FAMILIAL GROWTH-HORMONE DEFICIENCY - A MODEL OF DOMINANT AND RECESSIVE MUTATIONS AFFECTING A MONOMERIC PROTEIN

Two families with familial isolated GH deficiency (IGHD) were studied, type II (autosomal dominant) and type I (autosomal recessive), whose GH1 genes exhibit cosegregation with IGHD. DNA sequencing of the GH1 g enes of the first family (IGHD II) demonstrated heterozygosity for a T -->C transition in the sixth base of the donor splice site of intron I II. The GH1 gene mutation in the second family (IGHD I) was found, in a previous study, to be a G-->C transversion altering the first base o f the donor splice site of intron IV. Interestingly, analysis of the t ranscripts derived from the mutant IGHD II allele revealed that the se quences corresponding to exon III were absent due to an exon skip that causes the loss of amino acids 32-71 from the mature GH protein. In c ontrast, the IGHD I mutation activates a cryptic donor splice site 73 bases upstream of the normal exon TV donor splice site causing loss of amino acids 103-126 of exon IV followed by a reading frameshift, and synthesis of 94 novel amino acids before chain termination 88 nucleoti des downstream of the normal GH stop codon. It is hypothesized that, b ecause of the loss of protein sequences derived from exons IV and V, t he IGHD I mutation products are not transported to secretory granules and thus cannot perturb secretion of the normal monomeric GH protein. In contrast the T-->C IGHD II mutant allele product retains these sequ ences and is transported to secretory granules where it can interact w ith the normal allele product producing a dominant-negative effect at the protein level.