Clinical, biochemical, and molecular investigations of a genetic isolate of growth hormone insensitivity (Laron's syndrome).
Level 4 - case-series / case-control
Case series and genetic characterization of individuals from an isolated population
PubMed 9024234 · doi:10.1210/jcem.82.2.3784
What was done
Researchers evaluated clinical, biochemical, and molecular characteristics of individuals with growth hormone (GH) insensitivity (Laron's syndrome) from a Bahamian genetic isolate. They measured serum GH, insulin-like growth factor I (IGF-I), and GH-binding protein (GHBP) activity. Exons 2–7 of the GH receptor gene were screened using single-strand conformational polymorphism (SSCP) analysis, direct sequencing, and reverse transcription PCR of lymphocyte cDNA to evaluate mRNA splicing.
What was found
Affected individuals had heights ranging from -4.0 to -6.3 SD, normal to high serum GH concentrations, low serum IGF-I concentrations, and undetectable circulating GHBP activity. Genetic analysis identified homozygosity for a C to T transition at the third position of codon 236 in exon 7. RT-PCR demonstrated this silent mutation generated a novel splice donor site 63 bp 5' to the normal site, which was used exclusively in homozygotes and produced a predicted protein lacking 21 amino acids, including the extracellular WS-like motif.
Why it matters
This study defines the molecular basis of Laron's syndrome in a specific founder population, showing how an exonic synonymous mutation can disrupt normal splicing and eliminate functional GH receptor activity.
Limits
The abstract does not state the exact number of affected individuals or family members examined. Functional characterization is derived from predictive transcript modeling and lymphocyte cDNA without direct in vitro GH-binding assay quantification reported in the abstract.
Cited by
- supports Circulating IGF-1 levels in individuals with Laron syndrome are approximately 10% of normal circulating IGF-1 levels.