Filaggrin and Eczema

22% for dizygotic twins.The moststrikingclinicalfeatures 22% for dizygotic twins.The show concordance ratesof80%for monozygotic versus development ofeczema as reflected by twinstudies that factors are known toplay role animportant inthe Genetic disease (ordiseases)hasbeen a thornierproblem. theunderlying geneticsofthe rapidly changingincidence, ofenvironmentalimportance factorsisshown by this Whilethe provided richpickingsfor epidemiologists. more developed countriesover thepasttwo decadeshave andstudiesontheriseinitsincidence Western world, Eczema isoneofthemostprevalent diseasesofthe for othercommondiseases. searching tothose seeking complexgeneticexplanations heavily studieddiseasemust causemore thanalittlesoul- Mendelian geneticscanunderliesuchacommonand Therealisation thatsimple made indermatology. arguably yet beenthemostsignificant geneticdiscovery underlie almosthalfthecasesof AD inEurope has thatmutations Thediscovery inthefilaggringene off. althoughthisnow appears tobeflattening two decades, been increasing inmuch of Western Europe over thepast prevalence of skin.The life inassociationwithdry AD has affecting theflexuresin thefirsttwo andstarting years of generally Atopic dermatitisisanitchy skincondition, ECZEMA DECLARATION OFINTERESTS vulgaris protein/lipid squamesthatcomposethe Filaggriniscriticaltotheconversion ofkeratinocytes tothe well aseczema. includingasthmaas epidermal protein ofatopicdiseases, filaggrinintheaetiology ABSTRACT Filaggrin andeczema LIST OF ABBREVIATIONS KEYWORDS toenhancedantigenpenetrationthrough adeficientepidermalbarrier.secondary Immunological changesinatopicdiseaseare probably dermatitis andasthma. defect inskinbarrier functionthereforeA primary appears tounderlieatopic butnotintheabsenceof a backgroundAD. of AD isrelated toFLGnull status, Asthmaon since beenidentifiedinEuropean andnon-European with cohorts AD. FLGnull mutations have Furthermore, with AD inthree non-European cohorts. althoughthesetwo mutations are notassociated have inEurope, beenreported Nonegative studies between 2·8 and13·4. withodds ratiosvarying populations, in12independentEuropean atopicdermatitis, common distinctform ofeczema, association hasalsobeenshown between thesetwo mutations andthemost Anexceptionally strong sites (R501Xand2282del4)inthefilaggringene. was found tobeasemi-dominantMendelianconditionduemutations attwo In2006, layer oftheskin. ahlg,NnwlsHsia n eia col ude UK Dundee, NinewellsHospitalandMedicalSchool, Pathology, 1 1 Pa Pa eirLcue,Dprmn fDraooy nvriyo dnug,Edinburgh; University ofEdinburgh, ofDermatology, Department Senior Lecturer, Weller, R per per I) muolblnE(g) polymerase chainreaction (PCR) immunoglobulin E(IgE), (IV), 2 Recent genetic findings demonstrate an important roleRecent geneticfindingsdemonstrateanimportant for the H McLean WHI tp,ezm,flgrn gene, filaggrin, eczema, Atopy, icthyosis vulgaris tpcdraii A) filaggringene(FLG), Atopic dermatitis(AD), No conflictofinterests declared. ies hrceie ydy scaly skin, adiseasecharacterisedby dry, , stratum corneum ichthyosis vulgaris, ichthyosis , the outermostbarrier the , skin and biochemically by reduced orabsentfilaggrin in the hyperlinearity, ischaracterisedclinically by palmar 1:250 people, whichinitsmore subtlemanifestations affects condition, McLean’s initialstudywason between between 3·73and13·4. withodds ratiosof DanishandScottishcohorts, German, English, now beenindependently reproduced inIrish, developing findingshave inassociationwitheczema.These andalsotoasthma strongly predisposed toeczema, which alleles inthefilaggringene(R501Xand2282del4), Thegroup describedapairofnull possibly ofasthma. andquite ofeczema, understanding oftheaetiology Dundee produced thebiggestshiftfor decadesinthe apaper by IrwinMcLean’s group from In April 2006, FILAGGRIN environmental precipitants must underlieeczema. complex interactionbetween different genesand populations hasbeenpooranditassumedthata butreplication between centres and number ofhotspots, Genome-widescanshave identifieda aetiological factor. immunological dysfunctionas the key underlying and correspondingly much recent research haspostulated pruritusandinflammation, of eczemaare theerythema, 2 rfso fHmnGntc,Molecular andCellular Professor ofHumanGenetics, ichthyosis keratosis pilaris © 2008Royal CollegeofPhysicians ofEdinburgh Published online Published Correspondence to to Correspondence Department of Dermatology, of Department University of Edinburgh, Lauriston Edinburgh, of University Building, Lauriston Place, Place, Lauriston Building, Edinburgh EH3 9HA, UK 9HA, EH3 Edinburgh tel. tel. and finescalingoftheskin, J RCollPhysicians Edinb fax. fax. e-mail e-mail +44 (0)131 536 2041 536 (0)131 +44 ichthyosis vulgaris. ichthyosis +44 (0)131 229 8769 8769 229 (0)131 +44 [email protected] September 2007 September R Weller, R 2008; 38: This 45 45–7 EDUCATION R Weller,WHI McLean

skin and keratinocytes. Keratohyalin granules in the antigen exposure. Thus low-level exposure to such an stratum granulosum of the epidermis are predominantly antigen might give a survival advantage during episodes of formed of profilaggrin. This is cleaved to peptides of epidemic disease and increase the number of carriers of filaggrin, which aggregate the keratin cytoskeleton, thus filaggrin mutations. collapsing keratinocytes to form the squames of the stratum corneum. It is also involved in the synthesis of CLINICAL PHENOTYPES AND FILAGGRIN ‘natural moisturising factor’, the main humefactant of the stratum corneum. Mutations in FLG provide the most powerful predisposing factor yet discovered for eczema, but the Proving that FLG mutations cause IV had been difficult chain of events between deficient filaggrin production owing to the unusual structure of the gene. Most and eczema has not yet been explained. Asthma in profilaggrin is encoded in the third and final exon, where association with eczema correlates with the two 10–12 almost identical tandem repeats of the filaggrin predominant European FLG mutations, but asthma alone sequence occur. Such multiple repeats are hard to does not.The genetic evidence suggests that the primary sequence, but with advanced long-range PCR techniques cause of eczema is a defect in barrier function, which the Dundee group succeeded in sequencing the FLG gene also accounts for the ‘dry’ skin found in many patients and showing that IV is a semi-dominant Mendelian with chronic eczema. Presumably (although not yet condition. Heterozygotes for the R501X and 2282del4 proven) the barrier defect allows greater penetration of mutations of FLG have subtle signs of disease, which may antigens through the epidermis with resultant be missed, while homozygotes and compound stimulation of the immune system and secondary heterozygotes have a moderate or severe phenotype. immunological changes of eczema, and subsequently of The investigators observed that many IV patients had asthma. The classical pattern of the ‘atopic march’ in eczema, and that those homozygous or compound which childhood eczema precedes asthma and allergic heterozygous for the FLG mutations had more severe rhinitis is consistent with this, and suggests that the and/or persistent eczema. answer to reducing childhood asthma may be to prevent the development of eczema. Extending the study, initially to a cohort of Irish children, ascertained on the basis of atopic dermatitis rather than The World Allergy Organisation has divided eczema up IV, showed a striking association between atopic into extrinsic (‘allergic’) atopic eczema, in which patients dermatitis and the two FLG variants.The combined allele have a tendency to produce IgE antibodies in response frequency for the variant FLG in the AD cohort was to ordinary exposures to allergens, and intrinsic non- 0·330, as opposed to 0·042 in an unselected Irish control atopic eczema, in which IgE levels are normal. Filaggrin population.This association has now been confirmed in 12 null mutations predispose to AD persisting into adult EDUCATION separate European cohorts with no negative studies, and life, with early onset AD and with extrinsic atopic odds ratios varying between 2·8 and 13·4. Fifteen further dermatitis. The association of atopic eczema (high IgE FLG null alleles have since been identified. These are all levels) and FLG mutations may however be due to a nonsense or frameshift mutations that result in reduced recruitment bias. Elevated IgE is a marker of severity of epidermal filaggrin production and independently eczema, and a higher proportion of severe eczema associate with the risk of developing AD. Testing for these patients are found in hospitals from which most cohorts additional variants in the original Irish paediatric AD have been drawn. In a birth cohort study, non-atopic cohort shows around 47% to carry a filaggrin null allele. eczema was also identified with FLG null status. Different mutations appear to confer different degrees of risk of acquiring AD. The discovery of defects in a single gene underlying around half of the cases of such a common disease has Non-European populations have not been shown to carry been the most important genetic finding in dermatology the R501X and 2282del4 mutations. Bangladeshi, Japanese of the past decade, but many questions remain to be and Chinese cohorts with AD or IV have been studied to answered. Not all eczema patients have an identifiable date. Although they do not carry the common European FLG mutation. In such patients, is the disease different mutations, other FLG variants that reduce or prevent clinically, and are other barrier proteins defective? What filaggrin expression have been identified. Structural and is the link between failure of the skin barrier and the therefore functional defects in filaggrin thus appear to immunological changes of eczema, and how does this underlie eczema in communities around the world, but relate to the rise in incidence of atopic diseases seen in with independently acquired genetic mutations in the the last 20 years? How does asthma develop following different populations. Genetic drift in large populations is eczema? Will filaggrin or other skin barrier protein unlikely to account for such consistently occurring defects similarly be found to underlie eczema in non- mutations, and it may be that filaggrin mutations confer a European populations? Eczema research is certainly selective advantage, perhaps by allowing ‘natural entering an exciting era. vaccination’ to epidemic diseases through transepidermal

KEYPOINTS FURTHER READING

• Filaggrin is a key protein in the development of the • Barker JN, Palmer CN, Zhao YW et al. Null mutations in the barrier function of the skin. filaggrin gene (FLG) determine major susceptibility to early-onset • Filaggrin mutations cause ichthyosis vulgaris in a semi- atopic dermatitis that persists into adulthood. J Invest Dermatol 127: dominant Mendelian fashion. 2007; 564–7. • Irvine AD. Fleshing out filaggrin phenotypes. J Invest Dermatol • Filaggrin mutations are strongly associated with 2007; 127:504–7. eczema in all European populations so far tested. • Marenholz I, Nickel R, Ruschendorf F et al. Filaggrin loss-of- • Asthma in association with eczema is associated function mutations predispose to phenotypes involved in the with filaggrin mutations, but asthma without eczema atopic march. J Allergy Clin Immunol 2006; 118:866–71. • is not. Palmer CN, Irvine AD,Terron-Kwiatkowski A et al. Common loss- of-function variants of the epidermal barrier protein filaggrin are • A primary skin barrier defect probably underlies a major predisposing factor for atopic dermatitis. Nat Genet 2006; most cases of atopic dermatitis and atopic 38:441–6. dermatitis-associated asthma. • Sandilands A,Terron-Kwiatkowski A, Hull PR et al. Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema. Nat Genet 2007; 39(5):650–4. • Smith FJ, Irvine AD,Terron-Kwiatkowski A et al. Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nat Genet 2006; 38:337–42.

JOINT UK CONSENSUS CONFERENCE ON ACUTE MEDICINE

Thursday 13 – Friday 14 November 2008 EDUCATION At the Royal College of Physicians of Edinburgh

This multi-professional conference is being held jointly with the Royal College of Physicians of Edinburgh, the Society for Acute Medicine and the Royal College of General Practitioners (Scotland).

Key questions to be addressed at the conference:

• What is acute medicine and do we need it? • What is the optimal configuration for multi-professional working in the acute medical unit? • Ambulatory care – what is it and do we need it? • How is multi-professional training optimised in the acute environment? • What are the appropriate standards for acute medicine?

Poster abstracts based on the key questions are invited by 1 August 2008.the

Full details on the conference, including registration and poster submission, can be obtained from http://www.rcpe.ac.uk/education/events/consensus-acute-medicine-08.php

or by contacting Mrs Margaret Farquhar, Consensus Conference Co-ordinator, Royal College of Physicians of Edinburgh, 9 Queen Street, Edinburgh EH2 1JQ Tel: +44 (0) 131 247 3636 Email: [email protected]