Molecular analysis of lecithin-cholesterol acyltransferase (LCAT) deficiency

  • Maeda Eiichi
    Divisions of Diabetes, Digestive and Kidney Diseases, Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine

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  • レシチン コレステロール アシルトランスフェラーゼ (LCAT) 異常症の分子生物学的検討

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We studied the molecular basis of a Japanese patient who was clinically and biochemically diagnosed as a familial LCAT deficiency, a rare autosomal recessive inherited disease. Sequecing analysis revealed a single G to A transition within the sixth exon of LCAT gene resulting in the substitution of Met^<293> with Ile in mature LCAT. The familial study with PCR-RFLP demontrated association between the mutation and the disease. Specific cholesterol esterification activity of the recombinant mutant LCAT with apo A-I containing proteoliposomes was reduced to 8% of that of wild-type LCAT. Thus, it is considered that this mutation is responsible to the reduced LCAT activity in the patient's plasma. Phenotypic expression of this disease is heterogenous. This heterogeneity is caused by both residual enzyme activity and changes of lipoprotein-substrate specificities. To distinguish the patient from fish-eye disease, we compared the lipoprotein specific cholesterol esterification activities of the recombinant mutant LCATs. Cholesterol esterification activity with LDL (β-LCAT activity) was maintained in Thr^<123>→Ile mutant which causes fish-eye disease. On the other hand, recombinant LCAT with patient's mutation lacked β-LCAT activity. These results concluded that the subtype of LCAT deficiency of the patient is not fish-eye disease but partial LCAT deficiency.

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