O'Toole, E. A.

Smith, F. J. D.

Wilson, N. J.

Zamiri, M.

English

Striate palmoplantar keratoderma (SPPK) (OMIM 148700) is an autosomal dominant genodermatosis characterized by linear hyperkeratosis of the volar aspects of the fingers extending onto the palm, associated with focal to diffuse hyperkeratosis of the soles.1 It is caused by heterozygous mutations in four different genes: desmoglein 1 (DSG1), desmoplakin (DSP), keratin 1 (KRT1) and keratin 16 (KRT16).1-4 We report three families, one Scottish, one English and one American, with autosomal dominant PPK, due to three previously unreported DSG1 mutations, where the presence of a striate pattern appears linked to the severity of the phenotype. This article is protected by copyright. All rights reserved.</p

University of Dundee Online Publications

                                                                    University of DundeeNovel mutations in desmoglein 1Zamiri, M.; Wilson, N. J.; O'Toole, E. A.; Smith, F. J. D.Published in:British Journal of DermatologyDOI:10.1111/bjd.17839Publication date:2019Document VersionPeer reviewed versionLink to publication in Discovery Research PortalCitation for published version (APA):Zamiri, M., Wilson, N. J., O'Toole, E. A., & Smith, F. J. D. (2019). Novel mutations in desmoglein 1: Focalpalmoplantar keratoderma in milder phenotypes. British Journal of Dermatology, 181(3), 618-620.https://doi.org/10.1111/bjd.17839General rightsCopyright and moral rights for the publications made accessible in Discovery Research Portal are retained by the authors and/or othercopyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated withthese rights. • Users may download and print one copy of any publication from Discovery Research Portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain. • You may freely distribute the URL identifying the publication in the public portal.Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Download date: 03. Sep. 2023Accepted ArticleDR MOZHEH  ZAMIRI (Orcid ID : 0000-0001-5152-0792) Article type      : Research Letter    NOVEL MUTATIONS IN DESMOGLEIN 1: FOCAL PALMOPLANTAR KERATODERMA IN MILDER PHENOTYPES   M. Zamiri1, N. J. Wilson2, E. A. O’Toole3, F. J. D. Smith2,4     1Alan Lyell Centre for Dermatology, Queen Elizabeth University Hospital, Glasgow, UK 2Dermatology and Genetic Medicine, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee, UK 3Centre for Cell Biology and Cutaneous Research Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK 4Pachyonychia Congenita Project, Holladay, Utah, USA Author for correspondence:  Dr Mozheh Zamiri Alan Lyell Centre for Dermatology Queen Elizabeth University Hospital 1345 Govan Road, Glasgow G51 4TF Tel: 0141 452 3257 Email: mozheh.zamiri@glasgow.ac.uk Running Title: Novel DSG1 mutations causing focal keratoderma Conflict of interest: None This is the peer reviewed version of the following article: "Novel mutations in desmoglein 1: Focal palmoplantar keratoderma in milder phenotypes", British Journal of Dermatology (2019) which has been published in final form at https://doi.org/10.1111/bjd.17839. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.This article is protected by copyright. All rights reserved. Accepted ArticleThis article is protected by copyright. All rights reserved. Key words: focal palmoplantar keratoderma, striate palmoplantar keratoderma, desmoglein 1, autosomal dominant  Funding: FJDS, NJW and MZ were supported by The Centre for Dermatology and Genetic Medicine at the University of Dundee, which is funded by a Wellcome Trust Strategic Award (098439/Z/12/Z), and FJDS and NJW were supported by a grant from the Pachyonychia Congenita Project (to F.J.D.S,  www.pachyonychia.org).   Dear Editor,   Striate palmoplantar keratoderma (SPPK) (OMIM 148700) is an autosomal dominant genodermatosis characterized by linear hyperkeratosis of the volar aspects of the fingers extending onto the palm, associated with focal to diffuse hyperkeratosis of the soles.1 It is caused by heterozygous mutations in four different genes: desmoglein 1 (DSG1), desmoplakin (DSP), keratin 1 (KRT1) and keratin 16 (KRT16).1-4  We report three families, one Scottish, one English and one American, with autosomal dominant PPK, due to three previously unreported DSG1 mutations, where the presence of a striate pattern appears linked to the severity of the phenotype.   Family 1 presented to their local dermatology services. Families 2-3 were identified through the International Pachyonychia Congenita Research Registry. All reported having PPK since early childhood, with a positive family history in all pedigrees. No affected individuals had any history of skin fragility, blistering, nail, hair or cardiac abnormalities. Plantar pain was not a significant reported feature other than for the proband in family 2, whose palmar disease was severe, associated with his work as a manual labourer.  In family 1, all affected members had mild focal keratoderma of the palms and soles except for the proband’s brother, the most severe case in the family, who had striate keratoderma of the digits and palms bilaterally with the most severe focal pattern of the soles (Fig. 1a & Supplementary File, Accepted ArticleThis article is protected by copyright. All rights reserved. S1, available from the author on direct request). In family 2, the proband, a 34 year-old male, had a striate pattern of severe hyperkeratosis affecting both palms with painful, multiple deep fissures over the distal palm and fingers, a diffuse hyperkeratosis of the soles affecting the weight bearing surfaces and a dominant family history (S1).  In family 3, the proband had a focal pattern of hyperkeratosis affecting the palms and soles (S1). A skin biopsy for histological assessment was declined by all patients.  Following written informed consent and ethical approval by a Western Institutional Review Board that complies with the Declaration of Helsinki, genomic DNA was extracted from peripheral blood leukocytes or from saliva collected in an Oragene DNA sample collection kit (DNA Genotek, Ontario, Canada).   Family 1 was initially screened for focal pattern PPK/pachyonychia congenita mutations by polymerase chain reaction (PCR) and direct DNA Sanger sequencing of the keratin genes KRT6A, KRT6B, KRT6C, KRT16 and KRT17, before proceeding to DSG1 gene screening.1 The coding region and intron/exon boundaries of DSG1 were amplified using primers specific to DSG1 (available on request). Purified PCR products were sequenced on an ABI 3730 Automated DNA sequencing machine (Foster City, CA). Families 2 and 3 were screened using a 9-gene panel, designed using Agilent SureSelect (at myGenomics, Alpharetta, USA), which included these 5 keratin genes, and DSG1, TRPV3, GJB6 and AAGAB, with pathogenic variants confirmed by Sanger sequencing. Variants were confirmed as pathogenic through sequencing unaffected and unaffected family members, and by reference to the in silico prediction tool, Mutation Taster. None of the variants were present on the database of Single Nucleotide Polymorphisms (dbSNP), 1000 Genome Project, NHLBI Exome Variant Server, Exome Aggregation Consortium (ExAC) or the Genome Aggregation Database (gnomAD).    A previously unreported 1 bp heterozygous deletion mutation in DSG1, c.376_376delT, leading to a frameshift and premature stop codon, p.Tyr126Thrfs*5 was identified in the proband of family 1 and in three additional affected family members; two unaffected family members were wildtype. The proband of family 2 had a previously unreported nonsense mutation, p.Trp303*; c.909G>A. The mutation was present in his affected mother but not in his unaffected father. Another Accepted ArticleThis article is protected by copyright. All rights reserved. previously unreported nonsense mutation was identified in the proband of family 3, p.Leu337*; c.1010T>G; no other family members were available for screening.  It is postulated that DSG1 mutations (frameshift or nonsense) causing SPPK result in haploinsufficiency through nonsense mediated mRNA decay due to premature termination codons.5 Multiple mutations in DSG1, frameshift and nonsense, and very recently a missense mutation have been described causing inherited PPK with variations in the clinical patterns of keratoderma noted.6,7 Although initially the majority of reported DSG1 mutations were associated with a striate pattern of hyperkeratosis, there is increasing evidence of non-striate patterns of keratoderma being present.6,8 This series raises the possibility that only the more severe DSG1 phenotypes are associated with a striate pattern and that DSG1 screening should be considered routinely in focal PPK, particularly those with no plantar pain.  Acknowledgements We would like to thank the patients and their family members for their cooperation in this study, and Holly Evans of Pachyonychia Congenita Project for her help with data preparation. This work was supported by the Centre for Dermatology and Genetic Medicine (DGEM), the Dystrophic Epidermolysis Bullosa Research Association and the Pachyonychia Congenita Project/ (www.pachyonychia.org).      Accepted ArticleThis article is protected by copyright. All rights reserved. References  1. Hunt DM, Rickman L, Whittock NV et al. Spectrum of dominant mutations in the desmosomal cadherin desmoglein 1, causing the skin disease striate palmoplantar keratoderma. Eur J Hum Genet 2001; 9: 197-203. 2. Armstrong DK, McKenna KE, Purkis PE et al. Haploinsufficiency of desmoplakin causes a striate subtype of palmoplantar keratoderma. Hum Mol Genet 1999; 8: 143-8. 3. Whittock NV, Smith FJ, Wan H et al. Frameshift mutation in the V2 domain of human keratin 1 results in striate palmoplantar keratoderma. J Invest Dermatol 2002; 118: 838-44. 4. Almutawa F, Thusaringam T, Watters K et al. Pachyonychia congenita (K16) with unusual features and good response to acitretin. Case Rep Dermatol 2015; 7: 220-6. 5. Cui Y, Hagan KW, Zhang S, Peltz SW. Identification and characterization of genes that are required for the accelerated degradation of mRNAs containing a premature translational termination codon. Genes Dev 1995; 9: 423-36. 6. Lovgren M.-L, McAleer MA, Irvine AD et al. Mutations in desmoglein 1 cause diverse inherited palmoplantar keratoderma phenotypes: implications for genetic screening. Br J Dermatol 2017; 176: 1345-1350. 7. Vodo D, O’Toole EA, Malchin N et al. Striate palmoplantar keratoderma resulting from a missense mutation in DSG1. Br J Dermatol 2018 doi: 10.1111/bjd.16320.  8. Keren H, Gergman R, Mizrachi M et al. Diffuse nonepidermolytic palmoplantar keratoderma caused by a recurrent nonsense mutation in DSG1. Arch Dermatol 2005; 141: 625-8.  Figure Legends:  Figure 1. (a) Pedigree of family 1 showing an autosomal dominant history of palmoplantar keratoderma. The arrow indicates the proband.    Accepted ArticleThis article is protected by copyright. All rights reserved.    

Novel mutations in desmoglein 1:Focal palmoplantar keratoderma in milder phenotypes

                                                                    University of DundeeNovel mutations in desmoglein 1Zamiri, M.; Wilson, N. J.; O'Toole, E. A.; Smith, F. J. D.Published in:British Journal of DermatologyDOI:10.1111/bjd.17839Publication date:2019Document VersionPeer reviewed versionLink to publication in Discovery Research PortalCitation for published version (APA):Zamiri, M., Wilson, N. J., O'Toole, E. A., & Smith, F. J. D. (2019). Novel mutations in desmoglein 1: Focalpalmoplantar keratoderma in milder phenotypes. British Journal of Dermatology, 181(3), 618-620.https://doi.org/10.1111/bjd.17839General rightsCopyright and moral rights for the publications made accessible in Discovery Research Portal are retained by the authors and/or othercopyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated withthese rights. • Users may download and print one copy of any publication from Discovery Research Portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain. • You may freely distribute the URL identifying the publication in the public portal.Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Download date: 23. Jan. 2021Accepted ArticleDR MOZHEH  ZAMIRI (Orcid ID : 0000-0001-5152-0792) Article type      : Research Letter    NOVEL MUTATIONS IN DESMOGLEIN 1: FOCAL PALMOPLANTAR KERATODERMA IN MILDER PHENOTYPES   M. Zamiri1, N. J. Wilson2, E. A. O’Toole3, F. J. D. Smith2,4     1Alan Lyell Centre for Dermatology, Queen Elizabeth University Hospital, Glasgow, UK 2Dermatology and Genetic Medicine, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee, UK 3Centre for Cell Biology and Cutaneous Research Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK 4Pachyonychia Congenita Project, Holladay, Utah, USA Author for correspondence:  Dr Mozheh Zamiri Alan Lyell Centre for Dermatology Queen Elizabeth University Hospital 1345 Govan Road, Glasgow G51 4TF Tel: 0141 452 3257 Email: mozheh.zamiri@glasgow.ac.uk Running Title: Novel DSG1 mutations causing focal keratoderma Conflict of interest: None This is the peer reviewed version of the following article: "Novel mutations in desmoglein 1: Focal palmoplantar keratoderma in milder phenotypes", British Journal of Dermatology (2019) which has been published in final form at https://doi.org/10.1111/bjd.17839. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.This article is protected by copyright. All rights reserved. Accepted ArticleThis article is protected by copyright. All rights reserved. Key words: focal palmoplantar keratoderma, striate palmoplantar keratoderma, desmoglein 1, autosomal dominant  Funding: FJDS, NJW and MZ were supported by The Centre for Dermatology and Genetic Medicine at the University of Dundee, which is funded by a Wellcome Trust Strategic Award (098439/Z/12/Z), and FJDS and NJW were supported by a grant from the Pachyonychia Congenita Project (to F.J.D.S,  www.pachyonychia.org).   Dear Editor,   Striate palmoplantar keratoderma (SPPK) (OMIM 148700) is an autosomal dominant genodermatosis characterized by linear hyperkeratosis of the volar aspects of the fingers extending onto the palm, associated with focal to diffuse hyperkeratosis of the soles.1 It is caused by heterozygous mutations in four different genes: desmoglein 1 (DSG1), desmoplakin (DSP), keratin 1 (KRT1) and keratin 16 (KRT16).1-4  We report three families, one Scottish, one English and one American, with autosomal dominant PPK, due to three previously unreported DSG1 mutations, where the presence of a striate pattern appears linked to the severity of the phenotype.   Family 1 presented to their local dermatology services. Families 2-3 were identified through the International Pachyonychia Congenita Research Registry. All reported having PPK since early childhood, with a positive family history in all pedigrees. No affected individuals had any history of skin fragility, blistering, nail, hair or cardiac abnormalities. Plantar pain was not a significant reported feature other than for the proband in family 2, whose palmar disease was severe, associated with his work as a manual labourer.  In family 1, all affected members had mild focal keratoderma of the palms and soles except for the proband’s brother, the most severe case in the family, who had striate keratoderma of the digits and palms bilaterally with the most severe focal pattern of the soles (Fig. 1a & Supplementary File, Accepted ArticleThis article is protected by copyright. All rights reserved. S1, available from the author on direct request). In family 2, the proband, a 34 year-old male, had a striate pattern of severe hyperkeratosis affecting both palms with painful, multiple deep fissures over the distal palm and fingers, a diffuse hyperkeratosis of the soles affecting the weight bearing surfaces and a dominant family history (S1).  In family 3, the proband had a focal pattern of hyperkeratosis affecting the palms and soles (S1). A skin biopsy for histological assessment was declined by all patients.  Following written informed consent and ethical approval by a Western Institutional Review Board that complies with the Declaration of Helsinki, genomic DNA was extracted from peripheral blood leukocytes or from saliva collected in an Oragene DNA sample collection kit (DNA Genotek, Ontario, Canada).   Family 1 was initially screened for focal pattern PPK/pachyonychia congenita mutations by polymerase chain reaction (PCR) and direct DNA Sanger sequencing of the keratin genes KRT6A, KRT6B, KRT6C, KRT16 and KRT17, before proceeding to DSG1 gene screening.1 The coding region and intron/exon boundaries of DSG1 were amplified using primers specific to DSG1 (available on request). Purified PCR products were sequenced on an ABI 3730 Automated DNA sequencing machine (Foster City, CA). Families 2 and 3 were screened using a 9-gene panel, designed using Agilent SureSelect (at myGenomics, Alpharetta, USA), which included these 5 keratin genes, and DSG1, TRPV3, GJB6 and AAGAB, with pathogenic variants confirmed by Sanger sequencing. Variants were confirmed as pathogenic through sequencing unaffected and unaffected family members, and by reference to the in silico prediction tool, Mutation Taster. None of the variants were present on the database of Single Nucleotide Polymorphisms (dbSNP), 1000 Genome Project, NHLBI Exome Variant Server, Exome Aggregation Consortium (ExAC) or the Genome Aggregation Database (gnomAD).    A previously unreported 1 bp heterozygous deletion mutation in DSG1, c.376_376delT, leading to a frameshift and premature stop codon, p.Tyr126Thrfs*5 was identified in the proband of family 1 and in three additional affected family members; two unaffected family members were wildtype. The proband of family 2 had a previously unreported nonsense mutation, p.Trp303*; c.909G>A. The mutation was present in his affected mother but not in his unaffected father. Another Accepted ArticleThis article is protected by copyright. All rights reserved. previously unreported nonsense mutation was identified in the proband of family 3, p.Leu337*; c.1010T>G; no other family members were available for screening.  It is postulated that DSG1 mutations (frameshift or nonsense) causing SPPK result in haploinsufficiency through nonsense mediated mRNA decay due to premature termination codons.5 Multiple mutations in DSG1, frameshift and nonsense, and very recently a missense mutation have been described causing inherited PPK with variations in the clinical patterns of keratoderma noted.6,7 Although initially the majority of reported DSG1 mutations were associated with a striate pattern of hyperkeratosis, there is increasing evidence of non-striate patterns of keratoderma being present.6,8 This series raises the possibility that only the more severe DSG1 phenotypes are associated with a striate pattern and that DSG1 screening should be considered routinely in focal PPK, particularly those with no plantar pain.  Acknowledgements We would like to thank the patients and their family members for their cooperation in this study, and Holly Evans of Pachyonychia Congenita Project for her help with data preparation. This work was supported by the Centre for Dermatology and Genetic Medicine (DGEM), the Dystrophic Epidermolysis Bullosa Research Association and the Pachyonychia Congenita Project/ (www.pachyonychia.org).      Accepted ArticleThis article is protected by copyright. All rights reserved. References  1. Hunt DM, Rickman L, Whittock NV et al. Spectrum of dominant mutations in the desmosomal cadherin desmoglein 1, causing the skin disease striate palmoplantar keratoderma. Eur J Hum Genet 2001; 9: 197-203. 2. Armstrong DK, McKenna KE, Purkis PE et al. Haploinsufficiency of desmoplakin causes a striate subtype of palmoplantar keratoderma. Hum Mol Genet 1999; 8: 143-8. 3. Whittock NV, Smith FJ, Wan H et al. Frameshift mutation in the V2 domain of human keratin 1 results in striate palmoplantar keratoderma. J Invest Dermatol 2002; 118: 838-44. 4. Almutawa F, Thusaringam T, Watters K et al. Pachyonychia congenita (K16) with unusual features and good response to acitretin. Case Rep Dermatol 2015; 7: 220-6. 5. Cui Y, Hagan KW, Zhang S, Peltz SW. Identification and characterization of genes that are required for the accelerated degradation of mRNAs containing a premature translational termination codon. Genes Dev 1995; 9: 423-36. 6. Lovgren M.-L, McAleer MA, Irvine AD et al. Mutations in desmoglein 1 cause diverse inherited palmoplantar keratoderma phenotypes: implications for genetic screening. Br J Dermatol 2017; 176: 1345-1350. 7. Vodo D, O’Toole EA, Malchin N et al. Striate palmoplantar keratoderma resulting from a missense mutation in DSG1. Br J Dermatol 2018 doi: 10.1111/bjd.16320.  8. Keren H, Gergman R, Mizrachi M et al. Diffuse nonepidermolytic palmoplantar keratoderma caused by a recurrent nonsense mutation in DSG1. Arch Dermatol 2005; 141: 625-8.  Figure Legends:  Figure 1. (a) Pedigree of family 1 showing an autosomal dominant history of palmoplantar keratoderma. The arrow indicates the proband.    Accepted ArticleThis article is protected by copyright. All rights reserved.    

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Novel mutations in desmoglein 1:Focal palmoplantar keratoderma in milder phenotypes

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