title: Clinical features and genetic analysis of autosomal recessive hypercholesterolemia.
abstract: 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.
authors.affiliation: Department of Bioscience, National Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan. mshiba@ri.ncvc.go.jp
authors.forename: Mariko
authors.initials: M
authors.lastname: Harada-Shiba
authors.forename: Atsuko
authors.initials: A
authors.lastname: Takagi
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Miyamoto
authors.forename: Motoo
authors.initials: M
authors.lastname: Tsushima
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Shinji
authors.initials: S
authors.lastname: Yokoyama
authors.forename: Akira
authors.initials: A
authors.lastname: Yamamoto
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics*; D000328:Adult; D000595:Amino Acid Sequence / Q000235:genetics; D019943:Amino Acid Substitution; D015152:Blotting, Northern; D015153:Blotting, Western; D002874:Chromosome Mapping; D003062:Codon; D003596:Cytosine; D004251:DNA Transposable Elements; D005260:Female; D005808:Genes, Recessive; D006801:Humans; D006937:Hypercholesterolemia / Q000150:complications / Q000235:genetics* / Q000503:physiopathology*; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D014973:Xanthomatosis / Q000209:etiology / Q000473:pathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D003062:Codon; D004251:DNA Transposable Elements; C469745:LDLRAP1 protein, human; D003596:Cytosine