Loss of the transmembrane but not the soluble kit ligand isoform increases testicular germ cell tumor susceptibility in mice.
Several genetic variants act as modifiers of testicular germ cell tumor (TGCT) susceptibility in the 129/Sv mouse model of human pediatric TGCTs. One such modifier, the Steel locus, encodes the transmembrane-bound and soluble ligand of the kit receptor. Some (Sl and SlJ) but not all (Sld) mutations of the Steel locus increase TGCT incidence in heterozygous mutant mice. Because Sl and SlJ are large deletions that affect multiple transcripts and Sld is an intragenic deletion of the kit ligand (Kitl) from which only the soluble protein is produced, it was uncertain whether Kitl or a neighboring gene is a modifier of TGCT susceptibility. We tested the effect of the small Steel grizzle-belly (Slgb) deletion on TGCT susceptibility to determine whether Kitl is a TGCT modifier gene. An increase in TGCT incidence was observed in Slgb/+ heterozygotes, and fine mapping of the deletion breakpoints revealed that Kitl is the only conventional gene deleted by the mutation, suggesting that Kitl is the TGCT modifier gene at the Steel locus. Additionally, we propose that soluble KITL in Sld/+ heterozygous mutant mice complements a dosage effect of transmembrane-associated kit ligand on TGCT susceptibility and that the kit receptor (Kit) is haplosufficient for primordial germ cell development.
Heaney
Jason D
JD
Department of Genetics and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio 44106, USA. jdh36@case.edu
Lam
Man-Yee J
MY
Michelson
Megan V
MV
Nadeau
Joseph H
JH
D000818:Animals; D001483:Base Sequence; D004622:Embryo, Mammalian; D005260:Female; D018628:Gene Dosage; D020022:Genetic Predisposition to Disease; D006801:Humans; D040582:Inheritance Patterns; D019656:Loss of Heterozygosity / Q000502:physiology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009373:Neoplasms, Germ Cell and Embryonal / Q000453:epidemiology / Q000235:genetics*; D011247:Pregnancy; D015995:Prevalence; D020033:Protein Isoforms / Q000235:genetics; D012995:Solubility; D019089:Stem Cell Factor / Q000097:blood / Q000235:genetics*; D013736:Testicular Neoplasms / Q000453:epidemiology / Q000235:genetics*
D008565:Membrane Proteins; D020033:Protein Isoforms; D019089:Stem Cell Factor