Mice harboring Gnrhr E90K, a mutation that causes protein misfolding and hypogonadotropic hypogonadism in humans, exhibit testis size reduction and ovulation failure.
GnRH, produced in the hypothalamus, acts on pituitary gonadotropes to stimulate release of the gonadotropins LH and FSH. Reduced responsiveness of gonadotropes to GnRH is a primary cause of hypogonadotropic hypogonadism (HH), a disease characterized by gonadal dysfunction and low blood levels of gonadotropins. Loss-of-function mutations in the gene encoding the receptor for GnRH (GNRHR) are a common cause of HH. Sequencing of the GNRHR gene in patients with HH revealed mainly point mutations producing single amino acid substitutions that cause misfolding and misrouting of this G protein-coupled receptor. To generate a mouse model that mimics the human disease, we introduced a single amino acid substitution (E90K) into the mouse Gnrhr gene, which is identical to a known human recessive mutation. In humans, E90K causes severe HH by preventing formation of the E90-K121 salt bridge, which is essential for correct folding. In cell cultures, E90K causes misfolding that leads to almost complete retention by the protein quality control system and subsequent degradation. Here we report that the primary phenotype of mice homozygous for E90K is female infertility due to ovulation failure. Mutant males are fertile despite reduced gonadotropin levels and smaller testes. These results suggest decreased GnRH receptor signaling in the mutant animal, compared with wild type. Our findings suggest that a threshold level of GnRH receptor activity is required for ovulation.
Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
M David
MD
Stewart
Jian Ming
JM
Deng
C Allison
CA
Stewart
Rachael D
RD
Mullen
Ying
Y
Wang
Suhujey
S
Lopez
M Katalina
MK
Serna
Cheng-Chiu
CC
Huang
Jo Ann
JA
Janovick
Andrew J
AJ
Pask
Robert J
RJ
Schwartz
P Michael
PM
Conn
Richard R
RR
Behringer
D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D000858:Anovulation / Q000097:blood / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D001483:Base Sequence; D030762:Estrous Cycle; D005260:Female; D005786:Gene Expression Regulation; D006062:Gonadotropins / Q000097:blood; D006720:Homozygote; D006801:Humans; D007006:Hypogonadism / Q000097:blood / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D034461:Luteinization; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009929:Organ Size; D057165:Proteostasis Deficiencies / Q000235:genetics*; D011966:Receptors, LHRH / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D013737:Testis / Q000378:metabolism / Q000473:pathology*
D006062:Gonadotropins; D011966:Receptors, LHRH