A mammalian model for Laron syndrome produced by targeted disruption of the mouse growth hormone receptor/binding protein gene (the Laron mouse)

Abstract

Laron syndrome [growth hormone (GH) insensitivity syndrome] is a hereditary dwarfism resulting from defects in the GH receptor (GHR) gene. GHR deficiency has not been reported in mammals other than humans. Many aspects of GHR dysfunction remain unknown because of ethical and practical limitations in studying humans. To create a mammalian model for this disease, we generated mice bearing a disrupted GHR͞binding protein (GHR͞BP) gene through a homologous gene targeting approach. Homozygous GHR͞BP knockout mice showed severe postnatal growth retardation, proportionate dwarfism, absence of the GHR and GH binding protein, greatly decreased serum insulin-like growth factor I and elevated serum GH concentrations. These characteristics represent the phenotype typical of individuals with Laron syndrome. Animals heterozygous for the GHR͞BP defect show only minimal growth impairment but have an intermediate biochemical phenotype, with decreased GHR and GH binding protein expression and slightly diminished insulin-like growth factor I levels. These findings indicate that the GHR͞BP-deficient mouse (Laron mouse) is a suitable model for human Laron syndrome that will prove useful for the elucidation of many aspects of GHR͞BP function that cannot be obtained in humans.

Caloric restriction and growth hormone receptor knockout: Effects on expression of genes involved in insulin action in the heart

“…Growth hormone (GH) resistance or insensitivity with low circulating levels of insulin-like growth factor-1 (IGF1), insulin and glucose, all of which imply increased insulin sensitivity, are among the key characteristics of long-lived GH receptor/binding protein knockout (GHR-KO) mice (1,2). These knockout mice live approximately 40% longer than their normal siblings (3).…”

Differential effects of early-life nutrient restriction in long-lived GHR-KO and normal mice

“…Mice with growth hormone (GH) resistance produced by targeted disruption of the GH receptor/ binding protein gene (GHR/GHBP-KO, hereafter referred to as GHR-KO mice) (Zhou et al 1997) are characterized by normal prenatal growth, major retardation of postnatal growth and adult body size, and a major extension of longevity (Coschigano et al 2003). These animals thrive under a standard feeding regimen, but as adults fail to benefit from a regimen of calorie restriction (CR) that significantly extends longevity of their normal siblings Bonkowski et al 2006).…”

Aging-related characteristics of growth hormone receptor/binding protein gene-disrupted mice

“…In an effort to better characterize the many roles of GH, and also as a step toward the delineation of IGF-1-dependent and -independent actions, GH signaling was abolished in mice by targeted gene disruption of the GHR/BP gene (Zhou et al 1997). The resulting mouse serves as a mammalian model for the human autosomal recessive disease Laron syndrome, also known as primary GH resistance or insensitivity and as primary IGF-1deficiency (Zhou et al 1997;Kopchick and Laron 1999;Laron et al 1993).…”

“…The resulting mouse serves as a mammalian model for the human autosomal recessive disease Laron syndrome, also known as primary GH resistance or insensitivity and as primary IGF-1deficiency (Zhou et al 1997;Kopchick and Laron 1999;Laron et al 1993).…”

“…Removal of most of the fourth exon of the murine GHR gene and replacement with a bacterial neomycin gene segment resulted in undetectable levels of both GHR and GHBP in the homozygous gene-disrupted or knockout (KO) mice (GHR/BP j/j) ( Zhou et al 1997). An unexplainable residual GH binding activity was detected in liver extracts, suggesting the possible presence of a second GH receptor (Zhou et al 1997).…”