ACADS gene in lager populations for effectively used for the marker assisted selection.06/2012; 39(2). DOI:10.7744/cnujas.2012.39.2.219
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ABSTRACT: Short-chain acyl-CoA dehydrogenase (SCAD) deficiency is a rare inherited autosomal recessive disorder with not yet well established mechanisms of disease. In the present study, the mitochondrial proteome of five symptomatic patients homozygous for missense variations in the SCAD gene ACADS was investigated in an extensive large-scale proteomic study to map protein perturbations linked to the disease. Fibroblast cultures of patient cells homozygous for either c.319C>T/p.Arg107Cys (n=2) or c.1138C>T/p.Arg380Trp (n=3) in ACADS, and healthy controls (normal human dermal fibroblasts), were studied. The mitochondrial proteome derived from these cultures was analyzed by label free proteomics using high mass accuracy nanoliquid chromatography tandem mass spectrometry (nanoLC-MS/MS). More than 300 mitochondrial proteins were identified and quantified. Thirteen proteins had significant alteration in protein levels in patients carrying variation c.319C>T in ACADS compared to controls and they belonged to various pathways, such as the antioxidant system and amino acid metabolism. Twenty-two proteins were found significantly altered in patients carrying variation c.1138C>T which included proteins associated with fatty acid β-oxidation, amino acid metabolism and protein quality control system. Three proteins were found significantly regulated in both patient groups: adenylate kinase 4 (AK4), nucleoside diphosphate kinase A (NME1) and aldehyde dehydrogenase family 4 member A1 (ALDH4A1). Proteins AK4 and NME1 deserve further investigation because of their involvement in energy reprogramming, cell survival and proliferation with relevance for SCAD deficiency and related metabolic disorders.Molecular Genetics and Metabolism 01/2014; 111(3). DOI:10.1016/j.ymgme.2014.01.007 · 2.83 Impact Factor
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ABSTRACT: Purpose Rare endocrine–metabolic diseases (REMD) represent an important area in the field of medicine and pharmacology. The rare diseases of interest to endocrinologists involve all fields of endocrinology, including rare diseases of the pituitary, thyroid and adrenal glands, paraganglia, ovary and testis, disorders of bone and mineral metabolism, energy and lipid metabolism, water metabolism, and syndromes with possible involvement of multiple endocrine glands, and neuroendocrine tumors. Taking advantage of the constitution of a study group on REMD within the Italian Society of Endocrinology, consisting of basic and clinical scientists, a document on the taxonomy of REMD has been produced. Methods and results This document has been designed to include mainly REMD manifesting or persisting into adulthood. The taxonomy of REMD of the adult comprises a total of 166 main disorders, 338 including all variants and subtypes, described into 11 tables. Conclusions This report provides a complete taxonomy to classify REMD of the adult. In the future, the creation of registries of rare endocrine diseases to collect data on cohorts of patients and the development of common and standardized diagnostic and therapeutic pathways for each rare endocrine disease is advisable. This will help planning and performing intervention studies in larger groups of patients to prove the efficacy, effectiveness, and safety of a specific treatment.Journal of endocrinological investigation 11/2014; 38(2). DOI:10.1007/s40618-014-0202-6 · 1.55 Impact Factor