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Estimates of the frequency of GH deficiency range from 1:4,000 to 1:10,000. Most cases are sporadic and presumed to be secondary to a wide variety of aetiologies. However, in families with consanguinity, or when a second case occurs in the same family, a genetic cause may be suspected. Given that the patient is isolated GH deficient four distinct familial types of isolated GH deficiencies (IGHD) are well-differentiated on the basis of inheritance, hormonal deficiencies as well as molecular analyses. Two forms are autosomal recessively (IGHD type IA and IB), one is autosomal dominantly (IGHD type II) and one X-linked inherited. In this review, we focus on the secretory pathway of peptide hormones in general and on the possible mechanisms causing IGHD type II in detail. Most interestingly, in IGHD type II the apparently same phenotype of IGHD is caused by distinct GH-1 gene alterations leading to different blockades within the secretory pathway. Furthermore, this type of IGHD, in addition to some other specific GH-1 gene mutations, provides the most important opportunity to shed light on cell-biological mechanisms far beyond its pure description at the DNA/RNA level.

The treatment of GH4C1 cells, a prolactin-producing rat anterior pituitary cell line, with estradiol (1 nM), insulin (300 nM) and epidermal growth factor (10 nM) has been previously shown to substantially increase both the intracellular level of prolactin, as well as the number of secretory granules. In this study, we examined the effect of this treatment on levels of carboxypeptidase E (CPE), a prohormone-processing enzyme. GH4C1 cells contain CPE mRNA and enzymatic activity. The secretion of both prolactin and CPE activity from GH4C1 cells is stimulated 10-fold by 50 mM KCl and 2- to 3-fold by 100 nM thyrotropin-releasing hormone, suggesting that these two proteins are contained in secretory granules. Treatment of GH4C1 cells with estradiol, insulin, and epidermal growth factor causes an increase in the intracellular level of CPE to approximately 2-fold of control values. This change is much smaller than the change in the level of prolactin: intracellular prolactin is increased 140-fold by the treatment. Kinetic analysis of the CPE activity indicates that the treatment does not alter the Km of substrate hydrolysis, with the change in activity the result of an increase in apparent Vmax. Northern blot analysis indicates that the level of CPE mRNA is not influenced (less than 10%) by the treatment, whereas the level of prolactin mRNA is increased 9-fold. These results indicate that CPE is not coordinately regulated with prolactin in the GH4C1 cell line, although some regulation of CPE activity does occur.