The role of acid-labile subunit (ALS) in aetiology and diagnostic procedures of short stature
Authors:
L. Toni 1; K. Pádrová 2; L. Plachý 1; P. Dušátková 1; L. Elblová 1; S. Koloušková 1; M. Pechová 2; M. Šnajderová 1; Z. Šumník 1; Š. Průhová 1; J. Lebl 1
Authors‘ workplace:
Pediatrická klinika a 2Ústav lékařské chemie a klinické biochemie 2. lékařské fakulty UK a Fakultní nemocnice Motol, Praha
1
Published in:
Čes-slov Pediat 2020; 75 (4): 214-218.
Category:
Overview
Aims: Acid-labile subunit (ALS) as a glycoprotein component of the ternary complex IGF-1/IGFBP-3/ALS co-regulates bioactivity and prolongs half-life of IGF-1 and thus substantially contributes to regulation of statural growth. Protein component of ALS is encoded by IGFALS gene. We studied the impact of growth hormone (GH) on circulating levels of ALS and additional ternary complex components, and the option to identify carriers of pathogenic variants of IGFALS gene according to low ALS levels.
Methods: We studied interrelations between ternary complex components in 511 children on GH therapy. Children with low ALS levels underwent IGFALS sequencing. We monitored the effect of GH therapy on the ternary complex in 23 children treated for GH deficiency (GHD) or for short stature after having been born small for gestational age (SGA-SS).
Results: In 511 children with GHD and/or SGA-SS on long-term GH therapy ALS level was 8750 µg/l (median; Q1-Q3: 6353–10963), IGF-1 was 233 µg/l (Q1-Q3: 147–329), corresponding to +1.21 SD (Q1-Q3: from -0.11 to +2.45), and IGFBP-3 was 5660 µg/l (Q1-Q3: 4668–6800), corresponding to +3.65 SD (Q1-Q3: from +1.81 to +5.97 SD). ALS is strongly interrelated with IGF-1 (r=0.70; p<0.0001) and with IGFBP-3 (r=0.61; p<0.0001). IGFALS Sanger sequencing in three children with low ALS levels (369, 487 and 1490 µg/l) displayed normal results. In 23 children following 3–4 months of GH therapy, ALS increased from 4859 (median; Q1-Q3: 4176-6240) to 6681 (5413-8332) µg/l (p=0.0004), IGF-1 from 68 (46-114) to 146 (84-178) µg/l (p<0.0001) and IGFBP-3 from 3390 (2820–4030) to 4700 (3940–5300) µg/l (p<0.0001). The impact of GH is more pronounced in IGF-1 (213% increase) compared to IGFBP-3 (132%; p<0.0001) and ALS (139%; p<0.0001).
Conclusions: Our results suggest that estimation of ALS levels is ineffective to detect IGFALS gene mutations. Biochemical measurements of ALS do not substantially contribute to diagnostic work-up and to follow-up in short stature children, according to our experience.
Keywords:
Growth hormone – acid-labile subunit – IGF-1 – IGFBP-3 – ternary complex – IGFALS
Sources
1. Werner H, Stannard B, Bach MA. Regulation of insulin-like growth factor I receptor gene ex-pression in normal and pathological states. Adv Exp Med Biol 1991; 293: 263–272.
2. Allard JB, Duan C. IGF-binding proteins: Why do they exist and why are there so many? Front Endocrinol 2018; 9: 117.
3. Boisclair Y, Rhoads RP, Ueki I, et al. The acid-labile subunit (ALS) of the 150 kDa IGF-binding protein complex: an important but forgotten component of the circulating IGF system. J Endocrinol 2001; 170 (1): 63–70.
4. Domené HM, Bengolea SV, Martínez AS, et al. Deficiency of the circulating insulin-like growth factor system associated with inactivation of the acid-labile subunit gene. N Engl J Med 2004; 350 (6): 570–577.
5. Renes JS, van Doorn J, Hokken-Koelega A, et al. Current insights into the role of the growth hormone–insulin-like growth factor system in short children born small for gestational age. Horm Res Paediatr 2019; 92: 15–27.
6. Fofanova-Gambetti OV, Hwa V, Wit JM, et al. Impact of heterozygosity for acid-labile subunit (IGFALS) gene mutations on stature: results from the international acid-labile subunit consortium. J Clin Endocrinol Metab 2010; 95 (9): 4184–4191.
7. Högler W, Martin DD, Crabtree N, et al. IGFALS gene dosage effects on serum IGF-I and glucose metabolism, body composition, bone growth in length and width, and the pharmacokinetics of recombinant human IGF-I administration. J Clin Endocrinol Metab 2014; 99 (4): 703–712.
8. Domené HM, Scaglia PA, Martínez AS, et al. Heterozygous IGFALS gene variants in idiopa-thic short stature and normal children: impact on height and the IGF system. Horm Res Paediatr 2013; 80 (6): 413–423.
9. Renes JS, van Doorn J, Breukhoven PE, et al. Acid-labile subunit levels and the association with response to growth hormone treatment in short children born small for gestational age. Horm Res Paediatr 2014; 8 (2): 126–132.
10. Ertl D, Gleiss A, Sagmeister S, et al. Determining the normal range for IGF-I, IGFBP-3, and ALS: new reference data based on current internal standards. Wien Med Wochenschr 2014; 164: 343–352.
11. Pruhova S, Dusatkova P, Sumnik Z, et al. Glucokinase diabetes in 103 families from a country based study in the Czech Republic: geographically restricted distribution of two prevalent GCK mutations. Pediatr Diabetes 2010; 11 (8): 529–535.
12. Ueki I, Ooi GT, Tremblay ML, et al. Inactivation of the acid labile subunit gene in mice results in mild retardation of postnatal growth despite profound disruptions in the circulating insulin-like growth factor system. Proc Natl Acad Sci USA 2000; 97 (12): 6868–6873.
13. Plachy L, Strakova V, Elblova L, et al. High prevalence of growth plate gene variants in children with familial short stature treated with GH. J Clin Endocrinol Metab 2019; 104 (10): 4273–4281.
14. Heath KE, Argente J, Barrios V, et al. Primary acid-labile subunit deficiency due to recessive IGFALS mutations results in postnatal growth deficit associated with low circulating insulin growth factor (IGF)-I, IGF binding protein-3 levels, and hyperinsulinemia. J Clin Endocrinol Metab 2008; 93 (5): 1616–1624. Erratum in: J Clin Endocrinol Metab 2008; 93 (6): 2426.
15. Dominguez-Menéndez G, Poggi Mayorga H, Arancibia M, et al. ALS deficiency caused by an exon 2 deletion and a novel missense variant in the gene encoding ALS. Growth Horm IGF Res 2019; 48–49: 5–8.
16. Hwa V, Haeusler G, Pratt KL, et al. Total absence of functional acid labile subunit, resulting in severe insulin-like growth factor deficiency and moderate growth failure. J Clin Endocrinol Metab 2006; 91 (5): 1826–1831.
17. Shanxiang R., Yuxiang N, Aihong W. Effects of recombinant human growth hormone in the treatment of dwarfism and relationship between IGF-1, IGFBP-3 and thyroid hormone. Exp Ther Med 2016; 12: 3579–3582.
18. Ballerini MG, Braslavsky D, Scaglia PA, et al. Circulating IGF-I, IGFBP-3 and the IGF-I/IGFBP-3 molar ratio concentration and height outcome in prepubertal short children on rhGH treatment over two years of therapy. Horm Res Paediatr 2013; 80: 413–423.
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Neonatology Paediatrics General practitioner for children and adolescentsArticle was published in
Czech-Slovak Pediatrics
2020 Issue 4
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