Molecular defects of IGFBPs/ALS

HORACIO M. DOMENÉ

Orlando, Florida

Simposio; International Symposium on IGF-1, GH and Ghrelin/GHS; 2011

University of South Florida

Most of the IGFs circulate as a 150 kDa ternary complex bound to IGFBP-3 (or IGFBP-5), and an acid labile subunit (ALS). The main role of ALS is the extension of IGFs half life by protecting them from degradation and preventing their passage to the extra vascular compartment. In humans, complete ALS deficiency is characterized by severe reduction of IGF-I and IGFBP-3 that remain low after GH treatment, associated to mild growth retardation, much less pronounced than the IGF-I deficit. Pubertal delay in boys and insulin insensitivity are common findings. Since the original report of human ALS deficiency in 2004, at least 23 patients with ALS deficiency have been described presenting 17 different homozygous or compound heterozygous inactivating mutations of the IGFALS gene. Although the effect of ALS deficiency on prenatal growth is still uncertain, postnatal growth is clearly affected, with the majority of the patients presenting a height between -2 to -3 SDS before and during puberty. In the assessment of a child with short stature ALS deficiency should be considered in those patients presenting: 1) a normal response to GH stimulation test, 2) low IGF-I levels associated to more profoundly reduced IGFBP-3 levels, 3) a mild growth retardation, apparently out of proportion to the degree of IGF-I and IGFBP-3 deficits, 4) lack of response to an IGF generation test and 5) insulin insensitivity. The relatively mild growth retardation in relation to the severe IGF-I deficit might be related to the preserved autocrine/paracrine action of locally produced IGF-I. The clinical and biochemical findings of ALS deficiency closely resemble that observed in a subset of ISS children, in which near 30% present low IGF-I levels. Noteworthy, heterozygous carriers (HC) of IGFALS gene mutations are frequently shorter than their wild type (WT) first degree relatives and show levels of IGF-I, IGFBP-3 and ALS that are intermediate between ALS deficient patients and WT relatives. Preliminar studies have reported heterozygous gene variants in the IGFALS gene in a subgroup of ISS children. In families of ISS children, we have found that height, IGF-I, IGFBP-3 and ALS levels were lower in HC for IGFALS gene variants compared to WT, suggesting that both gene alleles are necessary to maintain normal levels of ALS, required to sustain circulating levels of IGF-I and IGFBP-3 within normal limits. In vitro expression of some of these genetics variants resulted in abnormal intracellular trafficking and reduction of secretion. These studies expand the spectrum of IGFALS gene defects in children with abnormal growth and confirm the crucial role of ALS in maintaining the integrity of the circulating IGF system, required for the attainment of maximal growth potential.