Connexin 26 (GJB2) mutation in an Argentinean patient with keratitis-ichthyosis-deafness (KID) syndrome: a case report

Abstract

Background: Keratitis-Ichthyosis-Deafness (KID) syndrome is a rare condition characterized by pre-lingual sensorineural deafness with skin hyperkeratinization. The primary cause of the disease is a loss-of-function mutation in the GJB2 gene. Mutations in Argentinean patients have not been described.

Case presentation: We studied a 2 year-old boy with bilateral congenital sensorineural deafness with dry skin over the entire body, hypotrichosis of the scalp, thin and light-blond hair. Analysis of the GJB2 gene nucleotide sequence revealed the substitution of guanine-148 by adenine predicted to result in an Asp50Asn amino acid substitution.

Conclusion: This is the first KID report in a patient from Argentina. This de novo mutation proved to be the cause of keratitis-ichthyosis-deafness syndrome (KID-syndrome) in the patient, and has implications in medical genetic practice.

Keywords: Connexin; Deafness; GJB2; KID syndrome; Mutations; p.Asp50Asn.

Fig. 1

Illustration and audiometry of KID Argentinean case. a Audioprofile of the patient after cochlear implantation showing good outcome. b The scalp hair was thin, sparse and light-blond. He had aged facial appearance and hypotrichosis

Fig. 2

Genetic testing. a Chromatogram of the patient’s GJB2 sequence shows an G → A transition (c.G148A), predicting a of Asn by Asp substitution in codon 50 (p.Asp50Asn). Upper diagram shows the wild type sequence and lower image the mutated version in the patient. b Patient’s family pedigree. c Schematic diagram of connexin 26 protein in the plasma membrane. Red circle marks the position of detected mutation which is localized in the E1 extracellular domain. IC: intracellular domain, TM: transmembrane domain, EC: extracellular domain

Fig. 3

Connexin alignment. The Cx26 sequences from different species were aligned using the Mega5 program, in order to investigate the evolutionary conservation of the aspartic residue located in codon. The multiple alignments revealed a total conservation of this residue across all species, suggesting that this residue is crucial for the protein functionality

Fig. 4

Modeling of the Asp50Asn mutant (D50N). In order simplify the figure the one letter nomenclature was used for amino acids. The figure was obtained using the software VMD. a and b show the location of D50 (red) in the structure of the channel. c shows the theoretical structural model of the D50N mutant. The direct contact interactions on a radial distribution of 5 Å for each mutant are shown in the corresponding panels. D50 makes contacts with D46, A49 and S183 of the same chain, and Q48, K61 and N62 of a contiguous chain. This residue is located in an internal region of the channel enriched in acidic residues (D46 and E47) balanced with basic residues (R184, K61, and K188). The mutation D50N decreases the negative charge of this environment as well as alters the core of the inter-protomer interactions. The theoretical model shows that the D50N mutation breaks a salt bridge that exists between D50 and K61 and produces a hydrogen bond between the side chain of N50 and D46