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Mutations in the GH receptor gene (GHR) cause congenital GH insensitivity, a genetic disorder characterized by severe growth retardation associated with high serum concentration of GH and low serum levels of IGF-I. Molecular defects have been identified in all GHR-coding exons, except exon 3, a sequence that encodes part of the extracellular domain of the receptor. In humans, GHR transcripts exist in two isoforms differing by the retention (GHRfl) or exclusion (GHRd3) of this particular exon. As shown recently, such a dimorphic expression pattern, of unknown significance, could result from a retrovirus-mediated deletion event involving exon 3. This model for the generation of those two isoforms, however, leaves open the possibility that GHRd3 transcripts also arise from GHRfl alleles through alternative splicing. Here we report the identification of the first mutation in exon 3 of the GHR (W16X) in a patient with GH insensitivity and who also carries another nonsense mutation in exon 4. Intrafamilial correlation analyses of genotypes (presence of normal or mutant GHRfl and/or GHRd3 alleles), GHR expression patterns, and phenotypes provided direct evidence against an alternative splicing of exon 3. In particular, this exon was retained into transcripts originating from the GHRfl-W16X allele in both the patient and his mother. These observations, given the normal phenotype of the heterozygous parents, revealed also that a single copy of either GHRfl or GHRd3 is sufficient for normal growth.

the journal of clinical endocrinology and metabolism/journal of clinical endocrinology and metabolism

Heterozygous Nonsense Mutation in Exon 3 of the Growth Hormone Receptor (GHR) in Severe GH Insensitivity (Laron Syndrome) and the Issue of the Origin and Function of the GHRd3 Isoform