Palmoplantar keratoderma with deafness phenotypic variability in a patient with an inherited GJB2 frameshift variant and novel missense variant. Issue 2 (14th January 2021)

• Record Type: Journal Article
• Authors: Bedoukian, Emma C.; Rentas, Stefan; Skraban, Cara; Shao, Qing; Treat, James; Laird, Dale W.; Sullivan, Kathleen E.
• Is Part Of: Molecular genetics & genomic medicine. Volume 9:Issue 2(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-01-14
• Subjects: connexin‐26 -- Cx26 -- deafness -- gap junction -- palmoplantar keratoderma; Medical genetics -- Periodicals; Genomics -- Periodicals; 616.042
• DOI: 10.1002/mgg3.1574
• Languages: English
• ISSNs: 2324-9269

Abstract

Abstract: Background: Variants in the GJB2 gene encoding the gap junction protein connexin‐26 (Cx26) can cause autosomal recessive nonsyndromic hearing loss or a variety of phenotypically variable autosomal dominant disorders that effect skin and hearing, such as palmoplantar keratoderma (PPK) with deafness and keratitis–ichthyosis–deafness (KID) syndrome. Here, we report a patient with chronic mucocutaneous candidiasis, hyperkeratosis with resorption of the finger tips, profound bilateral sensorineural hearing loss, and normal hair and ocular examination. Exome analysis identified a novel missense variant in GJB2 (NM_004004.5:c.101T>A, p.Met34Lys) that was inherited from a mosaic unaffected parent in the setting of a well‐reported GJB2 loss of function variant (NM_004004.5:c.35delG, p.Gly12Valfs*2) on the other allele. Method: Rat epidermal keratinocytes were transfected with cDNA encoding wildtype Cx26 and/or the Met34Lys mutant of Cx26. Fixed cells were immunolabeled in order to assess the subcellular location of the Cx26 mutant and cell images were captured. Results: Expression in rat epidermal keratinocytes revealed that the Met34Lys mutant was retained in the endoplasmic reticulum, unlike wildtype Cx26, and failed to reach the plasma membrane to form gap junctions. Additionally, the Met34Lys mutant acted dominantly to wildtype Cx26, restricting its delivery to the cell surface. Conclusion: Overall, we show the p.Met34Lys variant is a novel dominant acting variant causing PPK with deafness. The presence of a loss a function variant on the other allele creates a more severe clinical phenotype, with some features reminiscent of KID syndrome. Abstract : This is a case report about PPK with deafness due to a novel GJB2 variant in trans to a truncating variant. The pathogenicity of the variant was studied beyond correspondence to the patient phenotype by expressing it in rat epidermal keratinocytes and showing failure to form a gap junction channel in the plasma membrane. Our findings also provide evidence that variants causing PPK, when paired with a truncating variant on the other allele, may result in an expanded and more severe phenotypic presentation.