Cargando…

Palmoplantar keratoderma with deafness phenotypic variability in a patient with an inherited GJB2 frameshift variant and novel missense variant

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 a...

Descripción completa

Detalles Bibliográficos
Autores principales: Bedoukian, Emma C., Rentas, Stefan, Skraban, Cara, Shao, Qing, Treat, James, Laird, Dale W., Sullivan, Kathleen E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8077155/
https://www.ncbi.nlm.nih.gov/pubmed/33443819
http://dx.doi.org/10.1002/mgg3.1574
_version_ 1783684829417570304
author Bedoukian, Emma C.
Rentas, Stefan
Skraban, Cara
Shao, Qing
Treat, James
Laird, Dale W.
Sullivan, Kathleen E.
author_facet Bedoukian, Emma C.
Rentas, Stefan
Skraban, Cara
Shao, Qing
Treat, James
Laird, Dale W.
Sullivan, Kathleen E.
author_sort Bedoukian, Emma C.
collection PubMed
description 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.
format Online
Article
Text
id pubmed-8077155
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher John Wiley and Sons Inc.
record_format MEDLINE/PubMed
spelling pubmed-80771552021-04-29 Palmoplantar keratoderma with deafness phenotypic variability in a patient with an inherited GJB2 frameshift variant and novel missense variant Bedoukian, Emma C. Rentas, Stefan Skraban, Cara Shao, Qing Treat, James Laird, Dale W. Sullivan, Kathleen E. Mol Genet Genomic Med Clinical Reports 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. John Wiley and Sons Inc. 2021-01-14 /pmc/articles/PMC8077155/ /pubmed/33443819 http://dx.doi.org/10.1002/mgg3.1574 Text en © 2021 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Clinical Reports
Bedoukian, Emma C.
Rentas, Stefan
Skraban, Cara
Shao, Qing
Treat, James
Laird, Dale W.
Sullivan, Kathleen E.
Palmoplantar keratoderma with deafness phenotypic variability in a patient with an inherited GJB2 frameshift variant and novel missense variant
title Palmoplantar keratoderma with deafness phenotypic variability in a patient with an inherited GJB2 frameshift variant and novel missense variant
title_full Palmoplantar keratoderma with deafness phenotypic variability in a patient with an inherited GJB2 frameshift variant and novel missense variant
title_fullStr Palmoplantar keratoderma with deafness phenotypic variability in a patient with an inherited GJB2 frameshift variant and novel missense variant
title_full_unstemmed Palmoplantar keratoderma with deafness phenotypic variability in a patient with an inherited GJB2 frameshift variant and novel missense variant
title_short Palmoplantar keratoderma with deafness phenotypic variability in a patient with an inherited GJB2 frameshift variant and novel missense variant
title_sort palmoplantar keratoderma with deafness phenotypic variability in a patient with an inherited gjb2 frameshift variant and novel missense variant
topic Clinical Reports
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8077155/
https://www.ncbi.nlm.nih.gov/pubmed/33443819
http://dx.doi.org/10.1002/mgg3.1574
work_keys_str_mv AT bedoukianemmac palmoplantarkeratodermawithdeafnessphenotypicvariabilityinapatientwithaninheritedgjb2frameshiftvariantandnovelmissensevariant
AT rentasstefan palmoplantarkeratodermawithdeafnessphenotypicvariabilityinapatientwithaninheritedgjb2frameshiftvariantandnovelmissensevariant
AT skrabancara palmoplantarkeratodermawithdeafnessphenotypicvariabilityinapatientwithaninheritedgjb2frameshiftvariantandnovelmissensevariant
AT shaoqing palmoplantarkeratodermawithdeafnessphenotypicvariabilityinapatientwithaninheritedgjb2frameshiftvariantandnovelmissensevariant
AT treatjames palmoplantarkeratodermawithdeafnessphenotypicvariabilityinapatientwithaninheritedgjb2frameshiftvariantandnovelmissensevariant
AT lairddalew palmoplantarkeratodermawithdeafnessphenotypicvariabilityinapatientwithaninheritedgjb2frameshiftvariantandnovelmissensevariant
AT sullivankathleene palmoplantarkeratodermawithdeafnessphenotypicvariabilityinapatientwithaninheritedgjb2frameshiftvariantandnovelmissensevariant