Acid-labile subunit deficiency: phenotypic similarities and differences between human and mouse

Area of Science:

• Endocrinology
• Molecular Biology
• Genetics

Background:

• Insulin-like growth factors (IGFs) circulate in complexes with binding proteins (IGFBPs) and an acid-labile subunit (ALS).
• Ternary complex formation involving IGFs, IGFBP-3 or -5, and ALS sequesters IGFs in circulation, prolonging their half-life.
• Understanding ALS's physiological role is crucial for the IGF system.

Purpose of the Study:

• To investigate the physiological role of the acid-labile subunit (ALS) in the circulating IGF system.
• To compare the effects of ALS deficiency in a mouse model (ALS-KO) and human patients.

Main Methods:

• Utilized an animal model for ALS deficiency (ALS-KO mouse).
• Studied a patient with an inactivating mutation in the IGFALS gene.
• Assessed growth parameters, plasma IGF-I and IGFBP-3 concentrations, GH levels, insulin resistance, and bone mineral density (BMD).

Main Results:

• ALS deficiency did not affect fetal growth but caused modest postnatal growth reduction in both mice and humans.
• Markedly reduced plasma IGF-I and IGFBP-3 concentrations were observed in both ALS-deficient mice and patients.
• Reduced bone mineral density (BMD) was present in both species, while insulin resistance and pubertal delay were observed only in humans.

Conclusions:

• Complete ALS deficiency leads to impaired ternary complex formation, reduced circulating IGF-I, and decreased BMD, with similar phenotypes in mice and humans.
• ALS plays a vital role in maintaining the circulating IGF-I reservoir.
• The distinct human phenotypes suggest species-specific roles or interactions of ALS in metabolic regulation and development.