The KiLHRD582G knock-in allele has endogenous Lhcgr exon 11 replaced by a mutant encoding the constitutively-active D582G amino acid change analogous to the most common D578G mutation found in human boys with familial male-limited precocious puberty (FMPP). Heterozygous males exhibit several characteristics of the human disease (early puberty, Leydig cell hyperplasia and elevated testosterone). Heterozygotes females are also affected (early puberty, infertility, elevated steroid hormone levels, polycystic ovaries and granulosa cell tumors). The mice are useful for studying gonadotropin hormones and receptors in reproductive physiology and pathophysiology, as well as cancer.
Prema Narayan, Southern Illinois University School of Medicine
Genetic Background | Generation |
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|
Allele Type | Gene Symbol | Gene Name |
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Targeted | Lhcgr | luteinizing hormone/choriogonadotropin receptor |
The luteinizing hormone receptor (LHCGR), a member of the G protein-coupled receptor family, is essential for fertility in males and females, with implications for studying gonadotropin hormones and receptors in reproductive physiology and pathophysiology, as well as cancer.
The KiLHRD582G knock-in allele has the constitutively-active D582G mutation in exon 11 of the mouse luteinizing hormone/choriogonadotropin receptor locus (Lhcgr); analogous to the most common D578G mutation found in human boys with familial male-limited precocious puberty (FMPP).
The phenotype described below is for mice maintained on a B6129SF1/J genetic background.
Similar to boys with FMPP, heterozygous (KiLHRD582G/+) male mice exhibit precocious puberty (early puberty) by 15 days of age. Leydig cell hyperplasia and elevated testosterone (in the context of prepubertal [low] luteinizing hormone levels) is observed as early as 7 days of age and through adulthood (24 weeks old). In addition, the donating investigator reports that although heterozygous males have normal sperm count/motility, they show progressive infertility and fail to produce litters by ~5-6 months of age. Compared to wildtype males, KiLHRD582G/+ males are more aggressive to other males, but KiLHRD582G/+ males are not aggressive to breeder females.
While human females with the corresponding activating mutation exhibit no phenotypic abnormalities, female KiLHRD582G/+ mice exhibit early puberty (~15 days old), infertility, elevated steroid hormone levels (testosterone, estradiol and progesterone), polycystic ovaries (as early as three weeks of age) and granulosa cell tumors (~50% by six months of age). The donating investigator reports no increased aggression in KiLHRD582G/+ females.
Because of the phenotype, the donating investigator reports it can be difficult to maintain the colony. They use harem mating of a young heterozygous male (starting at seven weeks of age) to three units of B6129SF1/J female pairs; rotating the male to a new female pair every two weeks. It has not been attempted to make this strain homozygous to date (July 2016).
The KiLHRD582G knock-in allele was designed by Dr. Prema Narayan (Southern Illinois University). First, an exon 11 cDNA sequence from the mouse luteinizing hormone/choriogonadotropin receptor locus (Lhcgr) on chromosome 17 was altered via site-directed mutagenesis to change codon 582 from aspartic acid to glycine (D582G); this corresponds to the most common D578G mutation found in human boys with familial male-limited precocious puberty (FMPP). A targeting vector containing this mutant exon 11 and a downstream loxP::frt::PGK-neo::frt cassette was electroporated into (129X1/SvJ x 129S1/Sv)F1-Kitl+-derived R1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts. Chimeric males were bred with B6;SJL-Tg(ACTFLPe)9205Dym/J females (Stock No. 003800) for germline transmission and to excise the neomycin cassette. The resulting KiLHRD582G colony was maintained by breeding B6129SF1/J females (from Stock No. 101043) with young heterozygous (KiLHRD582G/+) males for ten generations. After that, B6129SF2/J females (equivalent to Stock No. 101045) were bred with young KiLHRD582G/+ males for several generations. In 2016, heterozygous males (either black or agouti coat color) were sent to The Jackson Laboratory Repository. Upon arrival, sperm was cryopreserved. To establish our live colony, an aliquot of frozen sperm was used to fertilize B6129SF1/J oocytes (Stock No. 101043).
Thereafter, our live colony will be maintained by breeding wildtype sibling females with heterozygous males (using males as early as seven weeks of age). Periodically, we will breed B6129SF1/J females (Stock No. 101043) with heterozygous males to maintain ~50/50% mix of C57BL/6 and 129 in our live colony.
Allele Name | targeted mutation 1.1, Prema Narayan |
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Allele Type | Targeted |
Allele Synonym(s) | KiLHRD582G |
Gene Symbol and Name | Lhcgr, luteinizing hormone/choriogonadotropin receptor |
Gene Synonym(s) | |
Strain of Origin | (129X1/SvJ x 129S1/Sv)F1-Kitl+ |
Chromosome | 17 |
Molecular Note | Nucleotide substitutions (GAC to GGA) in exon 11 result in the amino acid substitution of glycine for aspartic acid at position 582 (D582G). Flp-mediated recombination removed the FRT-flanked neomycin resistance cassette. |
When maintaining the live KiLHRD582G knock-in mouse colony at The Jackson Laboratory Repository, wildtype sibling females are bred to heterozygous males (using males as early as seven weeks of age). Periodically, we will breed B6129SF1/J females (Stock No. 101043) with heterozygous males to maintain ~50/50% mix of C57BL/6 and 129 in our live colony.
Heterozygous females are infertile. The donating investigator reports that heterozygous males have normal sperm count/motility but show progressive infertility and fail to produce litters by ~5-6 months of age. Compared to wildtype males, heterozygous males are more aggressive to other males, but heterozygous males are not aggressive to breeder females. The donating investigator reports it can be difficult to maintain the colony. They use harem mating of a young heterozygous male (starting at 7 weeks of age) to three units of B6129SF1/J female pairs; rotating the male to a new female pair every two weeks.
When using the KiLHRD582G mouse strain in a publication, please cite the originating article(s) and include JAX stock #029311 in your Materials and Methods section.
Facility Barrier Level Descriptions
Service/Product | Description | Price |
---|---|---|
Heterozygous or wildtype for Lhcgr<tm1.1Pnara> |
Frozen Mouse Embryo | B6129S-Lhcgr<tm1.1Pnara>/J | $2595.00 |
Frozen Mouse Embryo | B6129S-Lhcgr<tm1.1Pnara>/J | $2595.00 |
Frozen Mouse Embryo | B6129S-Lhcgr<tm1.1Pnara>/J | $3373.50 |
Frozen Mouse Embryo | B6129S-Lhcgr<tm1.1Pnara>/J | $3373.50 |
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