Identification of the genetic basis of inherited keratin skin disorders leading to advances in diagnosis for patients.
Submitting InstitutionUniversity of Dundee
Unit of AssessmentBiological Sciences
Summary Impact TypeHealth
Research Subject Area(s)
Biological Sciences: Biochemistry and Cell Biology
Summary of the impact
Keratins are major cytoskeletal proteins of epithelial cells. Pioneering
research at the University of Dundee led by Prof Irwin McLean FRSE and
Prof Birgit Lane FRSE showed the association of keratin mutations with
genetic skin fragility disorders. This has dramatically changed the
diagnosis of inherited skin disorders and has directly translated into
improved clinical management of patients both in the UK and
internationally. Further work on this disease has resulted in the first
clinical trial using siRNA for a skin condition.
Epithelia are barrier tissues that protect the body from physical and
chemical damage, dehydration, infection and heat loss. The epidermis is
the largest of the epithelial tissues and forms the first line of defence
against the outside world. The function of the keratinocyte cells of the
epidermis is to maintain epidermal integrity and withstand the mechanical
and chemical forces that the skin is subjected to every day. Much of its
strength comes from a dense meshwork of cytoplasmic intermediate filaments
composed of keratin proteins.
Epidermolysis bullosa (EB) is an inherited disease causing blisters in
the skin and mucosal membrane caused by a defect in anchoring between the
epidermis and dermis which results in skin fragility. Its severity ranges
from mild to lethal. In the 1990's, Prof Irwin McLean FRSE FMedSci
(then Honorary Lecturer at the CRC Cell Structure Research Group, College
of Life Sciences from 1992-1996) and Prof Birgit Lane FRSE FMedSci
(then Professor of Anatomy and Cell Biology, College of Life Sciences from
1990-2009) used a combination of candidate gene analysis and genome-wide
genetic linkage analysis to show, for the first time, the linkage of
keratin gene mutations with several severe skin disorders. This work was
published in a succession of high impact publications (1-5). In 1993,
mutations in keratin 5 and 14 were implicated by the Dundee team in the
skin fragility syndrome Weber-Cockayne Epidermolysis Bullosa Simplex
(EBSWC), the mildest form of the EB keratinizing disorders (1). In 1995,
they then described a null mutation in keratin 14 that results in severe
epidermal blistering due the complete absence of keratin 14 expression
(2). Profs Lane and McLean also discovered mutations in keratins 1 and 10
in bullous congenital ichthyosiform erythroderma (epidermolytic
hyperkeratosis), an inherited condition that causes severe blistering and
thickening of the skin (3). In a further study, McLean and Lane discovered
a mutation in the gene for plectin, a cytoskeleton-membrane anchorage
protein and showed that the absence of plectin protein in skin and muscle
cells caused a combination of muscular dystrophy with epidermolysis
A further skin disease that has been transformed by the work of the
University of Dundee is pachyonychia congenita (PC). PC is an inherited
skin disorder characterised by thickened toenails, calluses, blistering,
thickened skin, and plantar pain. Plantar pain is the most important
feature of PC affecting quality of life, as it can severely limit
mobility. In 1995, a team involving McLean and Lane identified the first
causative mutations for this disease in keratin genes 16 and 17 (5).
Identification of pathogenic mutations in these genes, and the subsequent
discovery of additional mutations in keratins 6A and 6B, was pivotal in
establishing genetic testing as the key criteria for diagnosis of PC.
More recent work by McLean (appointed as Prof of Human Genetics at the
College of Life Sciences in 2008) has focused on the development of
therapeutic siRNAs for genetic disorders in a variety of cell and animal
models (6) and this has resulted in the first skin disease siRNA clinical
trial (for PC).
References to the research
1. Rugg, E.L., Morley, S.M., Smith, F.J., Boxer, M., Tidman, M.J.,
Navsaria, H., Leigh, I.M. and Lane, E.B. (1993) Missing links:
Weber-Cockayne keratin mutations implicate the L12 linker domain in
effective cytoskeleton function. Nat Genet. 5, 294-300.
(doi:10.1038/ng1193-294). (Citations 64, Scopus Nov 2013).
2. Rugg, E.L., McLean, W.H.I., Lane, E.B., Pitera, R.,
McMillan, J.R., Dopping-Hepenstal, P.J., Navsaria, H.A., Leigh, I.M. and
Eady, R.A.J (1994). A functional `knock-out' of human keratin 14. Gen.
Dev. 8, 2563-2573. (doi:10.1101/gad.8.21.2563) (Citations 109,
Scopus Nov 2013).
3. McLean, W.H.I., Eady, R.A.J., Dopping-Heppenstal, P.J.C.,
McMillan, J.R., Leigh, I.M., Navsaria, H.A., Higgins, C., Harper, J.I.,
Paige, D.G., Morley, S.M., and Lane, E.B. (1994) Mutations in the
rod 1A domain of keratins 1 and 10 in bullous congenital ichthyosiform
erythroderma (BCIE). J. Invest.Dermatol. 102, 24-30.
(doi:10.1111/1523-1747.ep12371726) (Citations 65, Scopus Nov 2013).
4. Smith, F.J.D, Eady, R.A.J, Leigh, I.M., McMillan, J.R., Rugg, E.L.,
Kelsell, D.P., Bryant, S.P., Spurr, N.K., Geddes, J.F., Kirtschig, G.,
Milana, G., de Bono, A.G., Owaribe, K., Wiche, G., Pulkkinen, L., Uitto,
J., McLean, W.H.I and Lane, E.B. (1996) Plectin deficiency
results in muscular dystrophy with epidermolysis bullosa. Nat. Genet. 13,
450-7 (doi:10.1038/ng0896-450) (Citations 251, Scopus Nov 2013).
5. McLean, W.H.I., Rugg, E.L., Lunny, D.P., Morley, S.M., Lane,
E.B., Swensson, O., Dopping-Hepenstal, P.J.C., Griffiths, W.A.D.,
Eady, R.A.J., Higgins, C., Navsaria, H.A., Leigh, I.M., Strachan, T.,
Kunkeler, L., and Munro, C.S. (1995) Keratin 16 and keratin 17 mutations
cause pachyonychia congenita. Nat. Genet. 9, 273-278
(doi:10.1038/ng0395-273) (Citations 209, Scopus Nov 2013).
6. Smith, F.J.D., Hickerson, R.P., Sayers J.M., Reeves, R.E., Contag,
C.H., Leake, D., Kaspar, R.L., and McLean, W.H.I. (2008)
Development of therapeutic siRNA for pachyonychia congentia. J. Invest.
Dermatol. 128, 50-58. (doi:10.1038/sj.jid.5701040) (Citations 34,
Scopus Nov 2013).
Details of the impact
Inherited genetic skin disease patients and their clinicians.
Benefits and impacts:
(a) New diagnostics for several genetic skin diseases.
(b) Significant contribution to international patient registry and
(c) Initiation of the first human clinical trial for siRNA therapy of
The identification by the University of Dundee of many of the genes that
underlie keratinizing disorders, such as Epidermolysis Bullosa (EB) and
pachyonychia congenita (PC) has impacted on the diagnosis, clinical
genetic management and support of patients and families with these
disorders. Epidermolysis Bullosa can give rise to significant disability
and is thought to affect 1 in 17,000 live births. Pachyonychia congenita
is classified as an ultra-rare genetic skin disease but its effects on
patients are profound, causing painful blistering and calluses on the
feet, thickened nails and cysts.
The major impact of this research has been to transform the diagnosis for
several keratin disorders. Prior to the discovery of the genetic basis of
these diseases, several clinical classification schemes were proposed.
Unfortunately classifications by clinical criteria were hindered by
significant variability of the phenotype, even within affected members of
the same family. In the case of PC, the average general practitioner might
only see one or two cases in an entire career. Failure to correctly
diagnose keratin disorders due to the diversity in the clinical features
often resulted in incorrect or inadequate treatment. The advent of
mutational screening avoided the ambiguity of diagnosis, permitting
classification of the subtype, as well as the providing the option for
prenatal genetic diagnosis. Thus, while clinical diagnosis is important,
genetic testing has transformed the ability to verify the patient's
The UK Genetic Testing Network (UKGTN) advises the NHS on genetic testing
and assesses whether providing a test is likely to be of benefit to
patients. In 2003, as a direct result of the discovery of the causative
mutations by the team in Dundee, UKGTN approved a genetic test for
Epidermolysis Bullosa. As a consequence, the National Services Division of
the NHS has funded a UK-wide genetic testing service for Epidermolysis
Bullosa since 2007 (1). This genetic testing service is run in the
NHS-Tayside Molecular Genetics Unit at Ninewells Hospital in Dundee, which
has become the primary centre in the UK for genetic diagnosis for all
keratin disorders. Over 200 individuals have been identified with
Pachyonychia congentia by the genetic diagnosis service in Dundee over the
REF assessment period (2). The University of Dundee also runs the
international molecular diagnostic service for PC where state-of-the-art
sequencing methodologies are used to identify causative mutations. In the
case of PC, >1000 patients have been identified worldwide to date.
In addition to an earlier and more accurate diagnosis, a further impact
of approved genetic diagnosis for these disorders has been the opportunity
for disease prevention through pre-implantation diagnosis for couples
concerned about transmitting an inherited disease to their children.
Pre-implantation diagnosis detects a specific disease-causing genetic
mutation within an embryo before it is transferred to the womb.
Genetic diagnosis of PC by the laboratory of Prof McLean was highlighted
in the public domain in a recent episode of the Channel 4 show Embarrassing
Bodies on 16th April 2012 (3).
Creation of international patient registry and patient support
Often in rare diseases, individuals are widely scattered throughout the
world. As a consequence, little progress can be made on treatment.
Research in Dundee has directly resulted in the creation of an approved
patient registry, the International Pachyonychia Congenita Research
registry (IPCRR). Established in 2004, the registry collects clinical and
genetic data on patients with PC worldwide and is funded by the
organisation Pachyonychia Congentia Project, a public charity, founded to
support the development of treatments for PC (www.pachyonychia.org)
(4). Patients have now been identified in over 50 countries with over 750
patients registering on the IPCRR during the REF assessment period (5).
Genetic testing to confirm PC, genetic counselling and consultations with
dermatologists specialising in keratin disorders are all coordinated by
the PC project and are provided free of charge to patients
In 2006-2008, Prof McLean and his team made significant progress in the
development of therapeutic siRNAs for PC. As a consequence of this and the
creation of the PC research registry, the first clinical trial using siRNA
for PC commenced in January 2008. Funded by the PC Project, this is the
first phase 1b clinical trial for a skin condition and for specific
silencing of a mutant gene to successfully demonstrate the clinical
efficacy and safety of siRNA treatment (6).
Sources to corroborate the impact
- UK genetic diagnostic service for Epidermolysis Bullosa and other
keratin disorders Molecular Genetic Laboratory, East of Scotland
Regional Genetics Service
- External corroboration can be obtained from the Director of the
Pachyonychia Congenita Project.
Embarrassing Bodies, Channel 4
- International Pachyonychia Congenita Research registry (IPCRR)
- First clinical trial for a treatment for pachyonychia congentia
Leachman, S,A., Hickerson, R.P., Schwartz ME, Bullough, E.E.,
Hutcherson, S.L., Boucher, K.M., Hansen, C.D., Eliason, M.J., Srivatsa,
G.S., Kornbrust, D.J., Smith, F.J.D, McLean, W.H.I., Milstone, L.M.,
Kaspar, R.L. (2010) First-in-human mutation-targeted siRNA phase Ib
trial of an inherited skin disorder. Mol Ther. 18, 442-6 ClinicalTrials.gov