mutations in the three patients we describe were associated with a complex phenotype comprising congenital nephrotic syndrome, interstitial lung disease, and epidermolysis bullosa. The deletion mutation, which abolished integrin α3
, and the splice-site and missense mutations all led to similar clinical features. Both full knockout mouse models11,14
and organ-specific α3
support this conclusion.
knockout mice have defects in kidney and lung organogenesis and skin fragility, and they die within 24 hours after birth.11,14
Abnormal nephrogenesis, disorganized and widened glomerular basement membranes, and the absence of podocyte foot processes11
support the roles of integrin α3
during development, as well as in organization of the extracellular matrix, modulation of the actin cytoskeleton, and cell shape.3
Podocyte-specific integrin α3
knockout mice have massive postnatal proteinuria,12
as seen in our patients.
In the three patients, the lung findings were surprising and were not predicted by the animal models.11,13
In contrast to the severe clinical course and abnormal imaging findings, routine staining of lung-biopsy samples showed nonspecific changes. We speculate that the observed lung disease probably reflects the consequences of the basic genetic defect, since respiratory distress began in the first days of life, when severe abnormalities were already evident on chest radiography. Defects in bronchial development, as described in the integrin α3
knockout mouse model, were not documented. Surprisingly, mice with specific loss of integrin α3
in lung epithelial cells have no abnormalities of the alveolar architecture or respiratory function, but integrin α3
has been identified as a critical regulator of epithelial–mesenchymal transition and tissue remodeling in response to injury.13
We speculate that perturbed morphogenesis and abnormal functioning of the blood–air barrier accounted for reduced gas diffusion, resulting in respiratory failure in our patients.
Skin was mildly affected in our patients. Blisters and erosions began at the age of 2 to 4 months. Disorganization of the basement membrane diminished dermal–epidermal adhesion, and on exposure to external shearing stress, the basement membrane ruptured and blisters arose. The anomalies that are caused by loss of integrin α3
are unique and represent a new form of epidermolysis bullosa. In the context of the complex disorder, reepithelialization of the wounds was somewhat delayed in Patient 1, in contrast to the faster wound healing reported in keratinocyte-specific knockout mice.16,17
These three children with integrin α3
mutations had multiorgan involvement and survived the neonatal period. It is possible that the loss of integrin α3
has additional direct consequences (e.g., the involvement of the nervous system, since in the integrin α3
knockout mice the architecture of the cerebral cortex was perturbed, probably because of abnormal neuron–glia interactions during development).21,22
Taken together, this phenotype, consisting of congenital nephrotic syndrome, interstitial lung disease, and epidermolysis bullosa, reflects the developmental and postnatal pleiotropic functions of integrin α3
, showing that this integrin is indispensable for basement-membrane organization. The exquisite interdependence between the structural assembly of basement membranes and the modulation of the cytoskeleton in vivo is pivotal for adequate barrier functions in the kidney, lung, and skin. In contrast to in vitro systems, in which compensatory mechanisms have been described,17
these functions are insufficient in vivo.