title: Clinical, biochemical, and molecular investigations of a genetic isolate of growth hormone insensitivity (Laron's syndrome).
abstract: We have characterized the GH receptor mutation that is responsible for extreme short stature and GH insensitivity in a Bahamian genetic isolate. Heights of affected individuals ranged from -4.0 to -6.3 SD. Like others with Laron's syndrome, they had normal to high serum GH concentrations and low serum insulin-like growth factor I concentrations. Circulating levels of GH-binding protein activity were below limits of detection. Amplification of exons 2-7 and screening with single strand conformational polymorphism analysis located an abnormality in exon 7. Sequencing identified homozygosity for a C to T transition in the third position of codon 236. Reverse transcription and PCR amplification of complementary DNA from lymphocytes showed that this same sense mutation generated a new splice donor site 63 bp 5' to the normal exon 7 splice site. This novel site was used to the exclusion of the normal site in homozygotes. Both normal and variant messenger ribonucleic acid species were detected in heterozygotes. The predicted protein lacks 21 amino acids, including those defining the WS-like motif of the GH receptor 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 English settlement.
authors.affiliation: Department of Pediatrics, University of Miami School of Medicine, Florida 33136, USA.
authors.forename: L
authors.initials: L
authors.lastname: Baumbach
authors.forename: A
authors.initials: A
authors.lastname: Schiavi
authors.forename: R
authors.initials: R
authors.lastname: Bartlett
authors.forename: E
authors.initials: E
authors.lastname: Perera
authors.forename: J
authors.initials: J
authors.lastname: Day
authors.forename: M R
authors.initials: MR
authors.lastname: Brown
authors.forename: S
authors.initials: S
authors.lastname: Stein
authors.forename: M
authors.initials: M
authors.lastname: Eidson
authors.forename: J S
authors.initials: JS
authors.lastname: Parks
authors.forename: W
authors.initials: W
authors.lastname: Cleveland
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002675:Child, Preschool; D015331:Cohort Studies; D004351:Drug Resistance; D005260:Female; D005796:Genes; D019382:Human Growth Hormone / Q000502:physiology*; D006801:Humans; D007223:Infant; D008297:Male; D008661:Metabolism, Inborn Errors / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D008875:Middle Aged; D009154:Mutation; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D011986:Receptors, Somatotropin / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D012333:RNA, Messenger; D011986:Receptors, Somatotropin; D019382:Human Growth Hormone