Submission Details

The ITGA3 gene is located on chromosome 17 at q21.33 and encodes the protein integrin alpha 3 which dimerizes with integrin beta 1 to form the α3β1 integrin duplex that functions as an adhesion molecule between the podocyte and glomerular basement membrane.

ITGA3 was first reported in relation to autosomal recessive 'interstitial lung disease, nephrotic syndrome, and epidermolysis bullosa, congenital' in 2012 (Has et al., PMID: 22512483, OMIM:614748). The mechanism of pathogenicity is known to be loss of function. Interstitial lung disease, nephrotic syndrome, and epidermolysis bullosa, congenital is characterized by significant protein loss in the urine, severe lung disease and/or blistering skin disease within the first months of life causing generalized edema, respiratory failure and/or skin/nail abnormalities.

At least 10 variants (frameshift, splice, missense) have been reported in 10 probands in 9 publications (PMIDs: 22512483, 23114595, 25810266, 26854491, 32198874, 34023363, 34751145, 33768705 included in this curation). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached, considering case-level data.

This gene-disease relationship is also supported by animal models, expression studies, in vitro functional assays, and rescue assays (PMIDs: 9211352, 30466509, 9151677, 8951069, 17015618, 19118220). In particular, ITGA3 knockout mice caused congenital epidermolysis bullosa-phenotype (PMID 9211352), abnormal nephrogenesis and abnormal lung morphogenesis (PMID 30466509). Transgenic mice with ITGA3 knockout isolated to the podocyte (2.5P-Cre; ITGA3fl /fl) developed nephrotic syndrome with severe proteinuria, focal segmental glomerulosclerosis and podocyte effacement (PMID 17015618). Transgenic mice with ITGA3 knockout isolated to the skin (K14-Cre; ITGA3fl /fl) developed severe skin defects recapitulating the epidermolysis bullosa-phenotype (PMID 19118220). In-vitro functional assays demonstrated increased fibronectin expression in skin, kidney and lung cells of a patient with ITGA3 mutation and interstitial lung disease, nephrotic syndrome, and epidermolysis bullosa, congenital (PMID 30466509). This was associated with an increased keratinocyte migratory phenotype (also seen in the K14-Cre; ITGA3fl /fl mouse), which could be rescued using by retroviral re-expression of ITGA3 (PMID 30466509). A total of 5.5/6 pts. for experimental evidence was reached.

In summary, there is definitive evidence supporting the relationship between ITGA3 and autosomal recessive interstitial lung disease, nephrotic syndrome, and epidermolysis bullosa, congenital. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.