Disorders caused by genetic defects associated with GH-dependent genes: PAPPA2 defects

Area of Science:

• Endocrinology
• Human Physiology
• Genetics

Background:

• The growth hormone (GH) and insulin-like growth factor-1 (IGF-1) axis regulates human growth.
• IGF-1 bioavailability is modulated by binding proteins and the acid-labile subunit (ALS).
• Pregnancy-associated plasma protein-A2 (PAPP-A2) is a protease that cleaves IGF-binding proteins (IGFBPs).

Purpose of the Study:

• To review the function of PAPP-A2 in the GH-IGF axis.
• To examine PAPP-A2 deficiency in humans and mouse models.
• To emphasize the role of IGF-1 bioavailability in growth regulation.

Main Methods:

• Analysis of PAPP-A2 deficient patients.
• Study of PAPP-A2 deficient mouse models.
• Review of existing literature on PAPP-A2 and the GH-IGF axis.

Main Results:

• PAPP-A2 deficiency leads to growth failure, elevated total IGF-1 and IGFBPs, and reduced free IGF-1.
• Patients with PAPP-A2 deficiency exhibit impaired glucose metabolism and bone mineral density (BMD).
• Treatment with recombinant human IGF-1 (rhIGF-1) ameliorated growth and metabolic deficits.

Conclusions:

• PAPP-A2 is crucial for regulating IGF-1 bioavailability.
• PAPP-A2 deficiency highlights the importance of IGF-1 bioavailability for normal growth, glucose metabolism, and bone health.
• Understanding PAPP-A2 function offers insights into growth regulation and potential therapeutic targets.