Abstract
Laron syndrome is an autosomul recessive growth resistance condition genetically linked to the growth hormone receptor (GHR) gene. In the course of an IGF-1 therapeutic trial, we have analyzed 15 unrelated patients from various ethnic origins by means of denaturing gradient gel electrophoresis of PCR-amplified GHR fragments; in each of them, we have determined the nucleotide sequence of 6 intragenic polymorphic sites defining 8 GHR frameworks and examined all coding cxons along with the splice junctions of this gene. This procedure allowed us to identify mutations in the 30 chromosomes studied and to characterize the GHR frameworks associated with each GHR mutation. Direct sequencing of PCR products that showed an altered electrophoretic behavior has led to the characterization of 12 different point mutations including 2 nonsense mutations, 3 splicing delects and 7 missense mutations associated with various GHR frameworks. Two of these defects were found to be recurrent. These results further illustrate the allelie heterogeneity of this syndrome and confirm the independent origin of the molecular defects. We expect all the missense mutations to be deleterious since 1) they all involved conserved codons among GHR from different species and 2) those mutations which are located within the exoplasmic domain were found in patients who lacked plasma GH binding activity; examination of corresponding mutated cDNAs expressed in eukaryotic cells, currently underway, should explain the GH resistance phenotype observed in vivo and provide insights into the structure-function relationships of the GHR and related receptors. In addition, such studies may be helpful to genetic counselling of affected families.
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Amselem, S., Dastol, F., Duquesnoy, P. et al. SPECTRUM OF GROWTH HORMONE RECEPTOR MUTATIONS AND ASSOCIATED HAPLOTYPES IN LARON SYNDROME. Pediatr Res 33 (Suppl 5), S60 (1993). https://doi.org/10.1203/00006450-199305001-00341
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DOI: https://doi.org/10.1203/00006450-199305001-00341