Molecular basis of inherited medium-chain acyl-CoA dehydrogenase deficiency causing sudden child death.
Deficiency of medium-chain acyl-CoA dehydrogenase (MCAD) is an important cause of sudden death in children. The majority of surviving individuals with MCAD deficiency studied to date are homozygous for a single point mutation at bp 985 of the MCAD mRNA (A985G). We have now identified a four-base-pair deletion in exon 11 of one allele of the MCAD gene in an American child who died of MCAD deficiency. The deletion mutation results in a frameshift and premature termination codon in the mutant MCAD mRNA. The second mutant allele contained the common point mutation A985G, and thus the proband was a compound heterozygote. Protein immunoblot analysis of the child's liver proteins revealed that the mutant MCAD proteins were barely detectable. Allele-specific oligonucleotide hybridization analysis performed on amplified exon 11 of the child's MCAD gene clearly identified both mutations. MCAD RFLP analysis of the patient's DNA revealed heterozygosity at the Taq I MCAD RFLP site, thus, the two mutations are associated with different haplotypes. Therefore, we have identified a new mutation in the MCAD gene and have developed a nucleic-acid-based screening approach which allows the post mortem identification of MCAD deficiency.
Kelly
D P
DP
Cardiovascular Division, Washington University School of Medicine, St. Louis, MO 63110.
Hale
D E
DE
Rutledge
S L
SL
Ogden
M L
ML
Whelan
A J
AJ
Zhang
Z
Z
Strauss
A W
AW
D042964:Acyl-CoA Dehydrogenase; D044944:Acyl-CoA Dehydrogenases / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics; D000595:Amino Acid Sequence; D001483:Base Sequence; D002872:Chromosome Deletion; D004247:DNA / Q000737:chemistry; D005091:Exons; D006801:Humans; D007223:Infant; D008099:Liver / Q000737:chemistry; D008297:Male; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D013398:Sudden Infant Death / Q000209:etiology*
D004247:DNA; D044944:Acyl-CoA Dehydrogenases; D042964:Acyl-CoA Dehydrogenase