Mutations in three genes encoding proteins involved in hair shaft formation cause uncombable hair syndrome

E48 

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and GBP1. By inclusion into analysis of previously reported GWAS data,additionaldistinctinteractionsofgenemodules,revealedbyour analysis,withalreadyreportedgenescouldbeelucidated. Tothebestofourknowledge,thisisthefirststudyapplyingsystems biologyapproachtoidentifysharedmolecularmechanismsbetween pemphigusandSLEdiseases.Thismethodcouldbroadenourknowl-edgeaboutpathogenesisofautoimmunediseasesbyidentifyingnew possiblyinvolvedcandidategenes,aswellasimproveourunderstand- ingofunderlyinggeneticinteractionsandrevealnewpotentialthera-peutictargets.

P112 

| Diet shifts the genetic association of

multiple complex traits in outbred mice

A.Vorobyev;Y.Gupta;H.Koga;H.Körber-Ahrens;F.Beltsiou; J.Jascholt;P.Kouki;D.Zillikens;K.Bieber;S.M.Ibrahim; R.J.Ludwig

University of Lübeck, 23562 Lübeck, Germany

Genome-wideassociationandmappingstudiesidentifiedamultitude ofgeneticvariantsassociatedwithcomplextraitsinhumansandmice, thusconveyingdetailedinsightsintotheirgeneticarchitecture.Yet, thesegeneticvariationsonlypartiallyaccountforthephenotypicvari-ability.Thismissingheritabilitymaybeduetoepistasis,rarevariations and/ortheenvironment.Wehereaddressedthelater,byexposinga largecolonyofoutbredmicetodifferentdiets.Micewerefedcontrol choworwesterndietadlibidum,orwereheldatcaloricrestriction (n=350-400micepergroup).Weshowthatcomplexphenotypesde-pendonboth,geneticarchitectureanddiet.Full-genomesequencing ofparentalmiceandforwardgenomicsallowedlinkingtheassocia-tions to single genes. Considering diet as an interactive variable to determine the gene-phenotype association, leads to a considerable shiftofthegeneticassociation.Thus,gene-dietinteractionsexplain asignificantpartofthemissingheritability,whichallowsamorede-tailed understanding of complex traits.

P113 (OP06/04) 

| Mutations in three genes

encoding proteins involved in hair shaft formation

cause uncombable hair syndrome

F.B.Basmanav1_;L.Cau2_{;A.Tafazzoli}1_;M.Méchin2_{; S. Wolf}1_; M.T.Romano1_{;F.Valentin}3_{; H. Wiegmann}3_;A.Huchenq2_{; R.} Kandil1_{;N.GarciaBartels}4_;A.Kilic5_{; S. George}6_{; D. J. Ralser}1_; S. Bergner1_{; D. J. Ferguson}7_{; A. Oprisoreanu}8_{; M. Wehner}1_{; H.} Thiele9_{;J.Altmüller}9_{;P.Nürnberg}9_{; D. Swan}10_{; D. Houniet}10_; A.Büchner11_;L.Weibel11_;N.Wagner12_{; R. Grimalt}13_{; A.} Bygum14_{; G. Serre}4_{;U.Blume-Peytavi}4_{; E. Sprecher}15_{; S.} Schoch8_{; V. Oji}3_{; H. Hamm}16_;P.Farrant6_{; M. Simon}2_{; R. C.} Betz1

1_{Institute­of­Human­Genetics,­University­of­Bonn,­53127­Bonn,­Germany;­­}2_CNRS­

UMR5165­and­INSERM­U1056,­University­of­Toulouse,­31059­Toulouse,­France;­­

3_{Department of Dermatology, 48149 Münster, Germany;} 4_{Clinical Research Center}

for Hair and Skin Science, Department of Dermatology and Allergy, 10117 Berlin,

Germany; 5_{Balikesir University School of Medicine, Dermatology Department,}

10100 Balikesir, Turkey; 6_{Dermatology Department, Brighton and Sussex University}

Hospitals­NHS­Trust,­BN2­3EW­Brighton,­UK;­­7_{Nuffield­Department­of­Clinical­}

Laboratory­Science,­John­Radcliffe­Hospital,­University­of­Oxford,­OX3­9DU­Oxford,­ UK;­­8_{Department­of­Neuropathology­and­Department­of­Epileptology,­University­}

of Bonn, 53127 Bonn, Germany; 9_{Cologne Center for Genomics, University of}

Cologne, 50931 Cologne, Germany; 10_{Computational­Biology­Group,­Oxford­}

Gene­Technology,­OX5­1PF­Oxford,­UK;­­11_{Pediatric Dermatology Department,}

Zürich, Switzerland; 12_{Clinical Center Darmstadt, 64297 Darmstadt, Germany;} 13_{Universitat Internacional de Catalunya, 08195 Barcelona, Spain;} 14_Department

of Dermatology and Allergy Centre, Odense University Hospital, 5000 Odense, Denmark; 15_{Department of Dermatology, Tel Aviv Sourasky Medical Center, 64239}

Tel Aviv, Israel; 16_{Department of Dermatology, Venereology, and Allergology, 97080}

Würzburg, Germany

Uncombable hair syndrome (UHS), also known as “spun glass hair syndrome,”“pilitriangulietcanaliculi,”or“cheveuxincoiffables”isa rareanomalyofthehairshaftwhichoccursinchildrenandimproves withage.UHSischaracterizedbydry,frizzy,spanglyandoftenfair hairthatisresistanttobeingcombedflat.Uptodatebothsimplex andfamilialUHScaseswithautosomaldominantaswellasrecessive inheritancehavebeenreported.However,noneofthesecaseswere linkedtoamoleculargeneticcause.Here,wereporttheidentifica-tion of UHS causative mutations located in the three genes PADI3 (peptidylargininedeiminase3),TGM3(transglutaminase3)andTCHH (trichohyalin)inatotalofelevenchildren.Alloftheseindividualscarry homozygousorcompound heterozygousmutationsinoneofthese three genes, indicating an autosomal recessive inheritance pattern inthemajorityofUHScases.ThetwoenzymesPADI3andTGM3, responsibleforposttranslationalproteinmodifications,andtheirtar-getstructuralproteinTCHH,areallinvolvedinhairshaftformation. Elucidationofthemolecularoutcomesofthediseasecausingmuta-tionsbycellcultureexperimentsandtridimensionalproteinmodels demonstratedcleardifferencesinthestructuralorganizationandac-tivityofmutantandwild-typeproteins.Scanningelectronmicroscopy observationsrevealedmorphologicalalterationsinhaircoatofPadi3 knockout mice. All together, these findings elucidate the molecular geneticcausesofUHSandshedlightonitspathophysiology,andhair physiology in general.

HEALTH SERVICES RESEARCH

P114 

| Urticaria Activity Score – Results of the

available versions are comparable

K.Weller1_;T.Hawro1_;T.Ohanyan1_;M.Metz1 ;A.Peveling-Oberhag2_{;P.Staubach}2_{; M. Maurer}1

1_{Department of Dermatology and Allergy, 10117 Berlin, Germany;} 2_University

Medical Center Mainz, Department of Dermatology, 55131 Mainz, Germany

Background:Thesignsandsymptomsofchronicspontaneousurti- caria(CSU)stronglyfluctuatefromdaytodayandabiomarkerfordis-easeactivityisstillmissing.Currently,theonlywidelyacceptedtool todeterminediseaseactivityinCSUisthepatient-reportedUrticaria ActivityScore(UAS).TheUASdailydocumentswhealnumbersand intensityofpruritus,usuallyover7consecutivedays(UAS7).While