Total Absence of Functional Acid Labile Subunit, Resulting in Severe Insulin-Like Growth Factor Deficiency and Moderate Growth Failure

Hwa, Vivian; Haeusler, Gabriele; Pratt, Katherine L.; Little, Brian M.; Frisch, H; Koller, D. Y.; Rosenfeld, Ron G.

doi:10.1210/jc.2005-2842

Cited by 86 publications

(79 citation statements)

References 22 publications

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“…Creation of novel glycosylation sites can cause protein misfolding and rapid protein degradation (Freeze & Schachter 2009) and could explain ALS deficiency in the patients' circulation (Hwa et al 2006).…”

Section: Discussionmentioning

confidence: 99%

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

David

Kelley

Sternberg

2012

Journal of Molecular Endocrinology

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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 leucinerich 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.

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Section: Discussionmentioning

confidence: 99%

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

David

Kelley

Sternberg

2012

Journal of Molecular Endocrinology

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“…At the age of one week, weight was 2500 g and length was 47 cm, which is considered normal (33). In addition, from the second patient no data regarding gestation, birth weight or length are available (34). Since expression of ALS occurs late in fetal life (35), severe effects on intrauterine growth are unlikely.…”

Section: Intrauterine Growthmentioning

confidence: 99%

“…Two patients with ALS deficiency due to a mutation in the ALS gene have been described (33,34) and we have recently reported two affected siblings (59). They present with a variable degree of growth retardation: height at 14.6 years of age K2.05 SDS and final height K0.8 SDS in the patient described by Domene et al, K2.1 SDS at 15.5 years of age in the patient described by Hwa et al, final height was K4.2 SDS in one of the siblings and height was K4.3 SDS at the age of 16.5 years in the other sibling.…”

Section: Postnatal Growthmentioning

confidence: 99%

“…One female with a heterozygous IGF1R mutation had menarche at the age of 18 years (22), but one of the patients described by Abbuzahab et al had a normal onset of puberty (18). The first patient with a mutation of the ALS gene had a delayed onset of puberty (112), but a later report showed a normal onset of puberty (34). These findings suggest that IGF-I plays a role in pubertal onset.…”

Section: Puberty and Gonadal Functionmentioning

confidence: 99%

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Genetic disorders in the GH–IGF-I axis in mouse and man

Walenkamp

Wit²

2007

eur j endocrinol

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Animal knockout experiments have offered the opportunity to study genes that play a role in growth and development. In the last few years, reports of patients with genetic defects in GH-IGF-I axis have greatly increased our knowledge of genetically determined causes of short stature. We will present the animal data and human reports of genetic disorders in the GH-IGF-I axis in order to describe the role of the GH-IGF-I axis in intrauterine and postnatal growth. In addition, the effects of the GH-IGF-I axis on the development and function of different organ systems such as brain, inner ear, eye, skeleton, glucose homeostasis, gonadal function, and immune system will be discussed. The number of patients with genetic defects in the GH-IGF-I axis is small, and a systematic diagnostic approach and selective genetic analysis in a patient with short stature are essential to identify more patients. Finally, the implications of a genetic defect in the GH-IGF-I axis for the patient and the therapeutic options will be discussed.European Journal of Endocrinology 157 S15-S26

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“…A recent report noted that a frameshift mutation in the ALS gene (IGFALS) in nucleotide positions 1334 through to 1338 in exon 2 led to a complete absence of circulating ALS in a child with severe pubertal delay but only a modest degree of growth failure (8). Another study reported a point mutation in IGFALS at nucleotide position 1318 in a child presenting with short stature and relatively mild pubertal delay (9,10). Three other children, two with pubertal delay and one with significant short stature, have been reported in a family with novel compound heterozygous mutations in exon 2 of IGFALS (11).…”

Section: Introductionmentioning

confidence: 99%

Constitutional delay of growth and puberty is not commonly associated with mutations in the acid labile subunit gene.

Banerjee

Hanson

Perveen

et al. 2008

European Journal of Endocrinology

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Objectives: Constitutional delay of growth and puberty (CDGP) is a common clinical condition that may be inherited as an autosomal dominant, recessive or X-linked trait. However, single-gene defects underlying CDGP have not yet been identified. A small number of children (to date 10) with modest growth failure and in the majority delayed puberty, a phenotype similar to that of CDGP, have been reported to carry mutations in the IGF acid labile subunit (IGFALS) gene which encodes the ALS, a part of the ternary complex carrying IGF-I in the circulation. The aim of our study was to screen a wellcharacterised CDGP cohort exhibiting a range of growth retardation and pubertal delay for pathogenic sequence variants in IGFALS. Design and methods: We used denaturing high performance liquid chromatography (dHPLC) to screen for IGFALS mutations in DNA samples from 90 children (80 males) with CDGP of predominantly White European origin. DNA fragments generating abnormal waveforms were directly sequenced. Results: No IGFALS mutation was identified in the coding sequences or exon-intron boundaries in our CDGP cohort. One abnormal waveform pattern in dHPLC in 15 children with CDGP was found to represent a recognised synonymous single-nucleotide polymorphism of the coding transcript in the second exon in residue 210 of IGFALS. Conclusions: IGFALS sequence variants are unlikely to be a common association with pubertal delay in children with CDGP.

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Total Absence of Functional Acid Labile Subunit, Resulting in Severe Insulin-Like Growth Factor Deficiency and Moderate Growth Failure

Cited by 86 publications

References 22 publications

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

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

Genetic disorders in the GH–IGF-I axis in mouse and man

Constitutional delay of growth and puberty is not commonly associated with mutations in the acid labile subunit gene.

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