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Clinical Features and Genetic Analysis of Autosomal Recessive Hypercholesterolemia

Departments of Bioscience (M.H.-S.), Pharmacology (A.T.), and Etiology and Pathophysiology (Y.I., A.Y.), National Cardiovascular Center Research Institute, and Department of Medicine (Y.M., M.T.), National Cardiovascular Center, Osaka 565-8565; and Department of Biochemistry, Cell Biology, and Metabolism (S.Y.), Nagoya City University Graduate School of Medical Sciences, Aichi 467-8601, Japan

Address all correspondence and requests for reprints to: Dr. Mariko Harada-Shiba, Department of Bioscience, National Cardiovascular Center Research Institute, Fujishiro-dai, Suita, Osaka 565-8565, Japan. E-mail: mshiba{at}ri.ncvc.go.jp.

Previously we have reported on siblings with severe hypercholesterolemia, xanthomas, and premature atherosclerosis without any impairment of low-density lipoprotein receptor in their fibroblasts as a first characterization of autosomal recessive hypercholesterolemia (ARH). Recently, mutations were identified for this disease in a gene encoding a putative adaptor protein. The purpose of this study was to examine the molecular pathogenesis of ARH in Japanese siblings. A novel insertion mutation was discovered in the ARH gene of the siblings. An insertion of an extra cytosine residue was identified in a locus comprising eight consecutive cytosines at positions 599 through 606 in exon 6, resulting in a sequence of nine cytosines and generating an early stop codon at 657–659. The mother was heterozygous for this mutation. Neither transcription product nor protein of ARH was detected in the fibroblasts of the homozygous patients. A single nucleotide polymorphism was discovered among the normal control subjects at position 604 (cytosine to thymine: ARH-604C to ARH-604T), which changes the proline residue at 202 to serine. Interestingly, ARH is caused by a mutation of cytosine to adenine at this same position. Both siblings exhibited fatty liver, which may also be related to this mutation.

This work was supported in part by the Promotion of Fundamental Studies in Health Science of the Organization for Pharmaceutical Safety and Research (OPSR); Setsuro Fujii Memorial, the Osaka Foundation for Promotion of Fundamental Medical Research; and a Grant-in-Aid for Scientific Research (C) (no. 12670384) from the Ministry of Education, Science, Sports, and Culture, Japan.

Abbreviations: ARH, Autosomal recessive hypercholesterolemia; FCS, fetal calf serum; FH, familial hypercholesterolemia; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; LDL, low-density lipoprotein; PTB, phosphotyrosine binding; S-MEM, minimum essential culture medium.

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