Bad Connexins in the Skin: Can You Hear Me Now?

There are a handful of cornification disorders that are associated with sensorineural hearing loss (SNHL). Many of these conditions are now known to be caused by autosomal dominant mutations in the connexin gene, GJB2. GJB2 encodes for connexin 26 (Cx26), a critical component of the epidermal and inner ear gap junctions. Richard et al now describe another syndrome that appears to result from mutations in GJB2—Bart–Pumphrey Syndrome (BPS).

BPS is a rare autosomal dominant condition characterized by knuckle pads, leukonychia, palmoplantar keratoderma and deafness, all of which were found in the multigenerational Polish family analyzed in this study. Given the affinity of these phenotypes to other more established connexinopathies, the group performed mutational analysis of GJB2 and found a novel germline asparagines-54-lysine mutation. This mutation cosegregated with affected members of the family; furthermore, it was not detected in a cohort of 110 Northern European controls. In the Asn54Lys carriers, immunohistochemical analysis revealed reduced epidermal Cx26 expression but increased levels of another connexin, Cx30. These findings suggest that there is a certain amount of sibling rivalry within the connexin family of proteins within the epidermis.

At current count, there are now at least five conditions linked to GJB2 mutations—non-syndromic SNHL, SNHL associated with diffuse or transgradient palmoplantar keratoderma, Vohwinkel syndrome, keratitis-ichthyosis-deafness and BPS. Most of the associated mutations cluster in the first extracellular loop, known as E1, providing an elegant functional domain mapping experiment courtesy of nature's in vivo mutagenesis. A fascinating but yet unanswered aspect of connexin genetics is the pleiotropic manifestations of these mutations. It is conceivable that the clinical picture reflects a net sum of different effects in these distinct organ systems—such as mRNA stability, extent of functional compromise, and degree of compensation by other connexins. There is still much to be learned about the role of gap junctions in the skin—a full accounting of the documented defects is clearly a necessary first step.

When the Going Gets Rough...the Rough can't be Found

The study by Hayashi et al is reminiscent of a good Hollywood cliffhanger—the exposition and development lead you to an unanticipated climax only to leave you dangling at the dénouement.

The rough coat (rc) mouse is characterized by an unkempt disoriented appearance of the hair coat soon after birth followed by periods of shedding and regrowth. Histologically, the hair follicle is underdeveloped and underpigmented. Moreover, muscles of the heart and blood vessels show evidence of degeneration. Histological staining reveals a reduction in collagen and elastin in both the skin and heart of rc mice.

In an effort to explain the rc phenotype, Hayashi et al hypothesized that these defects may be related to dysfunction of the lysyl-oxidase like (LOXL) gene. Their initial analysis was quite supportive of LOXL being the causative rc gene. Mapping data co-localized both rc and LOXL to the same region on mouse chromosome 9. Both LOXL and LOX mRNA were reduced in the skin of rc mice along with its attendant amine oxidase activity. Immunostaining also showed reductions in LOXL protein levels in both the skin and heart of rc mice. Then the big question...where's the mutation?

Northern analysis did not show any major disruptions in the LOXL mRNA size while sequence analysis did not show any deleterious variants in the coding segments of LOXL. Most importantly, a cross between rc-/- and LOXL-/- successfully rescued the rc phenotype, suggesting that LOXL is not allelic to rc.

Much like the middle episodes of the Star Wars, Matrix or Lord of the Rings trilogies—in this study, we are left begging for more. The investigators do suggest several possible candidates from this mouse chromosomal region and clearly these genes are being actively investigated. Parallel refinements in mapping may allow these investigators to quickly exclude some rather large and cumbersome sequencing projects. Nevertheless, for those of us who enjoy a good gene hunt, we are all waiting with bated breath.