Gain-of-glycosylation mutations

Vogt, Guillaume; Vogt, B; Chuzhanova, Nadia; Julenius, Karin; Cooper, David Neil; Casanova, Jean‐Laurent

doi:10.1016/j.gde.2007.04.008

Cited by 65 publications

(59 citation statements)

References 65 publications

(55 reference statements)

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“…The repertoire of gain-of-glycosylation disorders is everexpanding, and gain-of-glycosylation mutations that disrupt integrin biosynthesis as the cause for a human disorder have previously been identified in the genes encoding integrin subunits β2 (causing leukocyte adhesion deficiency) and β3 (causing Glanzmann's thrombasthenia) (48)(49)(50). We now report a new gain-of-glycosylation mutation that prevents the biosynthesis of integrin α3β1, causing interstitial lung disease and congenital nephrotic syndrome.…”

Section: Figurementioning

confidence: 90%

Gain of glycosylation in integrin α3 causes lung disease and nephrotic syndrome

Nicolaou

Margadant

Kevelam³

et al. 2012

J. Clin. Invest.

112

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Integrins are transmembrane αβ glycoproteins that connect the extracellular matrix to the cytoskeleton. The laminin-binding integrin α3β1 is expressed at high levels in lung epithelium and in kidney podocytes. In podocytes, α3β1 associates with the tetraspanin CD151 to maintain a functional filtration barrier. Here, we report on a patient homozygous for a novel missense mutation in the human ITGA3 gene, causing fatal interstitial lung disease and congenital nephrotic syndrome. The mutation caused an alanine-to-serine substitution in the integrin α3 subunit, thereby introducing an N-glycosylation motif at amino acid position 349. We expressed this mutant form of ITGA3 in murine podocytes and found that hyperglycosylation of the α3 precursor prevented its heterodimerization with β1, whereas CD151 association with the α3 subunit occurred normally. Consequently, the β1 precursor accumulated in the ER, and the mutant α3 precursor was degraded by the ubiquitin-proteasome system. Thus, these findings uncover a gain-of-glycosylation mutation in ITGA3 that prevents the biosynthesis of functional α3β1, causing a fatal multiorgan disorder. IntroductionThe integrin family is comprised of 24 transmembrane heterodimeric αβ glycoproteins that link the extracellular matrix to the cytoskeleton (1). Most integrins connect to actin filaments and reside in cellular adhesion structures designated focal adhesions (FAs), which are highly enriched in tyrosine-phosphorylated proteins and serve as major hubs for signal transduction (2). Integrin-ligand binding can be controlled by conformational changes that tune integrin affinity (3). Furthermore, integrin function depends strongly on trafficking events, which include endocytosis, intracellular sorting and recycling, and delivery of de novo synthesized integrins to the plasma membrane by the biosynthetic route (4, 5). Both α and β subunits are synthesized as precursors. After N-linked glycosylation, folding, and association of the α and β subunits in the ER, the heterodimer is transported to the Golgi network, in which the N-linked high-mannose oligosaccharides are further processed into complex oligosaccharides. Subsequently, several of the α subunit precursors, including α3, are cleaved by proprotein convertases such as furin into a heavy and a light chain, which are held together by a disulphide bond to generate the mature form that is expressed at the plasma membrane (6, 7).A number of human congenital disorders have been associated with defective integrin-mediated adhesion, including the blistering disorder epidermolysis bullosa (integrin α6β4 in epithelia), the bleeding disorder Glanzmann's thrombasthenia (integrin αIIbβ3 on platelets), leukocyte adhesion deficiency-I (β2 integrins on leukocytes), and muscular dystrophy (integrin

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Section: Figurementioning

confidence: 90%

Gain of glycosylation in integrin α3 causes lung disease and nephrotic syndrome

Nicolaou

Margadant

Kevelam³

et al. 2012

J. Clin. Invest.

112

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“…There are 32 known gain of function N-glycosylation mutations that span a wide array of disease and have previously been reviewed (89). There are a few loss of function glycosylation mutations.…”

Section: N-glycosylation Sites-aberrant N-glycosylation Seems To Be Cmentioning

confidence: 99%

Viral infection and human disease - insights from minimotifs

Kadaveru¹

2008

Front Biosci

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Short functional peptide motifs cooperate in many molecular functions including protein interactions, protein trafficking, and posttranslational modifications. Viruses exploit these motifs as a principal mechanism for hijacking cells and many motifs are necessary for the viral life-cycle. A virus can accommodate many short motifs in its small genome size providing a plethora of ways for the virus to acquire host molecular machinery. Host enzymes that act on motifs such as kinases, proteases, and lipidation enzymes, as well as protein interaction domains, are commonly mutated in human disease, suggesting that the short peptide motif targets of these enzymes may also be mutated in disease; however, this is not observed. How can we explain why viruses have evolved to be so dependent on motifs, yet these motifs, in general do not seem to be as necessary for human viability? We propose that short motifs are used at the system level. This system architecture allows viruses to exploit a motif, whereas the viability of the host is not affected by mutation of a single motif.

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“…A number of such mutations have been identified and it is predicted that up to 1.4% of all known disease-causing missense mutations result in gains of glycosylation. 7,8 On the other hand, terminal variability in glycans is common (e.g., ABO blood groups) and contribute to the protein heterogeneity in a population that is advantageous for evading pathogens and adapting to changing environment. 9 Glycans display a much higher interspecies variability than proteins, [10][11][12] but glycome variability within a species has never been thoroughly examined.…”

Section: Introductionmentioning

confidence: 99%

Variability, Heritability and Environmental Determinants of Human Plasma N-Glycome

et al. 2008

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Plasma glycans were analyzed in 1008 individuals to evaluate variability and heritability, as well as the main environmental determinants that affect glycan structures. By combining HPLC analysis of fluorescently labeled glycans with sialidase digestion, glycans were separated into 33 chromatographic peaks and quantified. A high level of variability was observed with the median ratio of minimal to maximal values of 6.17 and significant age-and gender-specific differences. Heritability estimates for individual glycans varied widely, ranging from very low to very high. Glycome-wide environmental determinants were also detected with statistically significant effects of different variables including diet, smoking and cholesterol levels.

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Gain-of-glycosylation mutations

Cited by 65 publications

References 65 publications

Gain of glycosylation in integrin α3 causes lung disease and nephrotic syndrome

Gain of glycosylation in integrin α3 causes lung disease and nephrotic syndrome

Viral infection and human disease - insights from minimotifs

Variability, Heritability and Environmental Determinants of Human Plasma N-Glycome

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