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- W4387408799 abstract "Genome-wide association studies (GWAS) have identified a large number of candidate genes believed to affect longitudinal bone growth and bone mass. One of these candidate genes, TMEM263, encodes a poorly characterized plasma membrane protein. Single nucleotide polymorphisms in TMEM263 are associated with bone mineral density in humans and mutations are associated with dwarfism in chicken and severe skeletal dysplasia in at least one human fetus. Whether this genotype-phenotype relationship is causal, however, remains unclear. Here, we determine whether and how TMEM263 is required for postnatal growth. Deletion of the Tmem263 gene in mice causes severe postnatal growth failure, proportional dwarfism, and impaired skeletal acquisition. Mice lacking Tmem263 show no differences in body weight within the first two weeks of postnatal life. However, by P21 there is a dramatic growth deficit due to a disrupted GH/IGF-1 axis, which is critical for longitudinal bone growth. Tmem263-null mice have low circulating IGF-1 levels and pronounced reductions in bone mass and growth plate length. The low serum IGF-1 in Tmem263-null mice is due to a deficit in hepatic GH receptor (GHR) expression and GH-induced JAK2/STAT5 signaling. Consequently, Tmem263 loss-of-function results in GH insensitivity (GHI), and a dramatic alteration in the GH-regulated transcriptome in liver. Our data validates the causal role for Tmem263 in regulating postnatal growth and raises the possibility that rare mutations or variants of TMEM263 may potentially cause GHI and impair linear growth." @default.
- W4387408799 created "2023-10-07" @default.
- W4387408799 date "2023-10-06" @default.
- W4387408799 modified "2023-10-16" @default.
- W4387408799 title "Reviewer #3 (Public Review): Tmem263 deletion disrupts the GH/IGF-1 axis and causes dwarfism and impairs skeletal acquisition" @default.
- W4387408799 doi "https://doi.org/10.7554/elife.90949.1.sa3" @default.
- W4387408799 hasPublicationYear "2023" @default.
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