Identification of a common mutation in the carnitine palmitoyltransferase II gene in familial recurrent myoglobinuria patients

Abstract

Carnitine palmitoyltransferase (CPT) II deficiency is the most common inherited disorder of lipid metabolism affecting skeletal muscle. We have identified a missense mutation (Ser113Leu) in one patient with the classical muscular symptomatology. Transfection experiments in COS cells demonstrate that the mutation drastically depresses the catalytic activity of CPT II. The mutation results in normal synthesis but a markedly reduced steady-state level of the protein, indicating decreased stability of mutant CPT II. The Ser113Leu mutation is the most frequent cause of CPT II deficiency. The mutation can be detected easily by restriction analysis enabling molecular diagnosis of most patients and identification of heterozygous carriers.

The Mitochondrial Carnitine Palmitoyltransferase System — From Concept to Molecular Analysis

“…Taroni et al [lo41 designate this allele ILV. Whereas the presence of the two polymorphisms on the mutant allele appeared not to affect the low residual activity of the protein when expressed in COS cells, it exacerbated the deleterious impact of a second disease-causing mutation identified in an infantile case of CPT I1 deficiency as Arg631Cys [104]; the authors refer to the latter defective allele as ICV. One of the 25 adult patients studied in [lo41 proved to be a compound heterozygote carrying both ILV and ICV mutant alleles.…”

“…Particularly common among European subjects with the classical adult muscular form of the disorder is a C-T transition at nucleotide 439 which changes amino acid 113 from serine to leucine. In 25 such patients, all unrelated, the Serll3Leu mutation was found on 28 of the 50 mutant alleles, but in none of 31 unaffected control subjects [104]. Curiously, in all cases the defective allele also contained two polymorphic variants, Va1368Ile and Met647Va1, which occur in the general population with allele frequencies of 0.51 and 0.25, respectively [104].…”

“…In 25 such patients, all unrelated, the Serll3Leu mutation was found on 28 of the 50 mutant alleles, but in none of 31 unaffected control subjects [104]. Curiously, in all cases the defective allele also contained two polymorphic variants, Va1368Ile and Met647Va1, which occur in the general population with allele frequencies of 0.51 and 0.25, respectively [104]. Taroni et al [lo41 designate this allele ILV.…”

“…According to this view, a value of 15-25% of control is associated only with muscle symptoms, but below this threshold abnormal function extends to the liver and heart. Others have proposed that CPT I1 may form a physical association with distal components of the Boxidation machinery such that mutations at different sites in the protein result in variable efficiency of the overall system [104].…”

A novel splice site mutation in neonatal carnitine palmitoyl transferase II deficiency

“…Truncating CPT II mutations are often associated with the severe neonatal form, while "mild" missense mutations mostly lead to the infantile or adult form. The most common mutation in (adult) CPT II deficiency is the S113L substitution (Taroni et al 1993), while several other mutations have also been identified in individual patients suffering the late-onset and infantile forms. But to date, only four individual mutations, all located in the CPT II gene, have been found in patients with the neonatal form of CPT II deficiency (Bonnefont et al 1999).…”