TY - JOUR
T1 - Functional mutations of the ABCA1 gene in subjects of French-Canadian descent with HDL deficiency
AU - Alrasadi, Khalid
AU - Ruel, Isabelle L.
AU - Marcil, Michel
AU - Genest, Jacques
N1 - Funding Information:
The technical assistance of Shiona Dempster is gratefully acknowledged. This research was supported by the Canadian Institutes of Health Research (MOP-62834).
PY - 2006/10
Y1 - 2006/10
N2 - Mutations in the ABCA1 gene cause defective cellular lipid efflux and severe familial HDL deficiency. We examined the prevalence of mutations at the ABCA1 gene in 58 unrelated probands of French-Canadian descent with HDL deficiency (HDL-C < 5th percentile). A defective cellular cholesterol or phospholipid efflux (<75% and <70% of normal controls, respectively) was identified in 14/58 (24%) of subjects. Using direct sequencing of the ABCA1 gene, we found mutations in 12/58 (∼20%) of subjects. Four probands were previously identified with diverse ABCA1 gene defects. However, we identified a novel frameshift mutation (F1840L, L1869X); a proband was heteroallelic for the N1800H mutation, previously reported in a case of Tangier disease, and a novel missense mutation (Q2210H); a novel variant (G616V), predicted to impart a functional defect in the protein, was also found in another proband. Three probands had the S1731C mutation, while two others had the R1851X and K776N documented mutations, respectively. Taken together, these data suggest that ∼20% of French-Canadian patients with severe HDL deficiency are associated with a defective ABCA1. Interestingly, in two families studied, mutations in the ABCA1 gene did not segregate with the lipid efflux defect, suggesting that other proteins are involved in the ABCA1-mediated cellular lipid efflux.
AB - Mutations in the ABCA1 gene cause defective cellular lipid efflux and severe familial HDL deficiency. We examined the prevalence of mutations at the ABCA1 gene in 58 unrelated probands of French-Canadian descent with HDL deficiency (HDL-C < 5th percentile). A defective cellular cholesterol or phospholipid efflux (<75% and <70% of normal controls, respectively) was identified in 14/58 (24%) of subjects. Using direct sequencing of the ABCA1 gene, we found mutations in 12/58 (∼20%) of subjects. Four probands were previously identified with diverse ABCA1 gene defects. However, we identified a novel frameshift mutation (F1840L, L1869X); a proband was heteroallelic for the N1800H mutation, previously reported in a case of Tangier disease, and a novel missense mutation (Q2210H); a novel variant (G616V), predicted to impart a functional defect in the protein, was also found in another proband. Three probands had the S1731C mutation, while two others had the R1851X and K776N documented mutations, respectively. Taken together, these data suggest that ∼20% of French-Canadian patients with severe HDL deficiency are associated with a defective ABCA1. Interestingly, in two families studied, mutations in the ABCA1 gene did not segregate with the lipid efflux defect, suggesting that other proteins are involved in the ABCA1-mediated cellular lipid efflux.
KW - ABCA1
KW - Cellular cholesterol and phospholipid efflux
KW - Familial HDL deficiency
KW - Gene defects
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U2 - 10.1016/j.atherosclerosis.2005.10.048
DO - 10.1016/j.atherosclerosis.2005.10.048
M3 - Article
C2 - 16343503
AN - SCOPUS:33748039093
SN - 0021-9150
VL - 188
SP - 281
EP - 291
JO - Atherosclerosis
JF - Atherosclerosis
IS - 2
ER -