A G(-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(1) TO C)

Familial apolipoprotein C-II (ape C-II) deficiency is an autosomal rec essive genetic disorder characterized by fasting hypertriglyceridemia and accumulation of chylomicrons in the plasma. To elucidate the genet ic defect, the apo C-II gene of a neonatal Japanese patient (C-IITokyo ) was analyzed. Nucleotide sequence analysis showed a G(+1) to C trans version at the donor splice site of intron 2 (INT2 G(+1) to C). Restri ction fragment length polymorphism analyses of the patient's family me mbers with Hph I showed that the patient was homozygous and the parent s were heterozygous for the INT2 G(+1) to C mutation. Although consang uinity could not be demonstrated, haplotype analysis of the C-II gene revealed the identity of the patient's alleles on the mutation, sugges ting that the parents had a common Japanese ancestor. Sequence analysi s of the patient's cDNA isolated from peripheral blood lymphocytes rev ealed that the INT2 G(+1) to C mutation causes skipping of exon 2, whi ch encodes the initiation codon, and results in deficiency of apo C-II proteins. The outstanding feature of our patient was that he showed s evere 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 as sociated with higher levels of plasma triglycerides in subjects hetero zygous for the apo C-II mutation. Determination of the apo E isoform o f 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 E 2/3 in C-IIHamburg. We speculate that apo E4/4 aggravated the hypertri glyceridemia in our patient with apo C-II deficiency. (C) 1997 Elsevie r Science Ireland Ltd.