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Mep-1 gene controlling a kidney metalloendopeptidase is linked to the major histocompatibility complex in mice
Abstract:
Meprin, a glycoprotein with potent metalloendopeptidase activity, is an integral component of the brush border membrane of mouse kidney. Previously we reported that genealogically related inbred mouse strains (C3H and CBA) are markedly deficient in the activity of this enzyme. We report here that meprin deficiency is inherited as an autosomal recessive trait and that several other inbred strains also express low levels of meprin activity. All of the inbred strains deficient in meprin activity are of the H-2k haplotype; however, two strains of this haplotype (C58 and C57BR/cd) expressed normal levels of the proteinase. Congeneic and recombinant mouse strains were examined to determine whether the deficiency was linked to the H-2 complex. The gene controlling the activity of meprin (Mep-1) maps on chromosome 17 to the right of the D end of the major histocompatibility complex. The Mep-1 gene is closely linked to a gene that controls isoenzyme patterns of phosphoglycerate kinase (Pgk-2). This work represents the localization of a gene that determines the activity of an integral cellular endopeptidase in mammalian tissues. In addition, the Mep-1 gene is the only identified gene linked to the major histocompatibility complex that regulates a proteinase activity.
Insights
Meprin deficiency, an autosomal recessive trait in mice, is linked to the H-2k haplotype. The meprin (Mep-1) gene on chromosome 17 is the first identified gene regulating proteinase activity linked to the major histocompatibility complex.
Area of Science:
- Biochemistry
- Genetics
- Immunology
Background:
- Meprin is a metalloendopeptidase integral to mouse kidney brush border membranes.
- Previously identified meprin deficiency in C3H and CBA mouse strains.
- Meprin deficiency is inherited as an autosomal recessive trait.
Purpose of the Study:
- To investigate the genetic basis of meprin deficiency.
- To determine if meprin deficiency is linked to the H-2 complex.
- To map the gene responsible for meprin activity (Mep-1).
Main Methods:
- Analysis of meprin activity in various inbred, congenic, and recombinant mouse strains.
- Genetic mapping using chromosome 17 markers.
- Examination of linkage to the major histocompatibility complex (H-2).
Main Results:
- Meprin deficiency is an autosomal recessive trait.
- Several inbred strains exhibit low meprin activity, often associated with the H-2k haplotype.
- The Mep-1 gene is located on chromosome 17, right of the D end of the H-2 complex.
- Mep-1 is closely linked to the phosphoglycerate kinase-2 (Pgk-2) gene.
- Mep-1 is the first identified gene regulating proteinase activity linked to the H-2 complex.
Conclusions:
- The gene controlling meprin activity (Mep-1) is localized to chromosome 17.
- Mep-1 linkage to the H-2 complex provides a novel genetic marker.
- This study identifies the first gene regulating mammalian proteinase activity linked to the major histocompatibility complex.