Molecular Genetic Mapping of the Mouse Male Sterility and Histoincompatibility (mshi) Mutation on Proximal Chromosome 10

doi:10.1006/geno.1996.4475

Genomics

Volume 39, Issue 1, 1 January 1997, Pages 1-7

https://doi.org/10.1006/geno.1996.4475 Get rights and content

Abstract

The recessive male sterility and histoincompatibility (mshi) mutation in the mouse generates pleiotropic effects on histocompatibility and male reproduction, while female mutants appear to be reproductively normal. We have mapped themshimutation to mouse Chromosome (Chr) 10 by analysis of 126 progeny from an intraspecific backcross. Our analysis both places the male sterility and histoincompatibility controlled bymshiwithin a 20-cM interval between the markersD10Mit51/D10Mit212andD10Mit170and has allowed the ordering of several other microsatellite markers on Chr 10 that were previously unresolved. The high-resolution backcross panel we describe should facilitate the isolation of more tightly linked probe sequences and, ultimately, the molecular identification of the gene or genes affected by this interesting mutation.

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Cited by (7)

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Citation Excerpt :
However, mutations that affect both transplantation acceptance and a distinct developmental function are quite rare. We know of only one other example, the recessive H-mshi mutation (for “male sterility and histoincompatibility”, [37]) which causes aspermia in homozygous males, but was initially discovered as the loss of a cell-surface antigen, such that tail skin from +/+ mice is rejected by (otherwise genetically-matched) mshi/mshi mutants, which recognize the mshi+ antigen as “foreign” [13,22,30,34]. This sort of phenotypic complexity interests us for several reasons.
The spontaneous, curly whiskers mutation (abbreviated cw) generates kinky, brittle vibrissae in homozygous mice. Although cw has been mapped to the centromeric end of mouse Chromosome 9, no particular gene has been causally implicated, and this lack of genetic assignment has stymied cw's complete molecular and functional analysis. As a foundation for its positional cloning, we have fine-mapped cw to a small, 0.57 Mb interval that contains only three skin-expressed genes, including hephaestin-like 1 (Hephl1), which encodes a membrane-bound, multi-copper ferroxidase. Sequence analysis of all Hephl1 coding regions in cw/cw mutants revealed a single-base-pair substitution that alters Hephl1 mRNA splicing, and is specific to the cw allele, only. Sequence analysis of a second, independent, re-mutation to curly whiskers (that we verified by complementation testing with cw and have designated cw^2J) revealed a distinct defect in Hephl1 (a frame-shifting, single-base-pair insertion) that is specific to cw^2J. The results presented strongly suggest that defects in the Hephl1 gene are the molecular basis of the classical, curly-whiskers mutant phenotypes.
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Males homozygous for the mouse male sterility and histoincompatibility (mshi) mutation exhibit small testes and produce no sperm. In addition, mshi generates an “antigen-loss” histoincompatibility barrier, such that homozygous mutants reject skin grafts from wild type co-isogenic BALB/cByJ donors. To facilitate the molecular characterization of the pleiotropic mshi mutation, we genetically mapped mshi into a 0.68 megabasepair region which contains fewer than 10 candidate genes. Complementation testing showed that one of these, Mtap7, is disrupted in mshi mice. Sequence analysis has revealed a 13 kilobasepair deletion in BALB/cByJ-mshi/J mice that begins in Intron 10–11 of Mtap7, and ends less than 2000 base pairs downstream of the wild type gene. Analysis of the mutant cDNA predicts that Mtap7^mshi encodes a 457 amino acid protein, the first 423 of which are identical to wild type, and the last 34 of which are due to aberrant mRNA splicing with two cryptic exons in the Mtap7 to P04Rik intergenic region. This molecular assignment for the mshi mutation further supports an essential role for microtubule stabilization in spermatogenesis and indicates a new role in allograft transplantation.
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The existence of transplantation antigens, in addition to those encoded by genes in the MHC, has been known for over half a century. The molecular identification of these additional minor histocompatibility (H) antigens lagged behind that of their MHC counterparts, largely because minor H antigens are recognised by T cells and not by antibodies. In the past year, however, new minor H antigens have been identified at both the genetic and protein level and include Uty, a second novel gene encoding a male-specific epitope in mice, a novel autosomal gene encoding each of the H-13 alleles of mice, and a second male-specific epitope encoded by the SMCY gene.
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Regular ArticleMolecular Genetic Mapping of the Mouse Male Sterility and Histoincompatibility (mshi) Mutation on Proximal Chromosome 10

Abstract

Regular Article
Molecular Genetic Mapping of the Mouse Male Sterility and Histoincompatibility (mshi) Mutation on Proximal Chromosome 10