Crucial role of posttranslational modifications of integrin  3 in interstitial lung disease and nephrotic syndrome

Abstract

Interstitial lung disease, nephrotic syndrome and junctional epidermolysis bullosa is an autosomal recessive multiorgan disorder caused by mutations in the gene for the integrin α3 subunit (ITGA3). The full spectrum of manifestations and genotype-phenotype correlations is still poorly characterized. Here, we uncovered the disease-causing role and the molecular mechanisms underlying a homozygous ITGA3 mutation leading to the single amino acid substitution, p.R463W. The patient suffered from respiratory distress and episodes of cyanosis with onset in the first week of life and had a nephrotic syndrome. Although there was no clinical evidence for cutaneous fragility, the analysis of a skin sample and of skin epithelial cells enabled the direct assessment of the authentic mutant protein. We show that the mutation altered the conformation of the extracellular β-propeller domain of the integrin α3 subunit preventing correct processing of N-linked oligosaccharides, heterodimerization with β1 integrin and maturation through cleavage into heavy and light chains in the Golgi. Confocal microscopy demonstrated that the mutant protein accumulated intracellularly, but it was not present in focal adhesions or on the cell membrane as shown by flow cytometry. These findings highlight that single amino acid changes in the integrin α3 subunit may crucially alter the structure and complex processing of this integrin, completely preventing its functionality. The present report also underscores that ITGA3 mutations may account for atypical cases solely with early onset respiratory and renal involvement.

Interstitial Lung Disease in Children Younger Than 2 Years

“…73,74 Loss-of-function mutations within the integrin α 3 (ITGA3) gene have been associated with a fatal recessive multiorgan disorder consisting of congenital nephrotic syndrome, early-onset ILD, and skin fragility. [75][76][77] Lung involvement was the primary cause of death in all cases, and lung biopsy revealed abnormal alveolarization, consistent with distorted morphogenesis. ITGA3 mutations are probably underrecognized, as both the full spectrum of clinical manifestations and genotypephenotype correlations are poorly characterized.…”

Inherited epidermolysis bullosa: New diagnostics and new clinical phenotypes

“…Skin involvement may include blistering, erosions, erythema, skin atrophy, nail dystrophies, or may be absent, or remain clinically unrecognized (Figure D). The following renal anomalies were reported: congenital nephrotic syndrome, focal‐segmental glomerulosclerosis, bilateral renal cysts and a spectrum of CAKUT, including renal hypodysplasia, unilateral kidney hypoplasia and ectopic conjoint kidney . Most affected individuals died within the first years of life.…”

“…The following renal anomalies were reported: congenital nephrotic syndrome, focal-segmental glomerulosclerosis, bilateral renal cysts and a spectrum of CAKUT, including renal hypodysplasia, unilateral kidney hypoplasia and ectopic conjoint kidney. [11,[32][33][34][35][36] Most affected individuals died within the first years of life. Recently, viable siblings presenting with growth retardation, severe pulmonary fibrosis and skin anomalies, but without renal features were described.…”

Renal-skin syndromes

“…The single amino acid substitution p.Arg463Trp prevents the correct processing of N-linked oligosaccharides and the maturation of α3 by cleavage into light and heavy chains in the Golgi. Consequently, mutant integrin α3 accumulates in the cells and is not targeted to the membrane (Yalcin et al 2015). The mutation p.Arg628Pro in the calf-1 domain of integrin α3 causes conformational perturbations of the calf-1 domain impairing the transport from the ER to the Golgi (Yamada and Sekiguchi 2013).…”