ITGA3 – ILNEB Syndrome

Interstitial lung disease, nephrotic syndrome and junctional epidermolysis bullosa (ILNEB) is an autosomal recessive multisystem disorder caused by biallelic pathogenic variants in ITGA3 (HGNC:6139) and is catalogued as MONDO:0013881. Affected individuals present with early-onset respiratory distress, proteinuria progressing to nephrotic syndrome, and skin fragility due to defective basement membrane anchorage.

Genetic evidence supports a strong gene–disease relationship. At least twelve unrelated probands with homozygous or compound heterozygous ITGA3 variants have been described, including one adult survivor (PMID:34492382) and a neonatal-onset case undergoing renal transplantation (PMID:33470490). The most recurrent variant studied at the molecular level is c.1387C>T (p.Arg463Trp) in NM_002204.4, which has been shown to perturb integrin α3 glycosylation and heterodimerization.

Variant spectrum includes missense substitutions and likely loss-of-function alleles. The p.Arg463Trp change (c.1387C>T (p.Arg463Trp)) abolishes cleavage into heavy and light chains in the Golgi, prevents N-linked oligosaccharide processing, and blocks cell surface expression (PMID:25810266). Similarly, p.Arg628Pro disrupts posttranslational processing and CD151 association, leading to deficient ER-to-Golgi transport of α3β1 integrin (PMID:24220332).

Functional studies provide moderate experimental support. Patient-derived keratinocytes and heterologous cell lines expressing the R463W and R628P mutants show intracellular retention of α3β1, loss of focal adhesion localization, and impaired laminin binding, consistent with the human phenotype. No animal models have yet been reported.

Clinically, ILNEB patients typically succumb in infancy or early childhood due to progressive lung disease and nephrotic syndrome, although rare survivors have benefited from lung and kidney transplantation. Oral, nasal, and gynecological manifestations have been noted in adult survivors, expanding the phenotype.

Key Take-home: Biallelic ITGA3 variants cause ILNEB syndrome by disrupting integrin α3 processing and membrane expression; genetic testing enables early diagnosis and guides transplant-based management.

References

• European journal of medical genetics • 2021 • First patient with ILNEB syndrome due to pathogenic variants in ITGA3 surviving to adulthood. PMID:34492382
• Pediatric transplantation • 2021 • Successful kidney transplantation in a patient with neonatal-onset ILNEB. PMID:33470490
• Human molecular genetics • 2015 • Crucial role of posttranslational modifications of integrin α3 in interstitial lung disease and nephrotic syndrome PMID:25810266
• Biochemical and biophysical research communications • 2013 • Disease-associated single amino acid mutation in the calf-1 domain of integrin α3 leads to defects in its processing and cell surface expression PMID:24220332

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