Do cell junction protein mutations cause an airway phenotype in mice or humans?

Abstract

Cell junction proteins connect epithelial cells to each other and to the basement membrane. Genetic mutations of these proteins can cause alterations in some epithelia leading to varied phenotypes such as deafness, renal disease, skin disorders, and cancer. This review examines if genetic mutations in these proteins affect the function of lung airway epithelia. We review cell junction proteins with examples of disease mutation phenotypes in humans and in mouse knockout models. We also review which of these genes are expressed in airway epithelium by microarray expression profiling and immunocytochemistry. Last, we present a comprehensive literature review to find the lung phenotype when cell junction and adhesion genes are mutated or subject to targeted deletion. We found that in murine models, targeted deletion of cell junction and adhesion genes rarely result in a lung phenotype. Moreover, mutations in these genes in humans have no obvious lung phenotype. Our research suggests that simply because a cell junction or adhesion protein is expressed in an organ does not imply that it will exhibit a drastic phenotype when mutated. One explanation is that because a functioning lung is critical to survival, redundancy in the system is expected. Therefore mutations in a single gene might be compensated by a related function of a similar gene product. Further studies in human and animal models will help us understand the overlap in the function of cell junction gene products. Finally, it is possible that the human lung phenotype is subtle and has not yet been described.

Figure 1.

Diagram of cell junction proteins and their location. Representation of cell–cell junction (abbreviated as jx) proteins (tight junctions, adherens junctions, desmomsomal junctions, and gap junctions) and cell–matrix junction proteins (hemi-desmosomal junctions, focal adhesions, and integrins) between epithelia (ciliated and nonciliated).

Figure 2.

Representation of the two functions of the tight junction protein. (A) The tight junction can function as a gate by regulating paracellular transport between cells (demonstrated by red X). (B) The tight junction can also act as a fence, preventing apical cell membrane proteins from transporting to the basolateral surface and vice versa (demonstrated by red X).

Figure 3.

The tight junction regulating paracellular transport in health and disease. (A) In the cochlea, tight junctions of the cochlear membrane separate perilymph and endolymph, maintaining an endocochlear gradient necessary for hearing. The large font represents the ion in higher concentration, and the smaller font the ion in a smaller concentration. This is an example of a “tight” seal. (B) In the ascending loop of Henle in the kidney, the tight junction regulates the absorption of calcium and magnesium from the urine into the bloodstream. This is an example of a “leaky” seal. Mutations in claudin 16 prevent renal absorption of these ions, causing a buildup of calcium and magnesium in the urine that can lead to renal disease.

Figure 4.

Cell junction gene microarray analysis of in vivo and in vitro airway epithelia. (A) Tight junction proteins; (B) Adherens proteins; (C) Desmosomal, hemi-desmosomal, and focal adhesion proteins; (D) Integrin and gap junction proteins; *cell junction genes that exhibit a human phenotype when mutated

Figure 5.

Cell junction protein expression by organ system. Number of proteins expressed by immunochemistry based on Human Protein Atlas data (31). Nearly all of the proteins were expressed ubiquitously throughout multiple organ systems.

Figure 6.

Cell junction mutation phenotype in human organ systems. Cell junction mutations can exhibit a wide variety of phenotypes in multiple organ systems. Phenotypes in the skin, sensory organs, and cardiac system predominate. Surprisingly, there was no human lung phenotype found.