Overview

Also Known As:KiLHR^D582G

The KiLHR^D582G 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.

Donating Investigator

Prema Narayan, Southern Illinois University School of Medicine

Genetic overview

Genetic Background	Generation

Lhcgr^tm1.1Pnara

Allele Type	Gene Symbol	Gene Name
Targeted	Lhcgr	luteinizing hormone/choriogonadotropin receptor

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Research Applications

Reproductive Biology Research
Research Tools
Cancer Research
Developmental Biology Research
Endocrine Deficiency Research

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Base Price

Starting at:

$2,854.50 Domestic price Cryo Recovery

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Details

Detailed Description

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 KiLHR^D582G 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 (KiLHR^D582G/+) 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, KiLHR^D582G/+ males are more aggressive to other males, but KiLHR^D582G/+ males are not aggressive to breeder females.

While human females with the corresponding activating mutation exhibit no phenotypic abnormalities, female KiLHR^D582G/+ 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 KiLHR^D582G/+ 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).

Development

The KiLHR^D582G 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 KiLHR^D582G colony was maintained by breeding B6129SF1/J females (from Stock No. 101043) with young heterozygous (KiLHR^D582G/+) males for ten generations. After that, B6129SF2/J females (equivalent to Stock No. 101045) were bred with young KiLHR^D582G/+ 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.

Control Suggestions

Wild-type from the colony

Approximate Controls

101043 B6129SF1/J

Additional Information

Considerations for Choosing Controls

Selected References

McGee SR; Narayan P. 2013. Precocious puberty and Leydig cell hyperplasia in male mice with a gain of function mutation in the LH receptor gene. Endocrinology 154(10):3900-13PubMed: 23861372 MGI: J:203295

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Genetics

Lhcgr^tm1.1Pnara

Allele Symbol: Lhcgr^tm1.1Pnara

Allele Name	targeted mutation 1.1, Prema Narayan
Allele Type	Targeted
Allele Synonym(s)	KiLHR^D582G
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.

Disease/Phenotype

Disease Terms

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Reproductive Biology Research
- Gonadal Tumors
  - ovarian
  - Leydig cell hyperplasia
  - granulosa cell tumors
- Endocrine Deficiencies Affecting Gonads
- Developmental Defects Affecting Gonads
- Fertility Defects
Research Tools
- Reproductive Biology Research
  - male germ cells
  - oocyte
Cancer Research
- Increased Tumor Incidence
  - Gonadal Tumors: ovarian
Developmental Biology Research
- Internal/Organ Defects
  - ovary; uterus
  - gonads
Endocrine Deficiency Research
- Gonad Defects

Mammalian Phenotype Terms by Genotype

The following phenotype information is associated with a similar, but not exact match to this JAX^® Mice strain

Genotype: Lhcgr^tm1.1Pnara/Lhcgr⁺
involves: 129S1/SvImJ * 129X1/SvJ * C57BL/6J

endocrine/exocrine gland phenotype

abnormal adult Leydig cell differentiation
- precocious development of adult Leydig cells

decreased testis weight
- from P10

enlarged prostate gland
- at 3 weeks

enlarged seminal vesicle
- at 3 weeks

increased prostate gland weight
- from P10

increased seminal vesicle weight
- from 3 weeks

Leydig cell hyperplasia
- as early as 7 days, persisting through adulthood

mammalian phenotype

reproductive system phenotype
- Normal - mice exhibit normal Sertoli cell development and sperm

renal/urinary system phenotype

increased urine major urinary protein level
- at 15 days in male mice indicating precocious puberty

reproductive system phenotype

abnormal adult Leydig cell differentiation
- precocious development of adult Leydig cells

decreased testis weight
- from P10

early sexual maturation
- in male mice

enlarged prostate gland
- at 3 weeks

enlarged seminal vesicle
- at 3 weeks

increased epididymis weight
- P10 to 3 weeks

increased prostate gland weight
- from P10

increased seminal vesicle weight
- from 3 weeks

Leydig cell hyperplasia
- as early as 7 days, persisting through adulthood

homeostasis/metabolism phenotype

abnormal testosterone level
- increased in testes from P7

decreased circulating follicle stimulating hormone level

decreased circulating luteinizing hormone level

increased circulating testosterone level
- from 3 weeks

increased urine major urinary protein level
- at 15 days in male mice indicating precocious puberty

References

McGee SR; Narayan P. 2013. Precocious puberty and Leydig cell hyperplasia in male mice with a gain of function mutation in the LH receptor gene. Endocrinology 154(10):3900-13PubMed: 23861372 MGI: J:203295

Additional - Lhcgr^tm1.1Pnara related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Sanger sequencing:Lhcgr
- End Point Analysis:Lhcgr EP
- Genotyping resources and troubleshooting
Breeding Considerations

When maintaining the live KiLHR^D582G 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.
- Additional Breeding and Husbandry Support
Mating System
- WTSib or B6129SF1 (101043) females x HET male (no recip). If using WTSib females each generation, refresh to 101043 after every 5 generations
Citation
When using the KiLHR^D582G mouse strain in a publication, please cite the originating article(s) and include JAX stock #029311 in your Materials and Methods section.

Animal Health Reports

Facility Barrier Level Descriptions

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Pricing & Availability

Cryo Recovery

Domestic
International

Live Mouse

Age

Genotype

Price

weeks

Cryorecovery - Pricing

Service/Product	Description	Price
	Heterozygous or wildtype for Lhcgr<tm1.1Pnara>

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Frozen Mouse Embryo	B6129S-Lhcgr<tm1.1Pnara>/J	$2595.00
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Frozen Mouse Embryo	B6129S-Lhcgr<tm1.1Pnara>/J	$3373.50
Frozen Mouse Embryo	B6129S-Lhcgr<tm1.1Pnara>/J	$3373.50

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The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project. We do not guarantee breeding performance and therefore suggest that investigators order more than one breeding pair to avoid delays in their research.

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Also Known As:KiLHRD582G

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Control Suggestions

Approximate Controls

Additional Information

Selected References

Lhcgrtm1.1Pnara

Allele Symbol: Lhcgrtm1.1Pnara

Disease Terms

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Mammalian Phenotype Terms by Genotype

Genotype: Lhcgrtm1.1Pnara/Lhcgr+involves: 129S1/SvImJ * 129X1/SvJ * C57BL/6J

endocrine/exocrine gland phenotype

mammalian phenotype

renal/urinary system phenotype

reproductive system phenotype

homeostasis/metabolism phenotype

References

Additional - Lhcgrtm1.1Pnara related

Genotyping Protocols

Breeding Considerations

Mating System

Citation

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Live Mouse

Cryorecovery - Pricing

Related Products and Services

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms Of Use

Licensing Information

JAX® Mice, Products & Services Conditions of Use

No Warranty

Credit for PRODUCTS or SERVICES

Animal Care and Use for SERVICES

No Liability

Also Known As:KiLHR^D582G

Lhcgr^tm1.1Pnara

Allele Symbol: Lhcgr^tm1.1Pnara

Genotype: Lhcgr^tm1.1Pnara/Lhcgr⁺
involves: 129S1/SvImJ * 129X1/SvJ * C57BL/6J

Additional - Lhcgr^tm1.1Pnara related