Abstract 554 Endocrinology I Poster Symposium, Saturday, 5/1

Fanconi anemia (FA), an autosomal recessive disorder characterized by pancytopenia, chromosomal instability, cancer predisposition, congenital malformations, and short stature, is caused by mutations in at least eight different genes. The phenotype suggests that these mutations affect not only intracellular processes, but also the extracellular matrix. We therefore determined in seven FA patients, six of them assigned to complementation group A, the in vivo response of extracellular matrix elements to the endogenous secretion of growth hormone (GH). Using overnight 8PM-to-8AM serial sampling, we simultaneously quantified by specific immunoassay the serum levels of GH; PICP and PIIINP, the C- and N-terminal propeptides released during fibril formation from the precursors of type I and III collagens, respectively; as well as of C-IV and P1, antigens derived from the basement membrane components collagen type IV and laminin, respectively. All patients displayed varying degrees of GH deficiency and insulin resistance. As in control subjects, GH peaks triggered increases in PICP and C-IV levels with variable lag periods, achieving Pearson correlations of up to 0.69 and two-tailed significance levels of p≤0.01. However, despite subnormal GH secretion, lack of bone mass, and short stature in the FA patients, their serum PICP levels, which reflect synthesis of the collagen type most prominent in bone, skin, and tendon, were consistently elevated up to a 4-fold increase over age-adjusted normals. When analyzing in each FA patient the overnight averages of all parameters, we noted that only in this population, but not in matched GH-deficient (non-FA) subjects, the mean PICP values decreased as mean GH increased, whereas the means for PIIINP, C-IV, and P1 rose as expected. By contrast, mean insulin after glucose challenge, correlated directly with mean PICPs. Such a paradoxical pattern - progressive reduction of the PICP marker for type I collagen synthesis as endogenous GH increases - has not been noted before in any human disease. To resolve this challenge to a central part of the standard concept for hormonal control of connective tissue formation and human growth, we propose the following model: In FA, the intracellular quality control mechanism along the processing pathway for type I procollagen, which in normal cells retains and degrades up to 30% of all molecules formed, is dysfunctional and allows secretion of conformationally defective molecules with intact PICP epitope. GH not only enhances collagen gene expression and translation, but also improves the function of the intracellular quality control mechanism, causing enhanced, i.e., a more normal, retention of defective molecules, a decrease in extracellular PICP and thus, an apparent reduction in biosynthesis of collagen type I.

Supported by NIH RR06020 and HL32987