In the current study, we showed two-related patients who manifested massive HTG and acute pancreatitis with a low LPL post-heparin activity. Both probands present the same LPL genotype with a compound heterozygote for a known missense mutation A98T in exon3 and a novel missense mutation L279V in exon 6 of LPL gene. Moreover, the novel mutation L279V was also found in one of 70 HTG individuals.
To date, the majority disease-causing LPL gene mutations occurs at exon 4, 5 and 6 residues (117–312), which constitute a large N-terminal domain (residues 1–312) of the enzyme and this region is the most conserved and important for LPL catalytic functions. Exon 6 (residues 232–313) encodes two structurally relevant disulfide bridges (Cys278-Cys283 and Cys264-Cys275) for the binding of heparin. The novel mutation L279V constitutes one of these two disulfide bridges (Cys278-Cys283), which is important for catalytic function of heparin binding. Both patients had low post-heparin LPL activity but normal levels of mass, further demonstrating this possibility.
Furthermore, we also assessed the L279V mutation disease-causing potential by comparing it across various species. We found that the L279 site is indeed conserved throughout evolution from chimpanzee to zebra fish, suggesting that this residue may play a critical role in LPL function. In the current study, we found a total of four carriers of L279V mutation including the two patients and one family member, and an unrelated HTG individual, all of whom were heterozygotes for this missense mutation. This novel LPL mutation (L279V) was submitted to NCBI and the Submitter SNP accession number is ss#550039488. In addition, the known LPL gene mutation A98T has been described previously with lipoprotein lipase deficiency in the clinic. To date, there were three family members found to carry this mutation, one with a single mutation and others with compound heterozygous for another nonsense mutation S447X of LPL.
Patients with two defective LPL alleles will have no or markedly reduced LPL activity, thus, homozygous or compounds of heterozygous mutations lead to severe HTG while one defective LPL allele may have normal to moderately increased blood levels of fasting triglyceride[15–17]. In this study, the mother and daughter had the same LPL genotype with compound heterozygous mutations of A98T and L279V; thus, both manifested massive HTG and acute pancreatitis. In contrast, the family members who carried a single mutation either A98T or L279V, only presented mild HTG and had no history of acute pancreatitis. Moreover, another unrelated HTG individual, who had the compound heterozygote L279V and a known GPIHBP1 mutation, suffered from a severe HTG and acute pancreatitis.
In the current study, we found that two family members had compound LPL gene A98T and S447X mutations, but they also had mild elevated blood TG levels. The reason for this is unclear, but may be because of the special mutation S447X. In a previous study, LPL S447X mutation was shown to have a naturally occurring gain-function. This LPL mutation S447X is the only mutation that has a protective effect against the development of HTG and coronary heart disease by decreasing plasma TG levels in the clinic and increasing HDL production. Thus, gene therapy using the S447X variant has shown therapeutic promise in the study of LPL deficiency.