Missense mutation Leu72Pro located on the carboxyl terminal amphipathic helix of apolipoprotein C-II causes familial chylomicronemia syndrome.
BACKGROUND
Chylomicronemia syndrome can be caused by 2 autosomal recessive disorders - lipoprotein lipase (LPL) deficiency and apolipoprotein C-II (apo C-II) deficiency.


METHODS
We described 2 siblings with chylomicronemia syndrome of a consanguineous family. To determine the molecular basis of chylomicronemia syndrome in this family, we performed direct DNA sequencing of the LPL and APOC2 genes of the proband.


RESULTS
A novel homozygous mutation, Leu72Pro, in the APOC2 gene was found in both siblings whereas their parents were carriers. No LPL mutations were detected in the siblings. Apo C-II contains 3 amphipathic alpha helices; the C-terminal alpha helix is composed of residues 64 to 74. Substitution of residue 72 from a helix former leucine to a helix breaker, proline, is predicted to change the secondary structure of the C-terminal helix and subsequently alter the interaction between apo C-II and LPL.


CONCLUSIONS
To our knowledge, Leu72Pro is the first missense mutation identified in the C-terminal of apo C-II. The result is consistent with the current biochemical and structural findings that the C-terminal helix of apo C-II is important for activation of LPL.
Lam
Ching-Wan
CW
Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China. ching-wanlam@cuhk.edu.hk
Yuen
Yuet-Ping
YP
Cheng
Wai-Fun
WF
Chan
Yan-Wo
YW
Tong
Sui-Fan
SF
D053304:Apolipoprotein C-II; D001056:Apolipoproteins C / Q000172:deficiency / Q000235:genetics*; D001483:Base Sequence; D002675:Child, Preschool; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D008072:Hyperlipoproteinemia Type I / Q000201:enzymology / Q000235:genetics*; D007223:Infant; D008071:Lipoprotein Lipase / Q000172:deficiency / Q000235:genetics*; D020125:Mutation, Missense; D012689:Sequence Homology, Nucleic Acid; D035781:Siblings; D013577:Syndrome
D053304:Apolipoprotein C-II; D001056:Apolipoproteins C; D008071:Lipoprotein Lipase