Résumé
Familial hypercholesterolemia (FH) is a common autosomal dominant disorder caused by a defect in the low-density-lipoprotein (LDL) receptor, disrupting the normal control of cholesterol metabolism. We have collected 86 FH families for over 5 years who met following Dx criteria 1) hypercholesterolemia over 280 mg/dl 2) Achilles tendon xanthoma thicker than 9 mm, and 3) familial tendency, and characterized the pattern of mutations in Korea FH patients. METHOD: Mutation was screened with linkage analysis into two ways; large structural rearrangements were screened by genomic Southern blotting or long-PCR technique, and small structural rearrangements were screened by PCR of each exon followed by SSCP analysis. The exact mutation sites were confirmed by sequencing. RESULT: 1) Large mutation: Three different large deletions(FH110, FH29, FH32) were found in 7(11.5%) among 61 families screened. FH110 was a deletion of 5.7kb from intron 8 to 12, which was found in 5 unrelated families. FH29 was a deletion of 3.8kb from intron 6 to 8, and FH32 was a deletion of 2kb from intron 6 to 7. These three deletions have not been reported previously. The mechanism of deletion was unequal crossover from mispairing Alu-sequences. 2) Small or point mutations: Nineteen different small mutations were found in 19(31.4%) among 86 families screened . These mutations comprised 9 missense, 3 nonsense, 2 splicing mutations, 3 small deletions, and 2 small insertions. One missense mutation (Pro664Leu) was found in 6 unrelated families. Among these mutations, 12 have not been reported previously. CONCLUSIONS: LDL receptor gene mutations are heterogeneous in Korean FH patients. We could not observe founder mutation but detect common mutations.
Sujets)
Humains , Tendon calcanéen , Technique de Southern , Cholestérol , Exons , Hypercholestérolémie , Hyperlipoprotéinémie de type II , Introns , Corée , Lipoprotéines , Métabolisme , Mutation faux-sens , Mutation ponctuelle , Réaction de polymérisation en chaîne , Polymorphisme de conformation simple brin , Récepteurs aux lipoprotéines LDL , Récepteurs aux lipoprotéines , XanthomatoseRésumé
Familial hypercholesterolemia (FH) is a common autosomal dominant disorder caused by a defect in the low-density-lipoprotein (LDL) receptor, disrupting the normal control of cholesterol metabolism. We have collected 86 FH families for over 5 years who met following Dx criteria 1) hypercholesterolemia over 280 mg/dl 2) Achilles tendon xanthoma thicker than 9 mm, and 3) familial tendency, and characterized the pattern of mutations in Korea FH patients. METHOD: Mutation was screened with linkage analysis into two ways; large structural rearrangements were screened by genomic Southern blotting or long-PCR technique, and small structural rearrangements were screened by PCR of each exon followed by SSCP analysis. The exact mutation sites were confirmed by sequencing. RESULT: 1) Large mutation: Three different large deletions(FH110, FH29, FH32) were found in 7(11.5%) among 61 families screened. FH110 was a deletion of 5.7kb from intron 8 to 12, which was found in 5 unrelated families. FH29 was a deletion of 3.8kb from intron 6 to 8, and FH32 was a deletion of 2kb from intron 6 to 7. These three deletions have not been reported previously. The mechanism of deletion was unequal crossover from mispairing Alu-sequences. 2) Small or point mutations: Nineteen different small mutations were found in 19(31.4%) among 86 families screened . These mutations comprised 9 missense, 3 nonsense, 2 splicing mutations, 3 small deletions, and 2 small insertions. One missense mutation (Pro664Leu) was found in 6 unrelated families. Among these mutations, 12 have not been reported previously. CONCLUSIONS: LDL receptor gene mutations are heterogeneous in Korean FH patients. We could not observe founder mutation but detect common mutations.