title: A G+1 to C mutation in a donor splice site of intron 2 in the apolipoprotein (apo) C-II gene in a patient with apo C-II deficiency. A possible interaction between apo C-II deficiency and apo E4 in a severely hypertriglyceridemic patient.
abstract: Familial apolipoprotein C-II (apo C-II) deficiency is an autosomal recessive genetic disorder characterized by fasting hypertriglyceridemia and accumulation of chylomicrons in the plasma. To elucidate the genetic defect, the apo C-II gene of a neonatal Japanese patient (C-IITokyo) was analyzed. Nucleotide sequence analysis showed a G+1 to C transversion at the donor splice site of intron 2 (INT2 G+1 to C). Restriction fragment length polymorphism analyses of the patient's family members with Hph I showed that the patient was homozygous and the parents were heterozygous for the INT2 G+1 to C mutation. Although consanguinity could not be demonstrated, haplotype analysis of the C-II gene revealed the identity of the patient's alleles on the mutation, suggesting that the parents had a common Japanese ancestor. Sequence analysis of the patient's cDNA isolated from peripheral blood lymphocytes revealed that the INT2 G+1 to C mutation causes skipping of exon 2, which encodes the initiation codon, and results in deficiency of apo C-II proteins. The outstanding feature of our patient was that he showed severe hypertriglyceridemia beginning in the neonatal period, a feature not reported in a case of apo C-II deficiency (C-IIHamburg) with the same mutation as our patient. A previous report of another case of apo C-II deficiency (C-IIToronto) suggested that the apo E4 isoform is associated with higher levels of plasma triglycerides in subjects heterozygous for the apo C-II mutation. Determination of the apo E isoform of our patient revealed that apo E4 was coinherited with the INT2 G+1 to C mutation, whereas the apo E isoform has been reported to be E2/3 in C-IIHamburg. We speculate that apo E4/4 aggravated the hypertriglyceridemia in our patient with apo C-II deficiency.
authors.affiliation: Department of Endocrinology and Metabolism, Toranomon Hospital, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Okubo
authors.forename: Y
authors.initials: Y
authors.lastname: Hasegawa
authors.forename: Y
authors.initials: Y
authors.lastname: Aoyama
authors.forename: T
authors.initials: T
authors.lastname: Murase
mesh_terms: D053304:Apolipoprotein C-II; D053327:Apolipoprotein E4; D001056:Apolipoproteins C / Q000172:deficiency / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics*; D015139:Blotting, Southern; D002648:Child; D005784:Gene Amplification; D005838:Genotype; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D015228:Hypertriglyceridemia / Q000235:genetics*; D007438:Introns / Q000235:genetics*; D008297:Male; D010641:Phenotype; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D017422:Sequence Analysis, DNA
chemical_list: D053304:Apolipoprotein C-II; D053327:Apolipoprotein E4; D001056:Apolipoproteins C; D001057:Apolipoproteins E