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Gene Review

IGFALS  -  insulin-like growth factor binding protein...

Homo sapiens

Synonyms: ACLSD, ALS, Insulin-like growth factor-binding protein complex acid labile subunit
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Disease relevance of IGFALS

  • Both prednisolone and GH alleviated the hypoglycemia, concomitantly with increases in IGF-I, IGFBP-3, and ALS levels [1].
  • The aim of the study was to evaluate serum acid-labile subunit (ALS) concentrations and their relationship with other parameters of the human ternary IGF-I-binding protein (IGFBP) complex in girls with central precocious puberty (CPP) before and after pharmacological arrest of puberty [2].
  • Serum ALS levels were less than 5th percentile in 40 of 56 (71%) patients with adult GHD (32/43 (74%) for CO and 8/13 (62%) for AO), and more than 95th percentile in 38 of 43 (88%) patients with acromegaly, respectively [3].
  • In conclusion, a paradoxical gender dissociation within the GH/ IGF-I axis is evident in protracted critical illness, with men showing greater loss of pulsatility and regularity within the GH secretory pattern than women (despite indistinguishable total GH output) and concomitantly lower IGF-I and ALS levels [4].
  • ALS correlated significantly with indicators of liver dysfunction, including the Child-Turcotte score (r=-0.69, p<0.0001), IGF-I (r=0.82, p<0.0001) and IGFBP-3 (r=0.74, p<0.0001) [5].
  • The affected probands presented a similar phenotype characterized by a moderate postnatal growth deficit associated with undetectable ALS, low IGF-I, IGF-II, and IGFBP-3, and hyperinsulinemia, and, in two cases, delayed puberty [6].

Psychiatry related information on IGFALS

  • Despite GH hypersecretion, serum IGF-I, IGFBP-3, and ALS levels have all been reported to be low in patients with anorexia nervosa (AN), while the degree of ternary complex formation in AN is unknown [7].
  • The toxin beta-methylamino-l-alanine (BMAA) has been proposed to contribute to amyotrophic lateral sclerosis-Parkinsonism Dementia Complex of Guam (ALS/PDC) based on its ability to induce a similar disease phenotype in primates and its presence in cycad seeds, which constituted a dietary item in afflicted populations [8].
  • Both non-viral and viral delivery strategies are being undertaken for in vivo silencing of molecular targets by RNA interference, which has resulted in robust efficacy in animal models of Alzheimer's disease, ALS, Huntington's disease, spinocerebellar ataxia, anxiety, depression, neuropathic pain, encephalitis and glioblastoma [9].
  • Longitudinal predictors of psychological distress and self-esteem in people with ALS [10].
  • OBJECTIVE: To develop and evaluate the psychometric properties of an ALS-specific QOL instrument (the ALSSQOL) that would reflect overall QOL as assessed by the patient and would be valid and reliable across large samples [11].

High impact information on IGFALS

  • ALS: A Disease of Motor Neurons and Their Nonneuronal Neighbors [12].
  • The observation that such a diverse set of mutant SOD1 proteins behave so similarly in mitochondria of motoneuronal cells and so differently from wild-type SOD1 suggests that this behavior may explain the toxicity of ALS-mutant SOD1 proteins, which causes motor neurons to die [13].
  • Here we demonstrate that each of 12 different familial ALS-mutant SOD1s with widely differing biophysical properties are associated with mitochondria of motoneuronal cells to a much greater extent than wild-type SOD1, and that this effect may depend on the oxidation of Cys residues [13].
  • However, little is known about how ALS binds to IGFBP-3 or -5, which link the IGFs to ALS [14].
  • To examine this further, seven recombinant ALS mutants each lacking one of the seven glycan attachment sites were expressed in CHO cells [15].

Chemical compound and disease context of IGFALS


Biological context of IGFALS

  • These data suggest that GH stimulates hALS and mALS gene expression by a similar mechanism, which involves at least in part a conserved GLE in the ALS promoter [20].
  • The region spanning from -755 to -4 bp 5' to the hALS ATG translation start codon directs expression of a luciferase reporter gene in primary rat hepatocytes, and GH increases reporter expression in the presence of the native, but not a mutant, GLE in the hALS promoter [20].
  • Thus, ALS binding to IGFBP-3 complexes is much weaker than previously recognised, emphasising the importance of ALS dissociation as a controlling factor in the regulation of IGF bioavailability [21].
  • The amino acid sequence of ALS is largely composed of 18-20 leucine-rich repeats of 24 amino acids [22].
  • Full-length clones encoding ALS have been isolated from human liver cDNA libraries by using probes based on amino acid sequence data from the purified protein [22].

Anatomical context of IGFALS


Associations of IGFALS with chemical compounds

  • Among the well defined insulin-like growth factor (IGF)-binding proteins (IGFBPs), IGFBP-3 is characterized by its interaction with an acid-labile glycoprotein (ALS) in the presence of IGFs [26].
  • We have recently shown that insulin-like growth factor (IGF)-binding protein 5 forms ternary complexes with IGF-I or IGF-II and the acid-labile subunit (ALS) (Twigg, S. M., and Baxter, R. C. (1998) J. Biol. Chem. 273, 6074-6079) [27].
  • Prednisone monotherapy partially suppressed big IGF-2 secretion, and rhGH monotherapy acted on IGFBP-3 and ALS concentrations [28].
  • However, only prednisolone improved the ability of IGFBP-3 to bind ALS in vitro [1].
  • The ALS decrease seems to be the sole GH-dependent factor that parallels the decreases in steroid levels and growth velocity during GnRHa therapy [2].

Physical interactions of IGFALS

  • Pure ALS had no intrinsic IGF-binding activity and no effect on the binding of IGF-I or IGF-II to BP-53 [29].
  • These findings are consistent with the basic carboxyl-terminal domain on IGFBP-5 being the principal site in IGFBP-5 that binds to ALS [27].
  • We conclude that the carboxyl-terminal domain of IGFBP-3 contains an IGF-binding determinant and can form ternary complexes with ALS [30].

Regulatory relationships of IGFALS

  • To determine the importance of ALS in regulating the molecular distribution of hIGFBP-3, hALS was coinjected [31].

Other interactions of IGFALS

  • We conclude that residues 228-232 of IGFBP-3 are essential for cell association and are required for normal ALS binding affinity [26].
  • Using site-specific mutants, we have identified residues K(211)/R(214)/K(217)/R(218) within the carboxyl-terminal region of IGFBP-5 as being essential for ALS binding [32].
  • After further high performance anion exchange chromatography, an ALS preparation was obtained which contained only an 84-86-kDa protein doublet, converting to a single 70-kDa band on N-glycanase treatment, and having an amino-terminal sequence unrelated to IGF-binding proteins or receptors [29].
  • In conclusion, despite a slight but significant fall in ALS, IGFBP-3 levels rise after rhIGF-I administration in IDDM [33].
  • Of these proteins, ALS correlated best with serum levels of nutritional indicators, particularly prealbumin [34].

Analytical, diagnostic and therapeutic context of IGFALS


  1. Regulation of the insulin-like growth factors and their binding proteins by glucocorticoid and growth hormone in nonislet cell tumor hypoglycemia. Baxter, R.C., Holman, S.R., Corbould, A., Stranks, S., Ho, P.J., Braund, W. J. Clin. Endocrinol. Metab. (1995) [Pubmed]
  2. The acid-labile subunit of human ternary insulin-like growth factor-binding protein complex in girls with central precocious puberty before and during gonadotropin-releasing hormone analog therapy. Cisternino, M., Draghi, M., Lauriola, S., Scarcella, D., Bernasconi, S., Cavallo, L., De Luca, F., Lomeo, A., Tatò, L. J. Clin. Endocrinol. Metab. (2002) [Pubmed]
  3. Acid-labile subunit in growth hormone excess and deficiency in adults: evaluation of its diagnostic value in comparison with insulin-like growth factor (IGF)-I and IGF-binding protein-3. Fukuda, I., Hizuka, N., Itoh, E., Yasumoto, K., Ishikawa, Y., Murakami, Y., Sata, A., Takano, K. Endocr. J. (2002) [Pubmed]
  4. A paradoxical gender dissociation within the growth hormone/insulin-like growth factor I axis during protracted critical illness. Van den Berghe, G., Baxter, R.C., Weekers, F., Wouters, P., Bowers, C.Y., Veldhuis, J.D. J. Clin. Endocrinol. Metab. (2000) [Pubmed]
  5. The acid-labile subunit of the ternary insulin-like growth factor complex in cirrhosis: relation to liver dysfunction. Møller, S., Juul, A., Becker, U., Henriksen, J.H. J. Hepatol. (2000) [Pubmed]
  6. 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. Heath, K.E., Argente, J., Barrios, V., Pozo, J., Díaz-González, F., Martos-Moreno, G.A., Caimari, M., Gracia, R., Campos-Barros, A. J. Clin. Endocrinol. Metab. (2008) [Pubmed]
  7. Low levels of the 150-kD insulin-like growth factor binding protein 3 ternary complex in patients with anorexia nervosa: effect of partial weight recovery. Støving, R.K., Hangaard, J., Hagen, C., Flyvbjerg, A. Horm. Res. (2003) [Pubmed]
  8. BMAA selectively injures motor neurons via AMPA/kainate receptor activation. Rao, S.D., Banack, S.A., Cox, P.A., Weiss, J.H. Exp. Neurol. (2006) [Pubmed]
  9. Therapeutic potential of RNA interference for neurological disorders. Sah, D.W. Life Sci. (2006) [Pubmed]
  10. Longitudinal predictors of psychological distress and self-esteem in people with ALS. Goldstein, L.H., Atkins, L., Landau, S., Brown, R.G., Leigh, P.N. Neurology (2006) [Pubmed]
  11. The ALSSQOL: balancing physical and nonphysical factors in assessing quality of life in ALS. Simmons, Z., Felgoise, S.H., Bremer, B.A., Walsh, S.M., Hufford, D.J., Bromberg, M.B., David, W., Forshew, D.A., Heiman-Patterson, T.D., Lai, E.C., McCluskey, L. Neurology (2006) [Pubmed]
  12. ALS: A Disease of Motor Neurons and Their Nonneuronal Neighbors. Boill??e, S., Vande Velde, C., Cleveland, D.W. Neuron (2006) [Pubmed]
  13. Familial ALS-superoxide dismutases associate with mitochondria and shift their redox potentials. Ferri, A., Cozzolino, M., Crosio, C., Nencini, M., Casciati, A., Gralla, E.B., Rotilio, G., Valentine, J.S., Carrì, M.T. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  14. The acid-labile subunit of the serum insulin-like growth factor-binding protein complexes. Structural determination by molecular modeling and electron microscopy. Janosi, J.B., Ramsland, P.A., Mott, M.R., Firth, S.M., Baxter, R.C., Delhanty, P.J. J. Biol. Chem. (1999) [Pubmed]
  15. N-Linked glycosylation and sialylation of the acid-labile subunit. Role in complex formation with insulin-like growth factor (IGF)-binding protein-3 and the IGFs. Janosi, J.B., Firth, S.M., Bond, J.J., Baxter, R.C., Delhanty, P.J. J. Biol. Chem. (1999) [Pubmed]
  16. Insulin-like growth factor binding proteins as glucoregulators. Baxter, R.C. Metab. Clin. Exp. (1995) [Pubmed]
  17. Characterization of the IGF system in 15 patients with Alström syndrome. Maffei, P., Boschetti, M., Marshall, J.D., Paisey, R.B., Beck, S., Resmini, E., Collin, G.B., Naggert, J.K., Milan, G., Vettor, R., Minuto, F., Sicolo, N., Barreca, A. Clin. Endocrinol. (Oxf) (2007) [Pubmed]
  18. Protective effect of metabotropic glutamate receptor inhibition on amyotrophic lateral sclerosis-cerebrospinal fluid toxicity in vitro. Anneser, J.M., Chahli, C., Borasio, G.D. Neuroscience (2006) [Pubmed]
  19. Clinical pharmacokinetics of intravenous and oral 9-amino-1,2,3,4-tetrahydroacridine, tacrine. Hartvig, P., Askmark, H., Aquilonius, S.M., Wiklund, L., Lindström, B. Eur. J. Clin. Pharmacol. (1990) [Pubmed]
  20. Conservation of a growth hormone-responsive promoter element in the human and mouse acid-labile subunit genes. Suwanichkul, A., Boisclair, Y.R., Olney, R.C., Durham, S.K., Powell, D.R. Endocrinology (2000) [Pubmed]
  21. Insulin-like growth factor binding protein-3: factors affecting binary and ternary complex formation. Holman, S.R., Baxter, R.C. Growth Regul. (1996) [Pubmed]
  22. Structure and functional expression of the acid-labile subunit of the insulin-like growth factor-binding protein complex. Leong, S.R., Baxter, R.C., Camerato, T., Dai, J., Wood, W.I. Mol. Endocrinol. (1992) [Pubmed]
  23. The role of the acid-labile subunit in regulating insulin-like growth factor transport across human umbilical vein endothelial cell monolayers. Payet, L.D., Firth, S.M., Baxter, R.C. J. Clin. Endocrinol. Metab. (2004) [Pubmed]
  24. Isolation of the cDNA encoding the acid labile subunit (ALS) of the 150 kDa IGF-binding protein complex in cattle and ALS regulation during the transition from pregnancy to lactation. Kim, J.W., Rhoads, R.P., Segoale, N., Kristensen, N.B., Bauman, D.E., Boisclair, Y.R. J. Endocrinol. (2006) [Pubmed]
  25. Acid-labile subunit of human insulin-like growth factor-binding protein complex: measurement, molecular, and clinical evaluation. Khosravi, M.J., Diamandi, A., Mistry, J., Krishna, R.G., Khare, A. J. Clin. Endocrinol. Metab. (1997) [Pubmed]
  26. Structural determinants of ligand and cell surface binding of insulin-like growth factor-binding protein-3. Firth, S.M., Ganeshprasad, U., Baxter, R.C. J. Biol. Chem. (1998) [Pubmed]
  27. Insulin-like growth factor-binding protein 5 complexes with the acid-labile subunit. Role of the carboxyl-terminal domain. Twigg, S.M., Kiefer, M.C., Zapf, J., Baxter, R.C. J. Biol. Chem. (1998) [Pubmed]
  28. Treatment of hypoglycemia using combined glucocorticoid and recombinant human growth hormone in a patient with a metastatic non-islet cell tumor hypoglycemia. Bourcigaux, N., Arnault-Ouary, G., Christol, R., Périn, L., Charbonnel, B., Le Bouc, Y. Clinical therapeutics. (2005) [Pubmed]
  29. High molecular weight insulin-like growth factor binding protein complex. Purification and properties of the acid-labile subunit from human serum. Baxter, R.C., Martin, J.L., Beniac, V.A. J. Biol. Chem. (1989) [Pubmed]
  30. Ligand-binding characteristics of recombinant amino- and carboxyl-terminal fragments of human insulin-like growth factor-binding protein-3. Galanis, M., Firth, S.M., Bond, J., Nathanielsz, A., Kortt, A.A., Hudson, P.J., Baxter, R.C. J. Endocrinol. (2001) [Pubmed]
  31. Complex formation by human insulin-like growth factor-binding protein-3 and human acid-labile subunit in growth hormone-deficient rats. Lewitt, M.S., Saunders, H., Phuyal, J.L., Baxter, R.C. Endocrinology (1994) [Pubmed]
  32. Mutagenesis of basic amino acids in the carboxyl-terminal region of insulin-like growth factor binding protein-5 affects acid-labile subunit binding. Firth, S.M., Clemmons, D.R., Baxter, R.C. Endocrinology (2001) [Pubmed]
  33. The effects of recombinant human IGF-I administration on concentrations of acid labile subunit, IGF binding protein-3, IGF-I, IGF-II and proteolysis of IGF binding protein-3 in adolescents with insulin-dependent diabetes mellitus. Cheetham, T.D., Holly, J.M., Baxter, R.C., Meadows, K., Jones, J., Taylor, A.M., Dunger, D.B. J. Endocrinol. (1998) [Pubmed]
  34. Thirty-day monitoring of insulin-like growth factors and their binding proteins in intensive care unit patients. Baxter, R.C., Hawker, F.H., To, C., Stewart, P.M., Holman, S.R. Growth Horm. IGF Res. (1998) [Pubmed]
  35. Purified rat acid-labile subunit and recombinant human insulin-like growth factor (IGF)-binding protein-3 can form a 150-kilodalton binary complex in vitro in the absence of IGFs. Lee, C.Y., Rechler, M.M. Endocrinology (1995) [Pubmed]
  36. The high molecular weight insulin-like growth factor-binding protein complex: epitope mapping, immunoassay, and preliminary clinical evaluation. Khosravi, J., Diamandi, A., Mistry, J., Krischna, R.G. J. Clin. Endocrinol. Metab. (1999) [Pubmed]
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