* 601489

INSULIN-LIKE GROWTH FACTOR-BINDING PROTEIN, ACID-LABILE SUBUNIT; IGFALS


Alternative titles; symbols

IGFBP, SOLUBLE
ACID-LABILE SUBUNIT; ALS


HGNC Approved Gene Symbol: IGFALS

Cytogenetic location: 16p13.3     Genomic coordinates (GRCh38): 16:1,790,413-1,794,908 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
16p13.3 Acid-labile subunit, deficiency of 615961 AR 3

TEXT

Description

In vivo, insulin-like growth factors I (IGF1; 147440) and II (IGF2; 147470) are always complexed to one of a family of 6 IGF-binding proteins, IGFBP1 (146730), IGFBP2 (146731), IGFBP3 (146732), IGFBP4 (146733), IGFBP5 (146734), and IGFBP6 (146735). Until birth, binary IGFBP/IGF complexes of 50 kD predominate in serum, with IGFBP2 being the most frequently occurring IGFBP moiety. In juvenile and adult mammals, however, 80 to 85% of serum IGFs are found in a ternary complex of 150 kD composed of 1 molecule each of IGF, IGFBP3, and a protein that is found only in serum, the acid-labile subunit (ALS). ALS migrates at an apparent molecular mass of 84 to 86 kD. ALS retains the IGFBP3/IGF complexes in the vascular compartment and extends the half-life of IGFs in the circulation. Synthesis of ALS occurs mainly in liver after birth and is stimulated by growth hormone (139250) (summary by Boisclair et al., 1996).


Cloning and Expression

Dai and Baxter (1992) and Baxter and Dai (1994) studied the acid-labile subunit of the rat IGF binding protein complex. Boisclair et al. (1996) cloned and characterized the mouse Igfals gene.

Leong et al. (1992) isolated full-length clones encoding the acid-labile subunit of the IGF binding protein complex from human liver cDNA libraries by using probes based on amino acid sequence data from the purified protein. These clones encode a mature protein of 578 amino acids preceded by a 27-amino acid hydrophobic sequence indicative of a secretion signal. Expression of the cDNA clones in mammalian tissue culture cells resulted in the secretion into the culture media of ALS activity that could form the expected complex with IGF1 and IGFBP3. The amino acid sequence of ALS is largely composed of 18 to 20 leucine-rich repeats of 24 amino acids. These repeats are found in a number of diverse proteins that, like ALS, participate in protein-protein interactions.


Gene Structure

Boisclair et al. (1996) found that the mouse Igfals gene contains 2 exons. Domene et al. (2004) stated that the human IGFALS gene contains 2 exons.


Mapping

Domene et al. (2011) stated that the IGFALS gene maps to chromosome 16p13.3.

Boisclair et al. (1996) mapped the mouse Igfals gene to chromosome 17 by fluorescence in situ hybridization.


Molecular Genetics

In a 17-year-old boy with acid-labile subunit deficiency (ACLSD; 615961) who had delayed onset of puberty, slow pubertal progress, and only minimal slowing of linear growth, Domene et al. (2004) identified a homozygous inactivating mutation in the IGFALS gene (601489.0001).

In 3 sibs with acid-labile subunit deficiency, Domene et al. (2007) identified compound heterozygous mutations in the IGFALS gene (601489.0002-601489.0003).

Domene et al. (2011) stated that 16 unique homozygous or compound heterozygous inactivating mutations of the IGFALS gene had been identified in 21 patients with acid-labile subunit deficiency from 16 different families of various ethnic backgrounds. All of the mutations occurred in exon 2 and included missense mutations, frameshifts with a premature stop codon, in-frame insertions, and nonsense mutations. Thirteen of the mutations produced defects in the leucine-rich repeat region of the protein.


Animal Model

To evaluate the importance of IGFALS and ternary complexes, Ueki et al. (2000) generated mice in which the Igfals gene had been inactivated. The mutation was inherited in a mendelian manner, without any effects on survival rates and birth weights. A growth deficit was observed in null mice after 3 weeks of age and reached 13% by 10 weeks. This modest phenotype was observed despite reductions of 62% and 88% in the concentrations of plasma IGF1 and IGFBP3, respectively. Increased turnover accounted for these reductions because indices of synthesis in liver and kidney were not decreased. Surprisingly, absence of Igfals did not affect glucose and insulin homeostasis. Therefore, Igfals is required for postnatal accumulation of IGF1 and IGFBP3 but, consistent with findings supporting a predominant role for locally produced IGF1, is not critical for growth.


ALLELIC VARIANTS ( 3 Selected Examples):

.0001 ACID-LABILE SUBUNIT DEFICIENCY

IGFALS, 1-BP DEL, 1338G
  
RCV000008600

Domene et al. (2004) described a 17-year-old boy with delayed onset of puberty and slow pubertal progress. Childhood medical history was unremarkable, and psychomotor and neurologic development were normal. He was first referred at 14 years of age for evaluation of growth pubertal delay, at which time his height was 145.2 cm (2.05 SD below the mean) and his weight was 35.9 kg. He was Tanner stage 1 for both sexual development and pubic hair. Both testes were 3 ml in volume. Bone age was 12.5 years. Growth hormone responses to provocative tests were normal, but there was marked reduction of both IGF1 (147440) and IGFBP3 (146732), which remained unchanged after stimulation with growth hormone. The acid-labile subunit was undetectable in the serum before and after growth hormone stimulation (see ACLSD, 615961). Sequencing of exons 1 and 2 of the IGFALS gene revealed a 1-bp deletion, c.1338delG, which involved 1 of 5 consecutive guanines at positions 1334-1338. This frameshift point mutation resulted in the substitution of a lysine for a glutamic acid at codon 35 (E35K) and the appearance of a premature stop codon at position 120 of the precursor form of the acid-labile subunit. The patient was thought to be homozygous for the mutation; parental DNA was not available because the patient had been adopted. After 6 months of treatment with recombinant human growth hormone, reduction in the subscapular skinfold thickness was observed but there was no beneficial effect on either the velocity of growth or the serum levels of IGF1, IGFBP3, and the acid-labile subunit.


.0002 ACID-LABILE SUBUNIT DEFICIENCY

IGFALS, CYS540ARG
  
RCV000008601

Domene et al. (2007) described a family in which 3 sibs had complete acid-labile subunit deficiency (ACLSD; 615961). The index case was an adolescent male with delayed growth and pubertal development (Tanner stage I, -2.00 standard deviation (SD) score for height at the age of 15.3 years) and poor response to GH (139250) treatment. Complete sequencing of the IGFALS gene revealed compound heterozygosity for mutations in exon 2: a 1618C-T transition resulting in a cys540-to-arg (C540R) substitution on the maternal allele, and a 9-bp duplication (c.583_591dup9; 601489.0003) predicting the insertion of 3 extra amino acids in the seventh leucine-rich repeat (S195_197Rdup) on the paternal allele. The proband's affected brother and sister carried the same mutations; a fourth sib carried the duplication mutation. The 3 affected sibs had marked reduction of IGF1 (147440) and IGFBP3 (146732) levels, undetectable serum levels of acid-labile subunit, inability to form ternary complexes, and moderate insulin resistance. All of them attained a normal adult height that was nonetheless lower than that of their heterozygous brother. The IGF system was only modestly affected in the heterozygous carriers. Domene et al. (2007) concluded that haploinsufficiency of the IGFALS gene has no discernible clinical effects, with only modest impact on the IGF system.


.0003 ACID-LABILE SUBUNIT DEFICIENCY

IGFALS, 9-BP DUP, NT583
  
RCV000008602

For discussion of the 9-bp duplication in the IGFALS gene (c.583_591dup9) that was found in compound heterozygous state in sibs with complete acid-labile subunit deficiency (ACLSD; 615961) by Domene et al. (2007), see 601489.0002.


REFERENCES

  1. Baxter, R. C., Dai, J. Purification and characterization of the acid-labile subunit of rat serum insulin-like growth factor binding protein complex. Endocrinology 134: 848-852, 1994. [PubMed: 7507839, related citations] [Full Text]

  2. Boisclair, Y. R., Seto, D., Hsieh, S., Hurst, K. R., Ooi, G. T. Organization and chromosomal localization of the gene encoding the mouse acid labile subunit of the insulin-like growth factor binding complex. Proc. Nat. Acad. Sci. 93: 10028-10033, 1996. [PubMed: 8816745, related citations] [Full Text]

  3. Dai, J., Baxter, R. C. Molecular cloning of the acid-labile subunit of the rat insulin-like growth factor binding protein complex. Biochem. Biophys. Res. Commun. 188: 304-309, 1992. [PubMed: 1384485, related citations] [Full Text]

  4. Domene, H. M., Bengolea, S. V., Martinez, A. S., Ropelato, M. G., Pennisi, P., Scaglia, P., Heinrich, J. J., Jasper, H. G. Deficiency of the circulating insulin-like growth factor system associated with inactivation of the acid-labile subunit gene. New Eng. J. Med. 350: 570-577, 2004. [PubMed: 14762184, related citations] [Full Text]

  5. Domene, H. M., Hwa, V., Jasper, H. G., Rosenfeld, R. G. Acid-labile subunit (ALS) deficiency. Best Pract. Res. Clin. Endocr. Metab. 25: 101-113, 2011. [PubMed: 21396577, related citations] [Full Text]

  6. Domene, H. M., Scaglia, P. A., Lteif, A., Mahmud, F. H., Kirmani, S., Frystyk, J., Bedecarras, P., Gutierrez, M., Jasper, H. G. Phenotypic effects of null and haploinsufficiency of acid-labile subunit in a family with two novel IGFALS gene mutations. J. Clin. Endocr. Metab. 92: 4444-4450, 2007. [PubMed: 17726072, related citations] [Full Text]

  7. Leong, S. R., Baxter, R. C., Camerato, T., Dai, J., Wood, W. I. Structure and functional expression of the acid-labile subunit of the insulin-like growth factor-binding protein complex. Molec. Endocr. 6: 870-876, 1992. [PubMed: 1379671, related citations] [Full Text]

  8. Ueki, I., Ooi, G. T., Tremblay, M. L., Hurst, K. R., Bach, L. A., Boisclair, Y. R. 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. Nat. Acad. Sci. 97: 6868-6873, 2000. [PubMed: 10823924, images, related citations] [Full Text]


Carol A. Bocchini - updated : 8/25/2014
John A. Phillips, III - updated : 6/24/2008
Victor A. McKusick - updated : 2/24/2004
Carol A. Bocchini - updated : 8/30/2000
Victor A. McKusick - updated : 8/30/2000
Creation Date:
Victor A. McKusick : 11/7/1996
carol : 07/17/2020
mcolton : 08/18/2015
alopez : 10/22/2014
carol : 9/2/2014
carol : 8/25/2014
carol : 8/30/2013
carol : 1/4/2012
alopez : 6/24/2008
carol : 8/9/2007
joanna : 3/17/2004
tkritzer : 2/27/2004
terry : 2/24/2004
terry : 5/15/2001
carol : 8/30/2000
carol : 8/30/2000
alopez : 7/21/1998
jenny : 12/12/1996
terry : 12/9/1996
mark : 11/7/1996
mark : 11/7/1996
mark : 11/7/1996

* 601489

INSULIN-LIKE GROWTH FACTOR-BINDING PROTEIN, ACID-LABILE SUBUNIT; IGFALS


Alternative titles; symbols

IGFBP, SOLUBLE
ACID-LABILE SUBUNIT; ALS


HGNC Approved Gene Symbol: IGFALS

Cytogenetic location: 16p13.3     Genomic coordinates (GRCh38): 16:1,790,413-1,794,908 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
16p13.3 Acid-labile subunit, deficiency of 615961 Autosomal recessive 3

TEXT

Description

In vivo, insulin-like growth factors I (IGF1; 147440) and II (IGF2; 147470) are always complexed to one of a family of 6 IGF-binding proteins, IGFBP1 (146730), IGFBP2 (146731), IGFBP3 (146732), IGFBP4 (146733), IGFBP5 (146734), and IGFBP6 (146735). Until birth, binary IGFBP/IGF complexes of 50 kD predominate in serum, with IGFBP2 being the most frequently occurring IGFBP moiety. In juvenile and adult mammals, however, 80 to 85% of serum IGFs are found in a ternary complex of 150 kD composed of 1 molecule each of IGF, IGFBP3, and a protein that is found only in serum, the acid-labile subunit (ALS). ALS migrates at an apparent molecular mass of 84 to 86 kD. ALS retains the IGFBP3/IGF complexes in the vascular compartment and extends the half-life of IGFs in the circulation. Synthesis of ALS occurs mainly in liver after birth and is stimulated by growth hormone (139250) (summary by Boisclair et al., 1996).


Cloning and Expression

Dai and Baxter (1992) and Baxter and Dai (1994) studied the acid-labile subunit of the rat IGF binding protein complex. Boisclair et al. (1996) cloned and characterized the mouse Igfals gene.

Leong et al. (1992) isolated full-length clones encoding the acid-labile subunit of the IGF binding protein complex from human liver cDNA libraries by using probes based on amino acid sequence data from the purified protein. These clones encode a mature protein of 578 amino acids preceded by a 27-amino acid hydrophobic sequence indicative of a secretion signal. Expression of the cDNA clones in mammalian tissue culture cells resulted in the secretion into the culture media of ALS activity that could form the expected complex with IGF1 and IGFBP3. The amino acid sequence of ALS is largely composed of 18 to 20 leucine-rich repeats of 24 amino acids. These repeats are found in a number of diverse proteins that, like ALS, participate in protein-protein interactions.


Gene Structure

Boisclair et al. (1996) found that the mouse Igfals gene contains 2 exons. Domene et al. (2004) stated that the human IGFALS gene contains 2 exons.


Mapping

Domene et al. (2011) stated that the IGFALS gene maps to chromosome 16p13.3.

Boisclair et al. (1996) mapped the mouse Igfals gene to chromosome 17 by fluorescence in situ hybridization.


Molecular Genetics

In a 17-year-old boy with acid-labile subunit deficiency (ACLSD; 615961) who had delayed onset of puberty, slow pubertal progress, and only minimal slowing of linear growth, Domene et al. (2004) identified a homozygous inactivating mutation in the IGFALS gene (601489.0001).

In 3 sibs with acid-labile subunit deficiency, Domene et al. (2007) identified compound heterozygous mutations in the IGFALS gene (601489.0002-601489.0003).

Domene et al. (2011) stated that 16 unique homozygous or compound heterozygous inactivating mutations of the IGFALS gene had been identified in 21 patients with acid-labile subunit deficiency from 16 different families of various ethnic backgrounds. All of the mutations occurred in exon 2 and included missense mutations, frameshifts with a premature stop codon, in-frame insertions, and nonsense mutations. Thirteen of the mutations produced defects in the leucine-rich repeat region of the protein.


Animal Model

To evaluate the importance of IGFALS and ternary complexes, Ueki et al. (2000) generated mice in which the Igfals gene had been inactivated. The mutation was inherited in a mendelian manner, without any effects on survival rates and birth weights. A growth deficit was observed in null mice after 3 weeks of age and reached 13% by 10 weeks. This modest phenotype was observed despite reductions of 62% and 88% in the concentrations of plasma IGF1 and IGFBP3, respectively. Increased turnover accounted for these reductions because indices of synthesis in liver and kidney were not decreased. Surprisingly, absence of Igfals did not affect glucose and insulin homeostasis. Therefore, Igfals is required for postnatal accumulation of IGF1 and IGFBP3 but, consistent with findings supporting a predominant role for locally produced IGF1, is not critical for growth.


ALLELIC VARIANTS 3 Selected Examples):

.0001   ACID-LABILE SUBUNIT DEFICIENCY

IGFALS, 1-BP DEL, 1338G
SNP: rs587776686, ClinVar: RCV000008600

Domene et al. (2004) described a 17-year-old boy with delayed onset of puberty and slow pubertal progress. Childhood medical history was unremarkable, and psychomotor and neurologic development were normal. He was first referred at 14 years of age for evaluation of growth pubertal delay, at which time his height was 145.2 cm (2.05 SD below the mean) and his weight was 35.9 kg. He was Tanner stage 1 for both sexual development and pubic hair. Both testes were 3 ml in volume. Bone age was 12.5 years. Growth hormone responses to provocative tests were normal, but there was marked reduction of both IGF1 (147440) and IGFBP3 (146732), which remained unchanged after stimulation with growth hormone. The acid-labile subunit was undetectable in the serum before and after growth hormone stimulation (see ACLSD, 615961). Sequencing of exons 1 and 2 of the IGFALS gene revealed a 1-bp deletion, c.1338delG, which involved 1 of 5 consecutive guanines at positions 1334-1338. This frameshift point mutation resulted in the substitution of a lysine for a glutamic acid at codon 35 (E35K) and the appearance of a premature stop codon at position 120 of the precursor form of the acid-labile subunit. The patient was thought to be homozygous for the mutation; parental DNA was not available because the patient had been adopted. After 6 months of treatment with recombinant human growth hormone, reduction in the subscapular skinfold thickness was observed but there was no beneficial effect on either the velocity of growth or the serum levels of IGF1, IGFBP3, and the acid-labile subunit.


.0002   ACID-LABILE SUBUNIT DEFICIENCY

IGFALS, CYS540ARG
SNP: rs121909247, gnomAD: rs121909247, ClinVar: RCV000008601

Domene et al. (2007) described a family in which 3 sibs had complete acid-labile subunit deficiency (ACLSD; 615961). The index case was an adolescent male with delayed growth and pubertal development (Tanner stage I, -2.00 standard deviation (SD) score for height at the age of 15.3 years) and poor response to GH (139250) treatment. Complete sequencing of the IGFALS gene revealed compound heterozygosity for mutations in exon 2: a 1618C-T transition resulting in a cys540-to-arg (C540R) substitution on the maternal allele, and a 9-bp duplication (c.583_591dup9; 601489.0003) predicting the insertion of 3 extra amino acids in the seventh leucine-rich repeat (S195_197Rdup) on the paternal allele. The proband's affected brother and sister carried the same mutations; a fourth sib carried the duplication mutation. The 3 affected sibs had marked reduction of IGF1 (147440) and IGFBP3 (146732) levels, undetectable serum levels of acid-labile subunit, inability to form ternary complexes, and moderate insulin resistance. All of them attained a normal adult height that was nonetheless lower than that of their heterozygous brother. The IGF system was only modestly affected in the heterozygous carriers. Domene et al. (2007) concluded that haploinsufficiency of the IGFALS gene has no discernible clinical effects, with only modest impact on the IGF system.


.0003   ACID-LABILE SUBUNIT DEFICIENCY

IGFALS, 9-BP DUP, NT583
SNP: rs606231171, gnomAD: rs606231171, ClinVar: RCV000008602

For discussion of the 9-bp duplication in the IGFALS gene (c.583_591dup9) that was found in compound heterozygous state in sibs with complete acid-labile subunit deficiency (ACLSD; 615961) by Domene et al. (2007), see 601489.0002.


REFERENCES

  1. Baxter, R. C., Dai, J. Purification and characterization of the acid-labile subunit of rat serum insulin-like growth factor binding protein complex. Endocrinology 134: 848-852, 1994. [PubMed: 7507839] [Full Text: https://doi.org/10.1210/endo.134.2.7507839]

  2. Boisclair, Y. R., Seto, D., Hsieh, S., Hurst, K. R., Ooi, G. T. Organization and chromosomal localization of the gene encoding the mouse acid labile subunit of the insulin-like growth factor binding complex. Proc. Nat. Acad. Sci. 93: 10028-10033, 1996. [PubMed: 8816745] [Full Text: https://doi.org/10.1073/pnas.93.19.10028]

  3. Dai, J., Baxter, R. C. Molecular cloning of the acid-labile subunit of the rat insulin-like growth factor binding protein complex. Biochem. Biophys. Res. Commun. 188: 304-309, 1992. [PubMed: 1384485] [Full Text: https://doi.org/10.1016/0006-291x(92)92385-b]

  4. Domene, H. M., Bengolea, S. V., Martinez, A. S., Ropelato, M. G., Pennisi, P., Scaglia, P., Heinrich, J. J., Jasper, H. G. Deficiency of the circulating insulin-like growth factor system associated with inactivation of the acid-labile subunit gene. New Eng. J. Med. 350: 570-577, 2004. [PubMed: 14762184] [Full Text: https://doi.org/10.1056/NEJMoa013100]

  5. Domene, H. M., Hwa, V., Jasper, H. G., Rosenfeld, R. G. Acid-labile subunit (ALS) deficiency. Best Pract. Res. Clin. Endocr. Metab. 25: 101-113, 2011. [PubMed: 21396577] [Full Text: https://doi.org/10.1016/j.beem.2010.08.010]

  6. Domene, H. M., Scaglia, P. A., Lteif, A., Mahmud, F. H., Kirmani, S., Frystyk, J., Bedecarras, P., Gutierrez, M., Jasper, H. G. Phenotypic effects of null and haploinsufficiency of acid-labile subunit in a family with two novel IGFALS gene mutations. J. Clin. Endocr. Metab. 92: 4444-4450, 2007. [PubMed: 17726072] [Full Text: https://doi.org/10.1210/jc.2007-1152]

  7. Leong, S. R., Baxter, R. C., Camerato, T., Dai, J., Wood, W. I. Structure and functional expression of the acid-labile subunit of the insulin-like growth factor-binding protein complex. Molec. Endocr. 6: 870-876, 1992. [PubMed: 1379671] [Full Text: https://doi.org/10.1210/mend.6.6.1379671]

  8. Ueki, I., Ooi, G. T., Tremblay, M. L., Hurst, K. R., Bach, L. A., Boisclair, Y. R. 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. Nat. Acad. Sci. 97: 6868-6873, 2000. [PubMed: 10823924] [Full Text: https://doi.org/10.1073/pnas.120172697]


Contributors:
Carol A. Bocchini - updated : 8/25/2014
John A. Phillips, III - updated : 6/24/2008
Victor A. McKusick - updated : 2/24/2004
Carol A. Bocchini - updated : 8/30/2000
Victor A. McKusick - updated : 8/30/2000

Creation Date:
Victor A. McKusick : 11/7/1996

Edit History:
carol : 07/17/2020
mcolton : 08/18/2015
alopez : 10/22/2014
carol : 9/2/2014
carol : 8/25/2014
carol : 8/30/2013
carol : 1/4/2012
alopez : 6/24/2008
carol : 8/9/2007
joanna : 3/17/2004
tkritzer : 2/27/2004
terry : 2/24/2004
terry : 5/15/2001
carol : 8/30/2000
carol : 8/30/2000
alopez : 7/21/1998
jenny : 12/12/1996
terry : 12/9/1996
mark : 11/7/1996
mark : 11/7/1996
mark : 11/7/1996