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.
Research Unit for Molecular Medicine, Skejby and Faculty of Health Sciences, Aarhus University Hospital, Brendstrupgaardsvej 100, 8200, Aarhus, Denmark. cbak@ki.au.dk
Christina B
CB
Pedersen
Steen
S
Kølvraa
Agnete
A
Kølvraa
Vibeke
V
Stenbroen
Margrethe
M
Kjeldsen
Regina
R
Ensenauer
Ingrid
I
Tein
Dietrich
D
Matern
Piero
P
Rinaldo
Christine
C
Vianey-Saban
Antonia
A
Ribes
Willy
W
Lehnert
Ernst
E
Christensen
Thomas J
TJ
Corydon
Brage S
BS
Andresen
Søren
S
Vang
Lars
L
Bolund
Jerry
J
Vockley
Peter
P
Bross
Niels
N
Gregersen
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