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1.
Genetics ; 160(4): 1599-608, 2002 Apr.
Article in English | MEDLINE | ID: mdl-11973313

ABSTRACT

Therapeutic intervention for atherosclerosis has predominantly concentrated on regulating cholesterol levels; however, these therapeutics are not efficacious for all patients, suggesting that other factors are involved. This study was initiated to identify mechanisms that regulate atherosclerosis predisposition in mice other than cholesterol level regulation. To do so we performed quantitative trait locus analysis using two inbred strains that each carry the atherosclerosis phenotype-sensitizing Apoe deficiency and that have been shown to have widely disparate predilection to atherosclerotic lesion formation. One highly significant locus on chromosome 10 (LOD = 7.8) accounted for 19% of the variance in lesion area independent of cholesterol. Two additional suggestive loci were identified on chromosomes 14 (LOD = 3.2) and 19 (LOD = 3.2), each accounting for 7-8% of the lesion variance. In all, five statistically significant and suggestive loci affecting lesion size but not lipoprotein levels were identified. Many of these were recapitulated in an independent confirmatory cross. In summary, two independently performed crosses between C57BL/6 and FVB/N Apoe-deficient mice have revealed several previously unreported atherosclerosis susceptibility loci that are distinct from loci linked to lipoprotein levels.


Subject(s)
Apolipoproteins E/deficiency , Arteriosclerosis/genetics , Genetic Predisposition to Disease , Animals , Apolipoproteins E/genetics , Cholesterol/blood , Female , Gene Frequency , Lipids/blood , Male , Mice , Mice, Inbred C57BL , Phenotype , Quantitative Trait, Heritable
2.
Am J Med Genet ; 108(1): 16-22, 2002 02 15.
Article in English | MEDLINE | ID: mdl-11857544

ABSTRACT

Chediak-Higashi syndrome (CHS) is a rare autosomal recessive disorder characterized by severe immunologic defects, reduced pigmentation, bleeding tendency, and progressive neurological dysfunction. Most patients present in early childhood and die unless treated by bone marrow transplantation. About 10-15% of patients exhibit a much milder clinical phenotype and survive to adulthood, but develop progressive and often fatal neurological dysfunction. Very rare patients exhibit an intermediate adolescent CHS phenotype, presenting with severe infections in early childhood, but a milder course by adolescence, with no accelerated phase. Here, we describe the organization and genomic DNA sequence of the CHS1 gene and mutation analysis of 21 unrelated patients with the childhood, adolescent, and adult forms of CHS. In patients with severe childhood CHS, we found only functionally null mutant CHS1 alleles, whereas in patients with the adolescent and adult forms of CHS we also found missense mutant alleles that likely encode CHS1 polypeptides with partial function. Together, these results suggest an allelic genotype-phenotype relationship among the various clinical forms of CHS.


Subject(s)
Chediak-Higashi Syndrome/genetics , Fungal Proteins/genetics , Adolescent , Adult , Chediak-Higashi Syndrome/physiopathology , Child, Preschool , Chromosomes, Artificial, Bacterial , Chromosomes, Artificial, P1 Bacteriophage , Codon, Nonsense , Conserved Sequence , DNA Mutational Analysis , Evolution, Molecular , Exons , Frameshift Mutation , Genetic Linkage , Genotype , Humans , Introns , Mutation, Missense , Phenotype , Sequence Analysis, DNA
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