The ACADS gene variation spectrum in 114 patients with short-chain acyl-CoA dehydrogenase (SCAD) deficiency is dominated by missense variations leading to protein misfolding at the cellular level.
Short-chain acyl-CoA dehydrogenase (SCAD) deficiency is an inherited disorder of mitochondrial fatty acid oxidation associated with variations in the ACADS gene and variable clinical symptoms. In addition to rare ACADS inactivating variations, two common variations, c.511C > T (p.Arg171Trp) and c.625G > A (p.Gly209Ser), have been identified in patients, but these are also present in up to 14% of normal populations leading to questions of their clinical relevance. The common variant alleles encode proteins with nearly normal enzymatic activity at physiological conditions in vitro. SCAD enzyme function, however, is impaired at increased temperature and the tendency to misfold increases under conditions of cellular stress. The present study examines misfolding of variant SCAD proteins identified in patients with SCAD deficiency. Analysis of the ACADS gene in 114 patients revealed 29 variations, 26 missense, one start codon, and two stop codon variations. In vitro import studies of variant SCAD proteins in isolated mitochondria from SCAD deficient (SCAD-/-) mice demonstrated an increased tendency of the abnormal proteins to misfold and aggregate compared to the wild-type, a phenomenon that often leads to gain-of-function cellular phenotypes. However, no correlation was found between the clinical phenotype and the degree of SCAD dysfunction. We propose that SCAD deficiency should be considered as a disorder of protein folding that can lead to clinical disease in combination with other genetic and environmental factors.
Pedersen
Christina B
CB
Research Unit for Molecular Medicine, Skejby and Faculty of Health Sciences, Aarhus University Hospital, Brendstrupgaardsvej 100, 8200, Aarhus, Denmark. cbak@ki.au.dk
Kølvraa
Steen
S
Kølvraa
Agnete
A
Stenbroen
Vibeke
V
Kjeldsen
Margrethe
M
Ensenauer
Regina
R
Tein
Ingrid
I
Matern
Dietrich
D
Rinaldo
Piero
P
Vianey-Saban
Christine
C
Ribes
Antonia
A
Lehnert
Willy
W
Christensen
Ernst
E
Corydon
Thomas J
TJ
Andresen
Brage S
BS
Vang
Søren
S
Bolund
Lars
L
Vockley
Jerry
J
Bross
Peter
P
Gregersen
Niels
N
D000818:Animals; D044926:Butyryl-CoA Dehydrogenase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D019281:Dimerization; D004789:Enzyme Activation / Q000235:genetics; D005787:Gene Frequency; D006801:Humans; D008314:Malonates / Q000378:metabolism / Q000652:urine; D008661:Metabolism, Inborn Errors / Q000201:enzymology / Q000235:genetics* / Q000652:urine; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008958:Models, Molecular; D020125:Mutation, Missense / Q000502:physiology*; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D017510:Protein Folding; D013329:Structure-Activity Relationship
D008314:Malonates; C038080:ethylmalonic acid; D044926:Butyryl-CoA Dehydrogenase