RGD Reference Report - Molecular characterization of inherited carnitine palmitoyltransferase II deficiency. - Rat Genome Database

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Molecular characterization of inherited carnitine palmitoyltransferase II deficiency.

Authors: Taroni, F  Verderio, E  Fiorucci, S  Cavadini, P  Finocchiaro, G  Uziel, G  Lamantea, E  Gellera, C  DiDonato, S 
Citation: Taroni F, etal., Proc Natl Acad Sci U S A. 1992 Sep 15;89(18):8429-33.
RGD ID: 1600742
Pubmed: PMID:1528846   (View Abstract at PubMed)
PMCID: PMC49933   (View Article at PubMed Central)

Deficiency of carnitine palmitoyltransferase II (CPTase II; palmitoyl-CoA:L-carnitine O-palmitoyltransferase, EC 2.3.1.21) is a clinically heterogeneous autosomal recessive disorder of energy metabolism. We studied the molecular basis of CPTase II deficiency in an early-onset patient presenting with hypoketotic hypoglycemia and cardiomyopathy. cDNA and genomic DNA analysis demonstrated that the patient was homozygous for a mutant CPTase II allele (termed ICV), which carried three missense mutations: a G-1203----A transition, predicting a Val-368----Ile substitution (V368I); a C-1992----T transition, predicting an Arg-631----Cys substitution (R631C); and an A-2040----G transition, predicting a Met-647----Val substitution (M647V). Genomic DNA analysis of family members showed that the mutations cosegregated with the disease in the family. However, screening of 59 healthy controls demonstrated that both the V368I and M647V mutations are sequence polymorphisms with allele frequencies of 0.5 and 0.25, respectively. By contrast, the R631C substitution was not detected in 22 normal individuals or in 12 of 14 CPTase II-deficient patients with the adult muscular form. Notably, 2 adult CPTase II-deficient patients were heterozygous for the ICV allele, thus suggesting compound heterozygosity for this and a different mutant allele. The consequences of the three mutations on enzyme activity were investigated by expressing normal and mutated CPTase II cDNAs in COS cells. The R631C substitution drastically depressed the catalytic activity of CPTase II, thus confirming that this is the crucial mutation. Interestingly, the V368I and M647V substitutions, which did not affect enzyme activity alone, exacerbated the effects of the R631C substitution. Biochemical characterization of mutant CPTase II in patient's cells showed that the mutations are associated with (i) severe reduction of Vmax (approximately 90%), (ii) normal apparent Km values, and (iii) decreased protein stability.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
lipid metabolism disorder  IAGP 1600742infantile form CPT2 deficiency more ...RGD 
lipid metabolism disorder  ISOCPT2 (Homo sapiens)1600742; 1600742infantile form CPT2 deficiency more ...RGD 

Objects Annotated

Genes (Rattus norvegicus)
Cpt2  (carnitine palmitoyltransferase 2)

Genes (Mus musculus)
Cpt2  (carnitine palmitoyltransferase 2)

Genes (Homo sapiens)
CPT2  (carnitine palmitoyltransferase 2)


Additional Information