title: Heterozygote effects in mice with partial truncations in the growth hormone receptor cytoplasmic domain: assessment of growth parameters and phenotype.
abstract: The GH receptor (GHR) is essential for normal postnatal growth and development, and the molecular basis of GHR action has been studied intensively. Clinical case studies and more recently mouse models have revealed the extensive phenotype of impaired GH action. We recently reported two new mouse models, possessing cytoplasmic truncations at position 569 (plus Y539/545-F) and 391, which were created to identify functional subdomains within the cytoplasmic signaling domain. In the homozygous state, these animals show progressively impaired postnatal growth coupled with complex changes in gene expression. We describe here an extended phenotype analysis encompassing the heterozygote state to identify whether single copies of these mutant receptors bring about partial or dominant-negative phenotypes. It appears that the retention of the ubiquitin-dependent endocytosis motif in the N-terminal cytoplasmic domain permits turnover of these mutant receptors because no dominant-negative phenotype is seen. Nonetheless, we do observe partial impairment of postnatal growth in heterozygotes supporting limited haploinsufficiency. Reproductive function is impaired in these models in a progressive manner, in parallel with loss of signal transducer and activator of transcription-5 activation ability. In summary, we describe a more comprehensive phenotypic analysis of these mouse models, encompassing overall and longitudinal body growth, reproductive function, and hormonal status in both the heterozygote and homozygote state. Our results suggest that patients expressing single copies of similarly mutated GHRs would not display an obvious clinical phenotype.
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, St. Lucia, Australia.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Rowland
authors.forename: Linda M
authors.initials: LM
authors.lastname: Kerr
authors.forename: Mary
authors.initials: M
authors.lastname: White
authors.forename: Peter G
authors.initials: PG
authors.lastname: Noakes
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Waters
mesh_terms: D000818:Animals; D000831:Animals, Newborn / Q000235:genetics* / Q000254:growth & development* / Q000502:physiology; D003593:Cytoplasm; D005298:Fertility; D006579:Heterozygote; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009929:Organ Size; D010641:Phenotype; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism; D011986:Receptors, Somatotropin / Q000235:genetics*; D012727:Sex Characteristics; D013997:Time Factors
chemical_list: D012333:RNA, Messenger; D011986:Receptors, Somatotropin; D007334:Insulin-Like Growth Factor I