Journal of Clinical Endocrinology & Metabolism, Vol 76, 1224-1228, Copyright © 1993 by Endocrine Society

ARTICLES

Heterogeneous growth hormone (GH) gene mutations in familial GH deficiency

JD Cogan, JA Phillips 3d, N Sakati, H Frisch, E Schober and RD Milner
Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2578.

The GH1 genes of probands of two families with familial isolated GH deficiency (IGHD) were sequenced. Double stranded sequencing of the polymerase chain reaction (PCR) amplification products from genomic DNA of two affected cousins in a consanguineous Turkish family revealed a G- ->A transition in the 20th codon of the GH1 signal peptide. This substitution converts a TGG (Trp) to a TAG (stop) codon and generates a new AluI recognition site. PCR amplification of the GH1 alleles of family members, followed by AluI digestion, revealed that the G-->A transition segregated with the IGHD phenotype. In a Saudi Arabian family, a G-->C transversion was found that alters the first base of the donor splice site of intron IV. This substitution should perturb mRNA splicing, resulting in an altered protein product which should be unstable or bioinactive. This transversion also destroys an HphI site, which was used to assay samples from relatives. Digestion of PCR amplification products with HphI demonstrated cosegregation of the G-- >C transversion with IGHD. These results demonstrate that familial IGHD is a heterogeneous disease that perturbs different steps in the expression of the GH1 gene.