A complex plasma plant sterol locus on mouse chromosome 14 has at least two genes regulating intestinal sterol absorption

Abstract

We previously identified two inbred mouse strains, C57BL/6J and CASA/Rk, with different plasma plant sterol levels. An intercross between these strains revealed a broad plasma plant sterol locus on chromosome 14, which peaked at 17 centimorgan (cM) with a maximum logarithm of the odds score of 9.9. Studies in a chromosome 14 congenic strain, 14KK, with a 4-60 cM CASA/Rk interval on the C57BL/6J background revealed that males, but not females, had decreased plasma plant sterol levels and intestinal cholesterol absorption. In two subcongenic strains, 14PKK and 14DKK, with 4-19.5 and 19.5-60 cM CASA/Rk intervals, respectively, both males and females had decreased plasma plant sterol levels and decreased intestinal cholesterol absorption. Compatible with the decreased plasma plant sterol phenotype, 14PKK mice had increased biliary plant sterol excretion, whereas 14DKK mice did not. Therefore, gender-dependent interactions of genes at the 14PKK and 14DKK intervals are likely to underlie the 14KK interval effect on plasma plant sterol levels and sterol absorption from the intestine. These studies confirm the plasma plant sterol locus on mouse chromosome 14 and provide evidence that there are at least two sets of genes operating: one set affecting intestinal sterol absorption and biliary excretion, and the other set mainly affecting intestinal sterol

Identification of positional candidate genes for body weight and adiposity in subcongenic mice

“…The discovery that a congenic actually contains two or more quantitative trait genes is not novel. Several mapping studies with various complex traits have also isolated closely linked QTLs with the use of subcongenics, separating the effects of two or more causal genes (1,10,17,42). Our second body weight QTL is only suggestive, perhaps in part because of smaller numbers of mice studied in the B6.S-2D line or because the causal gene may have a small effect on body weight, not easily detectable in mice on a very low-fat chow diet.…”

Cathepsin B is a novel gender-dependent determinant of cholesterol absorption from the intestine

“…We used a mouse cross between inbred strains C57BL/6J and CASA/Rk to identify a locus on chromosome 14 in control of plasma plant sterol levels. A congenic strain of this locus (14KK) clearly displayed a gender-dependent effect ( 5 ). In agreement with their parental 14KK congenics, a gender-dependent effect clearly characterized the phenotype in subcongenics that covered the telomeric 70.4 Mb of the 14KK interval (herein designated as subcongenics A-G).…”

“…We previously published the linkage map on chromosome 14 ( 4,5 ). This map is characterized by two peaks, one at D14Mit18 and the other at D14Mit123, that map at 48.4 Mb and 66.8 Mb, respectively.…”

“…Generation of chromosome 14DKK congenics (here referred to as subcongenic A) on the C57BL/6J genetic background has been previously described ( 5 ). Construction of further subcongenic strains of the 14DKK interval was generated through backcrossing onto C57BL/6J animals, followed by microsatellite markers and single-nucleotide polymorphism (SNP) genotyping for identifi cation of recombinant events.…”

“…Interestingly, generation of two subcongenic strains, 14PKK and 14DKK, which consisted of the centromeric 20.8 Mb and telomeric 70. 4 Mb of the 14KK interval, respectively, displayed decreased cholesterol absorption in both genders ( 5 ). Here we describe the fi ne-mapping of the 14DKK subcongenic interval.…”