title: Missense mutations in APOB within the betaalpha1 domain of human APOB-100 result in impaired secretion of ApoB and ApoB-containing lipoproteins in familial hypobetalipoproteinemia.
abstract: Familial hypobetalipoproteinemia (FHBL) is associated with mutations in the APOB gene. We reported the first missense APOB mutation, R463W, in an FHBL kindred (Burnett, J. R., Shan, J., Miskie, B. A., Whitfield, A. J., Yuan, J., Tran, K., Mc-Knight, C. J., Hegele, R. A., and Yao, Z. (2003) J. Biol. Chem. 278, 13442-13452). Here we identified a second nonsynonymous APOB mutation, L343V, in another FHBL kindred. Heterozygotes for L343V (n = 10) had a mean plasma apoB at 0.31 g/liter as compared with 0.80 g/liter in unaffected family members (n = 22). The L343V mutation impaired secretion of apoB-100 and very low density lipoproteins. The secretion efficiency was 20% for B100wt and 10% for B100LV and B100RW. Decreased secretion of mutant apoB-100 was associated with increased endoplasmic reticulum retention and increased binding to microsomal triglyceride transfer protein and BiP. Reduced secretion efficiency was also observed with B48LV and B17LV. Biochemical and biophysical analyses of apoB domain constructs showed that L343V and R463W altered folding of the alpha-helical domain within the N terminus of apoB. Thus, proper folding of the alpha-helical domain of apoB-100 is essential for efficient secretion.
authors.affiliation: Department of Core Clinical Pathology and Biochemistry, Royal Perth Hospital, Australia. john.burnett@health.wa.gov.au
authors.forename: John R
authors.initials: JR
authors.lastname: Burnett
authors.forename: Shumei
authors.initials: S
authors.lastname: Zhong
authors.forename: Zhenghui G
authors.initials: ZG
authors.lastname: Jiang
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Hooper
authors.forename: Eric A
authors.initials: EA
authors.lastname: Fisher
authors.forename: Roger S
authors.initials: RS
authors.lastname: McLeod
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhao
authors.forename: P Hugh R
authors.initials: PH
authors.lastname: Barrett
authors.forename: Robert A
authors.initials: RA
authors.lastname: Hegele
authors.forename: Frank M
authors.initials: FM
authors.lastname: van Bockxmeer
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhang
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Vance
authors.forename: C James
authors.initials: CJ
authors.lastname: McKnight
authors.forename: Zemin
authors.initials: Z
authors.lastname: Yao
mesh_terms: D053299:Apolipoprotein B-100 / Q000737:chemistry / Q000235:genetics*; D001055:Apolipoproteins B / Q000235:genetics* / Q000378:metabolism; D005192:Family Health; D006801:Humans; D006995:Hypobetalipoproteinemias / Q000235:genetics*; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D020125:Mutation, Missense; D017510:Protein Folding; D017434:Protein Structure, Tertiary
chemical_list: D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D008079:Lipoproteins, VLDL