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. 1997 Nov 25;94(24):13215-20.
doi: 10.1073/pnas.94.24.13215.

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

Y Zhou  1 , B C Xu, H G Maheshwari, L He, M Reed, M Lozykowski, S Okada, L Cataldo, K Coschigamo, T E Wagner, G Baumann, J J Kopchick
Affiliations

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

Y Zhou et al. Proc Natl Acad Sci U S A. .

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 GHR/binding protein (GHR/BP) gene through a homologous gene targeting approach. Homozygous GHR/BP 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 GHR/BP 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 GHR/BP-deficient mouse (Laron mouse) is a suitable model for human Laron syndrome that will prove useful for the elucidation of many aspects of GHR/BP function that cannot be obtained in humans.

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Figures

Figure 1
Figure 1
Targeted disruption of the mGHR/BP gene. (A) Strategy for gene disruption. To construct the targeting vector, a DraIII–DraIII fragment containing a major portion of GHR exon 4 and ≈500 bp of intron 4/5 was replaced by the neomycin resistance (neo) gene. A herpes simplex virus thymidine kinase gene cassette (not shown) was placed at the 3′ end of the targeting vector for negative selection. The lengths (kilobases) of the left and right arms of the targeting vector and the important restriction fragments are indicated in the figure. B, BamHI; D, DraIII; E, EcoRI; and S, SacI. P1 and P2 denote hybridization probes. (B) Mouse genotyping with Southern blots using genomic DNA isolated from GHR/BP+/+, GHR/BP+/−, and GHR/BP−/− mice, digested with BamHI, and hybridized with 32P-labeled probes P1 or P2. The size of the native BamHI band was 15 kb, and that of the recombinant fragment was 4 kb. (C) Western blot analysis of liver GHR in a 4–12% gradient SDS/PAGE gel. The doublet appearance of the GHR is likely caused by variations in glycosylation. (D) GHBP activity in sera collected at 30 and 60 days of age (n = 6–7 mice in each group; data from 30- and 60-day-old animals pooled because they were not significantly different). No GHBP was detected in GHR/BP−/− mice (<30 pM). (E) Specific binding of [125I]-bGH to liver membrane preparations from 60-day-old mice (n = 9 animals in each group).
Figure 2
Figure 2
Retarded somatic growth of GHR/BP-deficient mice. (A) Photograph of female GHR/BP+/+, GHR/BP+/−, and GHR/BP−/− mice at 4 weeks of age. (B and C) Growth curves of male and female mice. (D) Body length at 60 days of age, determined from the tip of the nose to the anus (n = 3 in each group). (E) Organ weights of 60-day-old GHR/BP−/− mice, expressed as a percentage of the corresponding mean organ weight in GHR/BP+/+ mice (n = 3 for both groups).
Figure 3
Figure 3
Serum GH (A) and IGF-I (B) concentrations of GHR/BP+/+, GHR/BP+/−, and GHR/BP−/− mice. Blood was collected from 3–4 mice of each genotype on day 30 and day 60 after birth. Results from both time points were pooled.
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