CLINICAL, BIOCHEMICAL, AND MOLECULAR INVESTIGATIONS OF A GENETIC ISOLATE OF GROWTH-HORMONE INSENSITIVITY (LARONS SYNDROME)

We have characterized the GK receptor mutation that is responsible for extreme short stature and GH insensitivity in a Bahamian tic isolate. Heights of affected individuals ranged from -4.0 to -6.3 SD. Like oth ers with Laron's syndrome, they had normal to high serum GH concentrat ions and low serum insulin-like growth factor I concentrations. Circul ating levels of GH-binding protein activity were below limits of detec tion. Amplification of exons 2-7 and screening with single strand conf ormational polymorphism analysis located an abnormality in exon 7. Seq uencing identified homozygosity for a C to T transition in the third p osition of codon 236. Reverse transcription and PCR amplification of c omplementary DNA from lymphocytes showed that this same sense mutation generated a new splice donor site 63 bp 5' to the normal exon 7 splic e site. This novel site was used to the exclusion of the normal site i n homozygotes. Both normal and variant messenger ribonucleic acid spec ies were detected in heterozygotes. The predicted protein lacks 21 ami no acids, including those defining the WS-like motif of the GH recepto r extracellular domain. The high frequency of Laron's syndrome in this isolated island population probably reflects the introduction of the G236 splice mutation by a settler early in the 300-yr history of Engli sh settlement.