title: The dwarf phenotype in GH240B mice, haploinsufficient for the autism candidate gene Neurobeachin, is caused by ectopic expression of recombinant human growth hormone.
abstract: Two knockout mouse models for the autism candidate gene Neurobeachin (Nbea) have been generated independently. Although both models have similar phenotypes, one striking difference is the dwarf phenotype observed in the heterozygous configuration of the GH240B model that is generated by the serendipitous insertion of a promoterless human growth hormone (hGH) genomic fragment in the Nbea gene. In order to elucidate this discrepancy, the dwarfism present in this Nbea mouse model was investigated in detail. The growth deficiency in Nbea+/- mice coincided with an increased percentage of fat mass and a decrease in bone mineral density. Low but detectable levels of hGH were detected in the pituitary and hypothalamus of Nbea+/- mice but not in liver, hippocampus nor in serum. As a consequence, several members of the mouse growth hormone (mGH) signaling cascade showed altered mRNA levels, including a reduction in growth hormone-releasing hormone mRNA in the hypothalamus. Moreover, somatotrope cells were less numerous in the pituitary of Nbea+/- mice and both contained and secreted significantly less mGH resulting in reduced levels of circulating insulin-like growth factor 1. These findings demonstrate that the random integration of the hGH transgene in this mouse model has not only inactivated Nbea but has also resulted in the tissue-specific expression of hGH causing a negative feedback loop, mGH hyposecretion and dwarfism.
authors.affiliation: Department of Human Genetics, KU Leuven, Leuven, Belgium; Leuven Autism Research Consortium (LAuRes), KU Leuven, Leuven, Belgium.
authors.forename: Kim
authors.initials: K
authors.lastname: Nuytens
authors.affiliation: Department of Human Genetics, KU Leuven, Leuven, Belgium; Leuven Autism Research Consortium (LAuRes), KU Leuven, Leuven, Belgium.
authors.forename: Krizia
authors.initials: K
authors.lastname: Tuand
authors.affiliation: Department of Development and Regeneration, KU Leuven, Leuven, Belgium.
authors.forename: Quili
authors.initials: Q
authors.lastname: Fu
authors.affiliation: Department of Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Stijnen
authors.affiliation: Department of Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Vincent
authors.initials: V
authors.lastname: Pruniau
authors.affiliation: Department of Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Sandra
authors.initials: S
authors.lastname: Meulemans
authors.affiliation: Department of Development and Regeneration, KU Leuven, Leuven, Belgium.
authors.forename: Hugo
authors.initials: H
authors.lastname: Vankelecom
authors.affiliation: Department of Human Genetics, KU Leuven, Leuven, Belgium; Leuven Autism Research Consortium (LAuRes), KU Leuven, Leuven, Belgium.
authors.forename: John W M
authors.initials: JW
authors.lastname: Creemers
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D004392:Dwarfism / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D057895:Haploinsufficiency; D019382:Human Growth Hormone / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D010902:Pituitary Gland / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; C403265:Nbea protein, mouse; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; D019382:Human Growth Hormone