scholarly journals Short stature due to primary acid-labile subunit deficiency

2020 ◽  
Author(s):  
Keyword(s):  
Short Stature ◽  
Acid Labile Subunit ◽  
Acid Labile

scholarly journals A new structural model of the acid-labile subunit: pathogenetic mechanisms of short stature-causing mutations

2012 ◽  
Vol 49 (3) ◽  
pp. 213-220 ◽  
Author(s):  
Alessia David ◽  
Lawrence A Kelley ◽  
Michael J E Sternberg
Keyword(s):  
Protein Structure ◽  
Short Stature ◽  
Structure Prediction ◽  
Structural Model ◽  
Hydrophobic Interactions ◽  
Experimental Studies ◽  
Receptor Protein ◽  
Glycosylation Sites ◽  
Acid Labile Subunit ◽  
Acid Labile

The acid-labile subunit (ALS) is the main regulator of IGF1 and IGF2 bioavailability. ALS deficiency caused by mutations in the ALS (IGFALS) gene often results in mild short stature in adulthood. Little is known about the ALS structure–function relationship. A structural model built in 1999 suggested a doughnut shape, which has never been observed in the leucine-rich repeat (LRR) superfamily, to which ALS belongs. In this study, we built a new ALS structural model, analysed its glycosylation and charge distribution and studied mechanisms by which missense mutations affect protein structure. We used three structure prediction servers and integrated their results with information derived from ALS experimental studies. The ALS model was built at high confidence using Toll-like receptor protein templates and resembled a horseshoe with an extensively negatively charged concave surface. Enrichment in prolines and disulphide bonds was found at the ALS N- and C-termini. Moreover, seven N-glycosylation sites were identified and mapped. ALS mutations were predicted to affect protein structure by causing loss of hydrophobic interactions (p.Leu134Gln), alteration of the amino acid backbone (p.Leu241Pro, p.Leu172Phe and p.Leu244Phe), loss of disulphide bridges (p.Cys60Ser and p.Cys540Arg), change in structural constrains (p.Pro73Leu), creation of novel glycosylation sites (p.Asp440Asn) or alteration of LRRs (p.Asn276Ser). In conclusion, our ALS structural model was identified as a highly confident prediction by three independent methods and disagrees with the previously published ALS model. The new model allowed us to analyse the ALS core and its caps and to interpret the potential structural effects of ALS mutations.

scholarly journals Homozygous and heterozygous expression of a novel mutation of the acid-labile subunit

2008 ◽  
Vol 159 (2) ◽  
pp. 113-120 ◽  
Author(s):  
H A van Duyvenvoorde ◽  
M J E Kempers ◽  
Th B Twickler ◽  
J van Doorn ◽  
W J Gerver ◽  
...  
Keyword(s):  
Short Stature ◽  
Bone Mineral ◽  
Novel Mutation ◽  
Mineral Density ◽  
Bone Mineral Apparent Density ◽  
Igf I ◽  
Acid Labile Subunit ◽  
Heterozygous Carriers ◽  
Acid Labile ◽  
Igfbp 3

ContextAcid-labile subunit (ALS) deficiency due to homozygous inactivation of the ALS gene (IGFALS) is associated with moderate short stature, and in few cases pubertal delay. The clinical expression of heterozygosity is unknown.ObjectiveTo investigate the clinical, laboratory, and radiological features of homozygous and heterozygous carriers of a novel mutation in the ALS gene in comparison with non-carriers.SubjectsThree short Kurdish brothers and their relatives.ResultsThe index cases presented with short stature, microcephaly, and low circulating IGF-I and IGF-binding protein-3 (IGFBP-3), and undetectable ALS levels. Two were known with a low bone mineral density and one of them had suffered from two fractures. We found a novel homozygous ALS gene mutation resulting in a premature stop codon (c.1490dupT, p.Leu497PhefsX40). The IGF-I, IGFBP-3, and ALS 150 kDa ternary complex was absent, and ALS proteins in serum were not detected with western blot. IGFPB-1 and IGFPB-2 were low and there was a mild insulin resistance. Five heterozygous carriers tended to have a lower height and head circumference than five non-carriers, and had low plasma ALS and IGFBP-3 levels. Bone mineral (apparent) density was low in two out of three homozygous carriers, and also in four out of nine relatives.ConclusionsThe clinical presentation of homozygous ALS mutations may, besides short stature, include microcephaly. Heterozygous carriers may have less statural and head growth, suggestive for a gene dosage effect.

scholarly journals Ablation of Hepatic Production of the Acid-Labile Subunit in Bovine-GH Transgenic Mice: Effects on Organ and Skeletal Growth

Endocrinology ◽  
2017 ◽  
Vol 158 (8) ◽  
pp. 2556-2571 ◽  
Author(s):  
Zhongbo Liu ◽  
Tianzhen Han ◽  
Shannon Fishman ◽  
James Butler ◽  
Tracy Zimmermann ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Skeletal Growth ◽  
Acid Labile Subunit ◽  
Acid Labile

scholarly journals Phenotypic Effects of Null and Haploinsufficiency of Acid-Labile Subunit in a Family with Two NovelIGFALSGene Mutations

2007 ◽  
Vol 92 (11) ◽  
pp. 4444-4450 ◽  
Author(s):  
Horacio M. Domené ◽  
Paula A. Scaglia ◽  
Aida Lteif ◽  
Farid H. Mahmud ◽  
Salman Kirmani ◽  
...  
Keyword(s):  
Acid Labile Subunit ◽  
Acid Labile
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