H2NES mice carry arginine to alanine mutations at amino acids 260, 263, 264, 267 and 275, lysine to alanine mutations at amino acids 261, 270 and 272, arginine to leucine at residue 273, and aspartic acid to leucine at residue 276 of the estrogen receptor 1 (alpha) (Esr1) gene. ESR1 encodes nuclear hormone receptor that is predominantly expressed in the uterus, mammary glands, pituitary, hypothalamus, and ovarian theca cells and is important for hormone binding, DNA binding, and activation of transcription. The protein localizes to the nucleus where it may form a homodimer or a heterodimer with estrogen receptor 2 (ESR2). Estrogen and its receptors are essential for sexual development and reproductive function, but also play a role in other tissues such as bone. Estrogen receptors are also involved in pathological processes including breast cancer, endometrial cancer, and osteoporosis. The mutated region disrupts the nuclear localization sequence of the D domain, and also inserts a nuclear export sequence. This mutation excludes ESR1 from the nucleus, yet retains its signaling activity. H2NES female mice are infertile, having hypoplastic uteri and hyperemic ovaries that lack corpora lutea, similar to Esr1-null female mice. Males are also infertile and show testicular atrophy, similar to Esr1-null male mice. This loss of estrogenic action has been associated with development of the metabolic syndrome including obesity and insulin resistance, and reduced bone mineral density. Mice that are heterozygous for this H2NES allele are viable and fertile, while homozygous mice are infertile.&nbsp;

H2NES mice carry arginine to alanine mutations at amino acids 260, 263, 264, 267 and 275, lysine to alanine mutations at amino acids 261, 270 and 272, arginine to leucine at residue 273, and aspartic acid to leucine at residue 276 in the D domain of the estrogen receptor 1 (alpha) (Esr1) gene, which is associated with nuclear localization and export of the receptor.

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