GJB2 mutations in keratitis‐ichthyosis‐deafness syndrome including its fatal form

Abstract

Keratitis-ichthyosis-deafness syndrome (KID; MIM 148210) is a rare congenital disorder characterized by vascularizing keratitis, sensorineural hearing loss (HL), and progressive erythrokeratoderma. Clinical variability including a fatal course of KID in the first year of life has been reported. Germline missense mutations in GJB2, encoding connexin-26, were recently found to cause KID in 14 unrelated juvenile and adult patients. We identified a de novo GJB2 mutation G45E in a patient displaying the fatal form of the disease. No mutations were detected in five other connexin and mitochondrial genes. The G45E mutation was not reported previously in Caucasian patients but was the third most common GJB2 mutation (16% of disease alleles) in Japanese patients with autosomal recessive non-syndromic HL. This finding suggests different modes of action of the same GJB2 mutation depending on the genetic background. This hypothesis was further substantiated by our observation of a variable clinical course in unrelated KID patients from Austria harboring the common D50N mutation in GJB2.

Aberrant hemichannel properties of Cx26 mutations causing skin disease and deafness

“…While the rare fatal form of KIDS has been associated with Cx26-G45E in two unrelated Caucasian patients (14,17,21), it has also been linked to recessive nonsyndromic deafness in some Asian populations. In a large study of Japanese patients with nonsyndromic SNHL, G45E was detected in 16% of the GJB2 disease alleles (26).…”

“…Here, we report the functional characteristics of a Cx26 mutation (G45E) that was observed in two previously described infants with a rare fatal form of KIDS. The children harboring the G45E mutation in GJB2 had congenital deafness, hyper-keratosis of the skin, and recurrent severe skin infections, which eventually lead to septicemia and death within the first year of life (14,17,21). Using an in vitro expression assay, we show that Cx26-G45E hemichannels display a significant increase in membrane current flow that results in cell death.…”

Erythrokeratoderma Variabilis Caused by p.Gly45Glu in Connexin 31: Importance of the First Extracellular Loop Glycine Residue for Gap Junction Function

“…In that study, we showed that gap junctions containing p.Gly45Glu-mutant-Cx26 displayed aberrant gating activity (7). Indeed, the same heterozygous de novo p.Gly45Glu mutation in GJB2 has been previously reported to underlie a severe form of KID syndrome in an Austrian patient (8). Both these cases died from KID syndrome.…”

Bilateral limbal stem cell deficiency with chromosomal translocation of 3p and 9p

“…However, the present case is not consistent with KID syndrome for a number of reasons: (1) it did not show any dermal diseases; (2) pituitary dwarfi sm is not a complication of KID disease; and (3) KID syndrome is caused by the GJB2 gene, which encodes Connexin 26 and maps to 13q11-12. 1 Although the etiology of this case is unknown, we speculate that a chromosomal translocation t(3;9)(p27;p13) may have induced partial ectodermal dysplasia, including LSCD.…”

“…[1][2][3] Most IOFBs require surgical extraction because if the IOFB remains in the globe it may cause secondary damage to both the eyeball and vision. 4,5 However, some inert IOFBs such as fragments of glass, china, gold, and sand may be left alone if they are stationary and out of the visual axis.…”