Skip to main content

Main menu

  • Home
  • Our journals
    • Clinical Medicine
    • Future Healthcare Journal
  • Subject collections
  • About the RCP
  • Contact us

Clinical Medicine Journal

  • ClinMed Home
  • Content
    • Current
    • Ahead of print
    • Archive
  • Author guidance
    • Instructions for authors
    • Submit online
  • About ClinMed
    • Scope
    • Editorial board
    • Policies
    • Information for reviewers
    • Advertising

User menu

  • Log in

Search

  • Advanced search
RCP Journals
Home
  • Log in
  • Home
  • Our journals
    • Clinical Medicine
    • Future Healthcare Journal
  • Subject collections
  • About the RCP
  • Contact us
Advanced

Clinical Medicine Journal

clinmedicine Logo
  • ClinMed Home
  • Content
    • Current
    • Ahead of print
    • Archive
  • Author guidance
    • Instructions for authors
    • Submit online
  • About ClinMed
    • Scope
    • Editorial board
    • Policies
    • Information for reviewers
    • Advertising

Molecular genetics of the skin: the implications of understanding

Colin S Munro
Download PDF
DOI: https://doi.org/10.7861/clinmedicine.9-6-591
Clin Med December 2009
Colin S Munro
Alan Lyell Centre for Dermatology, Southern General Hospital, Glasgow
Roles: Consultant dermatologist; professor of dermatology
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: colin.munro@clinmed.gla.ac.uk
  • Article
  • Info & Metrics
Loading

Building on the foundations of biochemical studies in the 1970 and 1980s, in the past two decades molecular genetics has progressed rapidly in elucidating single gene disorders and complex traits of skin. The challenge now is to apply this knowledge in prevention and treatment. In a brief review it is possible only to give examples.

Single gene disorders: blistering

Study of single gene disorders causing blistering has contributed to a detailed picture of epidermal growth and differentiation, as well as of its integrity. For example, ultrastructural and immunocytochemical studies found that the severe blistering disorder recessive dystrophic epidermolysis bullosa (RDEB) is caused by loss of the anchoring fibrils, composed of type VII collagen, which attach the basement membrane to the dermis.1,2 Molecular genetics then defined the different mutations in the COL7A1 gene which cause dominant as well as and recessive forms of EB.3 Subsequently defects in other components of the basement membrane and hemidesmosomes – such as laminin 332, α6β4 integrin, collagen XVII and plectin – were shown to be responsible for other neonatal blistering disorders.4 Similarly, the biological properties of keratin intermediate filaments were established biochemically and ultrastructurally,5,6 but molecular genetics demonstrated that defects in specific keratins in epidermis, appendages and mucosa are responsible for a wide range of phenotypes – blistering and hyperkeratosis, pigmentary and hair defects – which reflect not only the tissue and differentiation-specific distribution of the keratins,7 but also their non-structural properties. Blistering and hyperkeratotic phenotypes also result from defects in cell adhesion: directly in the case of desmosomal proteins or, with endoplasmic reticulum (ER) and Golgi calcium ATPase dysfunction in Darier and Hailey-Hailey disease, via abnormal membrane protein processing. Intriguingly, the widespread distribution of these ATPases contrasts with the cutaneous localisation of the disorders. For example SERCA2, defective in Darier disease, is the major cardiac ER calcium ATPase. Conversely, the association of some defects in plakoglobin and desmoplakin with arrhythmogenic cardiomyopathies reflect the broader importance of cell junctions.

These discoveries have implications for clinical care. RDEB produces lifelong skin and mucosal bullous disease, leading to contractures and strictures, disability and, by early adult life in a majority of cases, aggressive and often fatal squamous cell cancer. Better care for children with EB in the UK has been championed by the charity DEBRA (www.debra.org.uk), which has also been a major supporter of research. In prevention, prenatal diagnosis has spared many families a second affected child.8 Diagnostic techniques have paralleled better understanding, progressing from prenatal skin biopsy, to chorionic villus sampling for DNA analysis, and preimplantation genetic diagnosis. In treatment, cell and molecular therapy is tantalising. Approaches under investigation include restoration of collagen VII expression via transfected fibroblasts, bone-marrow transplantation, and grafting with genetically modified autologous epidermis.9–11 For other disorders caused by dominant dystrophic gene defects, knockdown of gene expression using small interfering RNAs (siRNA) offers a prospect of specific therapy.12 In disorders due to premature termination codons, agents promoting read-through may permit restoration of gene expression.13 Despite proof of principle for many of these approaches, practical delivery remains challenging.

Complex traits: inflammatory skin disease

Common inflammatory skin diseases for which there is a major genetic component include psoriasis, eczema, acne, alopecia areata and many others. For psoriasis and eczema, conventional mapping studies and genome-wide analysis have shown multiple susceptibility loci. The significance of all these loci is not yet understood, but the recent finding that polymorphisms in the interleukin 23 receptor and its ligand interleukin 12 influence susceptibility to psoriasis reflects evidence that biological therapy directed against these cytokines is effective.14,15 In the case of atopic eczema, a predisposition locus at the epidermal differentiation complex is due at least in part to common null mutations in the gene encoding the epidermal barrier protein filaggrin.16 Ten per cent of European subjects carry such mutations, which in the homozygous state cause ichthyosis vulgaris.17 In the heterozygous state they produce a threefold increased risk of not only atopic eczema, but also of other atopic disease, and are a marker for persistence of eczema into adult life.18 The relevance of epidermal defects to systemic atopic disease is even clearer in Netherton syndrome, in which absence of a serine protease inhibitor (LEKTI) in skin produces neonatal erythroderma and ichthyosis, but also severe cutaneous and respiratory atopy. These discoveries suggest new avenues for prevention and therapy of atopic disease.

Genetic predisposition to skin cancer

Study of the skin has also contributed to progress in cancer biology. Defects in the complex of proteins underlying different forms of xeroderma pigmentosum, trichothiodystrophy and Cockayne syndrome have provided opportunities to understand DNA repair.19 The human hedgehog signalling pathway has been dissected in part as a result of recognition of PATCH defects in Gorlin (naevoid basal cell carcinoma) syndrome.20 Other pathways relevant to skin cancer are diverse21; ranging from skin colour (see below), cyclin-dependent kinase inhibitor 2A (CDKN2A/p16INK4a) in familial melanoma, detoxifying cytochromes in basal cell carcinoma, to gap junction communication in keratitis, ichthyosis, deafness (KID) syndrome. In many other disorders, molecular defects leading to internal neoplasia are accessibly manifest in skin.22

Skin colour

Among the most critical genetic adaptations during human history have been those in genes regulating skin and hair colour. In European populations, there is evidence of positive selection for skin colour variants (for example those in the melanocortin 1 receptor (MC1R) which underlie the red hair/fair skin phenotype) probably because fair skin increases ultraviolet (UV)-dependent vitamin D synthesis in northern latitudes.23 Other skin colour genes include SLC24A5, TYR, and OCA2 and genome-wide analysis has identified more loci.24,25 Increased UV exposure is, however, also associated with increased skin cancer susceptibility, including melanoma, so it is not surprising that pigmentary loci also influence cancer risk.26–28 However, susceptibility may not be solely dependent on the pigmentary pathways.26

Summary

During recent decades, discoveries in genetic skin disease have produced insights into the biology of the skin, and in some cases permitted preventive prenatal diagnosis, but application of this knowledge in palliation or cure remains a tantalising prospect.

  • © 2009 Royal College of Physicians

References

  1. ↵
    1. Anton-Lamprecht I
    , Schnyder UW. Epidermolysis bullosa dystrophica dominans – a defect of the anchoring. Dermatologica 1973;147:289–98.doi:10.1007/BF00569978
    OpenUrlPubMed
  2. ↵
    1. Eady RA
    . Babes, blisters and basement membranes: from sticky molecules to bullosa. Clin Exp Dermatol 1987;12:161–70.doi:10.1111/j.1365-2230.1987.tb01886.x
    OpenUrlPubMed
  3. ↵
    1. Bruckner-Tuderman L
    . Hereditary skin diseases of anchoring fibrils. J Dermatol Sci 1999;20:122–33.doi:10.1016/S0923-1811(99)00018-3
    OpenUrlCrossRefPubMed
  4. ↵
    1. McGrath JA
    , Mellerio JE. Epidermolysis bullosa. Br J Hosp Med (Lond) 2006;67:188–91.
    OpenUrlPubMed
  5. ↵
    1. Sun TT
    , Eichner R, Nelson WG et al. Keratin classes: molecular markers for different types of epithelial differentiation. J Invest Dermatol 1983;81:109s–15s.
    OpenUrlCrossRefPubMed
  6. ↵
    1. Anton-Lamprecht I
    . Genetically induced abnormalities of epidermal differentiation and in ichthyoses and epidermolyses: pathogenesis, heterogeneity, manifestation, and prenatal diagnosis. J Invest Dermatol 1983;81:149s–56s.doi:10.1111/1523-1747.ep12540961
    OpenUrlCrossRefPubMed
  7. ↵
    1. Irvine AD
    . Inherited defects in keratins. Clin Dermatol 2005;23:6–14.doi:10.1016/j.clindermatol.2004.09.014
    OpenUrlCrossRefPubMed
  8. ↵
    1. Fassihi H
    , Eady RA, Mellerio JE et al. Prenatal diagnosis for severe inherited skin disorders: 25 years. Br J Dermatol 2006;154:106–13.doi:10.1111/j.1365-2133.2005.07012.x
    OpenUrlPubMed
  9. ↵
    1. Wong T
    , Gammon L, Liu L et al. Potential of fibroblast cell therapy for recessive dystrophic bullosa. J Invest Dermatol 2008;128:2179–89.doi:10.1038/jid.2008.78
    OpenUrlCrossRefPubMed
    1. Uitto J
    . Epidermolysis bullosa: prospects for cell-based therapies. J Invest Dermatol 2008;128:2140–2.doi:10.1038/jid.2008.216
    OpenUrlCrossRefPubMed
  10. ↵
    1. Ferrari S
    , Pellegrini G, Matsui T et al. Gene therapy in combination with tissue engineering to treat bullosa. Expert Opin Biol Ther 2006;6:367–78.doi:10.1517/14712598.6.4.367
    OpenUrlCrossRefPubMed
  11. ↵
    1. Leachman SA
    , Hickerson RP, Hull PR et al. Therapeutic siRNAs for dominant genetic skin disorders including congenita. J Dermatol Sci 2008;51:151–7.doi:10.1016/j.jdermsci.2008.04.003
    OpenUrlCrossRefPubMed
  12. ↵
    1. Kellermayer R
    . Translational readthrough induction of pathogenic nonsense. Eur J Med Genet 2006;49:445–50.doi:10.1016/j.ejmg.2006.04.003
    OpenUrlCrossRefPubMed
  13. ↵
    1. Capon F
    , Di Meglio P, Szaub J et al. Sequence variants in the genes for the interleukin-23 receptor (IL23R) ligand (IL12B) confer protection against psoriasis. Hum Genet 2007;122:201–6.doi:10.1007/s00439-007-0397-0
    OpenUrlCrossRefPubMed
  14. ↵
    1. Leonardi CL
    , Kimball AB, Papp KA et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet 2008;371:1665–74.doi:10.1016/S0140-6736(08)60725-4
    OpenUrlCrossRefPubMed
  15. ↵
    1. Palmer CN
    , Irvine AD, Terron-Kwiatkowski A et al. Common loss-of-function variants of the epidermal barrier protein major predisposing factor for atopic dermatitis. Nat Genet 2006;38:441–6.doi:10.1038/ng1767
    OpenUrlCrossRefPubMed
  16. ↵
    1. Smith FJ
    , Irvine AD, Terron-Kwiatkowski A et al. Loss-of-function mutations in the gene encoding filaggrin cause vulgaris. Nat Genet 2006;38:337–42.doi:10.1038/ng1743
    OpenUrlCrossRefPubMed
  17. ↵
    1. Barker JN
    , Palmer CN, Zhao Y et al. Null mutations in the filaggrin gene (FLG) determine major early-onset atopic dermatitis that persists into adulthood. J Invest Dermatol 2007;127:564–7.doi:10.1038/sj.jid.5700587
    OpenUrlCrossRefPubMed
  18. ↵
    1. Kraemer KH
    , Patronas NJ, Schiffmann R et al. Xeroderma pigmentosum, trichothiodystrophy and Cockayne syndrome: a genotype-phenotype relationship. Neuroscience 2007;145:1388–96.doi:10.1016/j.neuroscience.2006.12.020
    OpenUrlCrossRefPubMed
  19. ↵
    1. Quinn AG
    , Epstein E Jr.. Patched, hedgehog, and skin cancer. Methods Mol Biol 2003;222:85–95.doi:10.1385/1-59259-328-3:085
    OpenUrlPubMed
  20. ↵
    1. Healy E
    , Irvine AD, Lear JT, Munro CS. Diseases of the epidermis and appendages, skin pigmentation and skin cancer. In: Kumar D, Weatherall D (eds), Genomics and clinical medicine. Oxford: Oxford University Press, 2008:507–28.
  21. ↵
    1. Winship IM
    , Dudding TE. Lessons from the skin – cutaneous features of familial cancer. Lancet Oncol 2008;9:462–72.doi:10.1016/S1470-2045(08)70126-8
    OpenUrlCrossRefPubMed
  22. ↵
    1. Sabeti PC
    , Varilly P, Fry B et al. Genome-wide detection and characterization of positive selection in populations. Nature 2007;449:913–8.doi:10.1038/nature06250
    OpenUrlCrossRefPubMed
  23. ↵
    1. Lamason RL
    , Mohideen MA, Mest JR et al. SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish humans. Science 2005;310:1782–6.doi:10.1126/science.1116238
    OpenUrlAbstract/FREE Full Text
  24. ↵
    1. Sulem P
    , Gudbjartsson DF, Stacey SN et al. Genetic determinants of hair, eye and skin pigmentation in Europeans. Nat Genet 2007;39:1443–52.doi:10.1038/ng.2007.13
    OpenUrlCrossRefPubMed
  25. ↵
    1. Raimondi S
    , Sera F, Gandini S et al. MC1R variants, melanoma and red hair color phenotype: a meta-analysis. Int J Cancer 2008;122:2753–60.doi:10.1002/ijc.23396
    OpenUrlCrossRefPubMed
    1. Gudbjartsson DF
    , Sulem P, Stacey SN et al. ASIP and TYR pigmentation variants associate with cutaneous melanoma and cell carcinoma. Nat Genet 2008;40:886–91.doi:10.1038/ng.161
    OpenUrlCrossRefPubMed
  26. ↵
    1. Fernandez LP
    , Milne RL, Pita G et al. SLC45A2: a novel malignant melanoma-associated gene. Hum Mutat 2008;29:1161–7.doi:10.1002/humu.20804
    OpenUrlCrossRefPubMed
Back to top
Previous articleNext article

Article Tools

Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Citation Tools
Molecular genetics of the skin: the implications of understanding
Colin S Munro
Clinical Medicine Dec 2009, 9 (6) 591-592; DOI: 10.7861/clinmedicine.9-6-591

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Molecular genetics of the skin: the implications of understanding
Colin S Munro
Clinical Medicine Dec 2009, 9 (6) 591-592; DOI: 10.7861/clinmedicine.9-6-591
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Single gene disorders: blistering
    • Complex traits: inflammatory skin disease
    • Genetic predisposition to skin cancer
    • Skin colour
    • Summary
    • References
  • Info & Metrics

Related Articles

  • No related articles found.
  • PubMed
  • Google Scholar

Cited By...

  • No citing articles found.
  • Google Scholar

More in this TOC Section

  • Current key developments
  • Current key developments
  • Revitalising glucocorticoids for (rheumatoid) arthritis
Show more Current Key Developments

Similar Articles

Navigate this Journal

  • Journal Home
  • Current Issue
  • Ahead of Print
  • Archive

Related Links

  • ClinMed - Home
  • FHJ - Home
clinmedicine Footer Logo
  • Home
  • Journals
  • Contact us
  • Advertise
HighWire Press, Inc.

Follow Us:

  • Follow HighWire Origins on Twitter
  • Visit HighWire Origins on Facebook

Copyright © 2021 by the Royal College of Physicians