Expanding The Phenotypic Spectrum of Cx26 Disorders: Bart–Pumphrey Syndrome is Caused by a Novel Missense Mutation in GJB2 Gabriele Richard, Nkecha Brown,

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Expanding The Phenotypic Spectrum of Cx26 Disorders: Bart–Pumphrey Syndrome is Caused by a Novel Missense Mutation in GJB2 Gabriele Richard, Nkecha Brown, Akemi Ishida-Yamamoto, Alfons Krol Journal of Investigative Dermatology Volume 123, Issue 5, Pages 856-863 (November 2004) DOI: 10.1111/j.0022-202X.2004.23470.x Copyright © 2004 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Mutation analysis and sequence conservation. (a) Top: pedigree of the Bart–Pumphrey syndrome (BPS) family demonstrating the intrafamilial variability. The clinical features of affected individuals are listed below the standard symbols. HL, hearing loss; PPK, palmoplantar keratoderma; KP, knuckle pads; L, leukonychia. The arrow indicates that the proband, participating family members are labeled by asterisks. Bottom: sequence chromatograms of GJB2 from affected (II-1 and III-1) and unaffected (II-2) family members depicting the heterozygous transversion 162C→A (arrow) at codon 54 encoding lysine instead of asparagine (N54K). (b) Amino acid sequence alignment of all 20 human connexins and 9 different mammalian Cx26 homologues across the first extracellular loop. The gray box highlights evolutionary conservation of asparagine 54 in Cx26 and its homologues. Other dominant GJB2 mutations and their phenotypes are shown atop the alignment. Red: Bart–Pumphrey syndrome; blue: Keratitis–Ichthyosis–Deafness syndrome; Green: Palmoplantar keratoderma and deafness; black: non-syndromic sensorineural hearing loss. Journal of Investigative Dermatology 2004 123, 856-863DOI: (10.1111/j.0022-202X.2004.23470.x) Copyright © 2004 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Clinical features of Bart–Pumphrey syndrome (BPS). (a) III-1. 24-y-old man with leukonychia, hyperkeratotic, verruciform plaques over metacarpo- and interphalangeal joints (knuckle pads) and (b) diffuse palmoplantar keratoderma with formation of hard, keratotic bands in the interphalangeal folds. (c) II-1. 58-y-old mother of III-1. Note the rough, grainy surface of the plantar keratoderma and (d) the lack of knuckle pads and very discrete leukonychia of the right hand. (e). Photomicrograph of a skin biopsy of a knuckle pad (H&E stain) shows compact orthokeratotic hyperkeratosis, hypergranulosis, and acanthosis of the epidermis. (f) Transmission electron micrograph demonstrating a normal-appearing gap junction plaque between granular keratinocytes. Journal of Investigative Dermatology 2004 123, 856-863DOI: (10.1111/j.0022-202X.2004.23470.x) Copyright © 2004 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Immunostaining of Cx26, Cx30, and Cx43 in lesional palmar and knuckle skin of III-1. (a) Complete absence of Cx26 staining (green) in knuckle skin and (d) very weak staining in the spinous layers of palmar epidermis indicated by arrows but (e) normal punctate staining in epithelial cells of the sweat ducts. (b) In contrast, Cx30 (red) is widely distributed throughout the granular and spinous layers. (c) Normal expression of Cx43 (red) throughout the epidermis. Note that all connexins show the typical punctate pattern outlining the cell membranes, suggestive for gap junction plaques. (f) Extensive co-localization of Cx26 and Cx30 in the sweat ducts. (g) Normal-appearing expression of Cx26 by the epithelium of an eccrine sweat duct with punctate staining of the plasma membranes. Note the focal co-localization of Cx26 with Cx43 limited to suprabasal keratinocytes surrounding the sweat duct. D, dermis; E, epidermis; sd, sweat duct; sg, sweat gland. Scale bar=160 μm (a), 80 μm (b, c), 40 μm (d), 30 μm (e, f), and 60 μm (g). Journal of Investigative Dermatology 2004 123, 856-863DOI: (10.1111/j.0022-202X.2004.23470.x) Copyright © 2004 The Society for Investigative Dermatology, Inc Terms and Conditions