Full text data of FLG
FLG
[Confidence: low (only semi-automatic identification from reviews)]
Filaggrin
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Filaggrin
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P20930
ID FILA_HUMAN Reviewed; 4061 AA.
AC P20930; Q01720; Q5T583; Q9UC71;
DT 01-FEB-1991, integrated into UniProtKB/Swiss-Prot.
read moreDT 20-DEC-2005, sequence version 3.
DT 22-JAN-2014, entry version 121.
DE RecName: Full=Filaggrin;
GN Name=FLG;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-591, AND TISSUE SPECIFICITY.
RX PubMed=1429717;
RA Presland R.B., Haydock P.V., Fleckman P., Nirunsuksiri W., Dale B.A.;
RT "Characterization of the human epidermal profilaggrin gene. Genomic
RT organization and identification of an S-100-like calcium binding
RT domain at the amino terminus.";
RL J. Biol. Chem. 267:23772-23781(1992).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 2389-2804.
RX PubMed=2740331; DOI=10.1073/pnas.86.13.4848;
RA McKinley-Grant L.J., Idler W.W., Bernstein I.A., Parry D.A.D.,
RA Cannizzaro L., Croce C.M., Huebner K., Lessin S.R., Steinert P.M.;
RT "Characterization of a cDNA clone encoding human filaggrin and
RT localization of the gene to chromosome region 1q21.";
RL Proc. Natl. Acad. Sci. U.S.A. 86:4848-4852(1989).
RN [4]
RP PROTEIN SEQUENCE OF 2741-2760 AND 3065-3084, AND N-TERMINAL
RP PROCESSING.
RC TISSUE=Foreskin;
RX PubMed=7612609; DOI=10.1021/bi00027a018;
RA Thulin C.D., Walsh K.A.;
RT "Identification of the amino terminus of human filaggrin using
RT differential LC/MS techniques: implications for profilaggrin
RT processing.";
RL Biochemistry 34:8687-8692(1995).
RN [5]
RP CITRULLINATION.
RX PubMed=8780679; DOI=10.1006/bbrc.1996.1240;
RA Senshu T., Kan S., Ogawa H., Manabe M., Asaga H.;
RT "Preferential deimination of keratin K1 and filaggrin during the
RT terminal differentiation of human epidermis.";
RL Biochem. Biophys. Res. Commun. 225:712-719(1996).
RN [6]
RP INVOLVEMENT IN SUSCEPTIBILITY TO ATOD2.
RX PubMed=16815158; DOI=10.1016/j.jaci.2006.05.004;
RA Weidinger S., Illig T., Baurecht H., Irvine A.D., Rodriguez E.,
RA Diaz-Lacava A., Klopp N., Wagenpfeil S., Zhao Y., Liao H., Lee S.P.,
RA Palmer C.N.A., Jenneck C., Maintz L., Hagemann T., Behrendt H.,
RA Ring J., Nothen M.M., McLean W.H.I., Novak N.;
RT "Loss-of-function variations within the filaggrin gene predispose for
RT atopic dermatitis with allergic sensitizations.";
RL J. Allergy Clin. Immunol. 118:214-219(2006).
RN [7]
RP INVOLVEMENT IN SUSCEPTIBILITY TO ATOD2.
RX PubMed=17030239; DOI=10.1016/j.jaci.2006.07.026;
RA Marenholz I., Nickel R., Rueschendorf F., Schulz F.,
RA Esparza-Gordillo J., Kerscher T., Grueber C., Lau S., Worm M.,
RA Keil T., Kurek M., Zaluga E., Wahn U., Lee Y.-A.;
RT "Filaggrin loss-of-function mutations predispose to phenotypes
RT involved in the atopic march.";
RL J. Allergy Clin. Immunol. 118:866-871(2006).
RN [8]
RP INVOLVEMENT IN ICHTHYOSIS VULGARIS.
RX PubMed=16444271; DOI=10.1038/ng1743;
RA Smith F.J.D., Irvine A.D., Terron-Kwiatkowski A., Sandilands A.,
RA Campbell L.E., Zhao Y., Liao H., Evans A.T., Goudie D.R.,
RA Lewis-Jones S., Arseculeratne G., Munro C.S., Sergeant A., O'Regan G.,
RA Bale S.J., Compton J.G., DiGiovanna J.J., Presland R.B., Fleckman P.,
RA McLean W.H.I.;
RT "Loss-of-function mutations in the gene encoding filaggrin cause
RT ichthyosis vulgaris.";
RL Nat. Genet. 38:337-342(2006).
RN [9]
RP INVOLVEMENT IN SUSCEPTIBILITY TO ATOD2.
RX PubMed=16550169; DOI=10.1038/ng1767;
RA Palmer C.N.A., Irvine A.D., Terron-Kwiatkowski A., Zhao Y., Liao H.,
RA Lee S.P., Goudie D.R., Sandilands A., Campbell L.E., Smith F.J.D.,
RA O'Regan G.M., Watson R.M., Cecil J.E., Bale S.J., Compton J.G.,
RA DiGiovanna J.J., Fleckman P., Lewis-Jones S., Arseculeratne G.,
RA Sergeant A., Munro C.S., El Houate B., McElreavey K., Halkjaer L.B.,
RA Bisgaard H., Mukhopadhyay S., McLean W.H.I.;
RT "Common loss-of-function variants of the epidermal barrier protein
RT filaggrin are a major predisposing factor for atopic dermatitis.";
RL Nat. Genet. 38:441-446(2006).
RN [10]
RP INVOLVEMENT IN SUSCEPTIBILITY TO ATOD2.
RX PubMed=17291859; DOI=10.1016/j.jaci.2006.12.646;
RA Nomura T., Sandilands A., Akiyama M., Liao H., Evans A.T., Sakai K.,
RA Ota M., Sugiura H., Yamamoto K., Sato H., Palmer C.N.A., Smith F.J.D.,
RA McLean W.H.I., Shimizu H.;
RT "Unique mutations in the filaggrin gene in Japanese patients with
RT ichthyosis vulgaris and atopic dermatitis.";
RL J. Allergy Clin. Immunol. 119:434-440(2007).
CC -!- FUNCTION: Aggregates keratin intermediate filaments and promotes
CC disulfide-bond formation among the intermediate filaments during
CC terminal differentiation of mammalian epidermis.
CC -!- TISSUE SPECIFICITY: Keratohyalin granules.
CC -!- PTM: Filaggrin is initially synthesized as a large, insoluble,
CC highly phosphorylated precursor containing many tandem copies of
CC 324 AA, which are not separated by large linker sequences. During
CC terminal differentiation it is dephosphorylated and
CC proteolytically cleaved. The N-terminal of the mature protein is
CC heterogeneous, and is blocked by the formation of pyroglutamate.
CC -!- PTM: Undergoes deimination of some arginine residues
CC (citrullination).
CC -!- DISEASE: Ichthyosis vulgaris (VI) [MIM:146700]: The most common
CC form of ichthyosis inherited as an autosomal dominant trait. It is
CC characterized by palmar hyperlinearity, keratosis pilaris and a
CC fine scale that is most prominent over the lower abdomen, arms,
CC and legs. Ichthyosis vulgaris is characterized histologically by
CC absent or reduced keratohyalin granules in the epidermis and mild
CC hyperkeratosis. The disease can be associated with frequent
CC asthma, eczema or hay fever. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- DISEASE: Dermatitis atopic 2 (ATOD2) [MIM:605803]: Atopic
CC dermatitis is a complex, inflammatory disease with multiple
CC alleles at several loci thought to be involved in the
CC pathogenesis. It commonly begins in infancy or early childhood and
CC is characterized by a chronic relapsing form of skin inflammation,
CC a disturbance of epidermal barrier function that culminates in dry
CC skin, and IgE-mediated sensitization to food and environmental
CC allergens. It is manifested by lichenification, excoriation, and
CC crusting, mainly on the flexural surfaces of the elbow and knee.
CC Note=Disease susceptibility is associated with variations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the S100-fused protein family.
CC -!- SIMILARITY: Contains 2 EF-hand domains.
CC -!- SIMILARITY: Contains 23 filaggrin repeats.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/FLG";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; AL356504; CAI19595.1; -; Genomic_DNA.
DR EMBL; L01089; AAA60177.1; -; Genomic_DNA.
DR EMBL; M24355; AAA52454.1; -; mRNA.
DR PIR; A32947; A32947.
DR PIR; A45135; A45135.
DR PIR; A48118; A48118.
DR RefSeq; NP_002007.1; NM_002016.1.
DR UniGene; Hs.654510; -.
DR ProteinModelPortal; P20930; -.
DR SMR; P20930; 11-84.
DR IntAct; P20930; 4.
DR STRING; 9606.ENSP00000357789; -.
DR PhosphoSite; P20930; -.
DR DMDM; 84028206; -.
DR PaxDb; P20930; -.
DR PeptideAtlas; P20930; -.
DR PRIDE; P20930; -.
DR Ensembl; ENST00000368799; ENSP00000357789; ENSG00000143631.
DR GeneID; 2312; -.
DR KEGG; hsa:2312; -.
DR UCSC; uc001ezu.1; human.
DR CTD; 2312; -.
DR GeneCards; GC01M152274; -.
DR H-InvDB; HIX0022704; -.
DR HGNC; HGNC:3748; FLG.
DR HPA; CAB002210; -.
DR HPA; HPA030188; -.
DR HPA; HPA030189; -.
DR MIM; 135940; gene.
DR MIM; 146700; phenotype.
DR MIM; 605803; phenotype.
DR neXtProt; NX_P20930; -.
DR Orphanet; 462; Autosomal dominant ichthyosis vulgaris.
DR PharmGKB; PA28169; -.
DR eggNOG; NOG12793; -.
DR HOGENOM; HOG000112591; -.
DR InParanoid; P20930; -.
DR OMA; HGSRHPR; -.
DR OrthoDB; EOG7ZWD1D; -.
DR GeneWiki; Filaggrin; -.
DR GenomeRNAi; 2312; -.
DR NextBio; 9389; -.
DR PRO; PR:P20930; -.
DR ArrayExpress; P20930; -.
DR Bgee; P20930; -.
DR CleanEx; HS_FLG; -.
DR Genevestigator; P20930; -.
DR GO; GO:0016023; C:cytoplasmic membrane-bounded vesicle; IDA:UniProtKB.
DR GO; GO:0005882; C:intermediate filament; NAS:UniProtKB.
DR GO; GO:0005509; F:calcium ion binding; IEA:InterPro.
DR GO; GO:0005198; F:structural molecule activity; NAS:UniProtKB.
DR GO; GO:0030216; P:keratinocyte differentiation; TAS:BHF-UCL.
DR Gene3D; 1.10.238.10; -; 1.
DR InterPro; IPR011992; EF-hand-dom_pair.
DR InterPro; IPR018247; EF_Hand_1_Ca_BS.
DR InterPro; IPR002048; EF_hand_dom.
DR InterPro; IPR003303; Filaggrin.
DR InterPro; IPR001751; S100/CaBP-9k_CS.
DR InterPro; IPR013787; S100_Ca-bd_sub.
DR Pfam; PF03516; Filaggrin; 23.
DR Pfam; PF01023; S_100; 1.
DR PRINTS; PR00487; FILAGGRIN.
DR PROSITE; PS00018; EF_HAND_1; 1.
DR PROSITE; PS50222; EF_HAND_2; 2.
DR PROSITE; PS00303; S100_CABP; 1.
PE 1: Evidence at protein level;
KW Calcium; Citrullination; Coiled coil; Complete proteome;
KW Developmental protein; Direct protein sequencing; Ichthyosis;
KW Metal-binding; Phosphoprotein; Polymorphism; Reference proteome;
KW Repeat.
FT CHAIN 1 4061 Filaggrin.
FT /FTId=PRO_0000144036.
FT DOMAIN 6 43 EF-hand 1.
FT DOMAIN 49 84 EF-hand 2.
FT REPEAT 258 306 Filaggrin 1.
FT REPEAT 374 428 Filaggrin 2.
FT REPEAT 579 630 Filaggrin 3.
FT REPEAT 698 753 Filaggrin 4.
FT REPEAT 904 955 Filaggrin 5.
FT REPEAT 1023 1077 Filaggrin 6.
FT REPEAT 1228 1279 Filaggrin 7.
FT REPEAT 1347 1401 Filaggrin 8.
FT REPEAT 1552 1603 Filaggrin 9.
FT REPEAT 1671 1725 Filaggrin 10.
FT REPEAT 1876 1927 Filaggrin 11.
FT REPEAT 1995 2050 Filaggrin 12.
FT REPEAT 2201 2252 Filaggrin 13.
FT REPEAT 2320 2374 Filaggrin 14.
FT REPEAT 2525 2576 Filaggrin 15.
FT REPEAT 2644 2698 Filaggrin 16.
FT REPEAT 2849 2900 Filaggrin 17.
FT REPEAT 2968 3022 Filaggrin 18.
FT REPEAT 3173 3224 Filaggrin 19.
FT REPEAT 3292 3346 Filaggrin 20.
FT REPEAT 3497 3548 Filaggrin 21.
FT REPEAT 3616 3670 Filaggrin 22.
FT REPEAT 3821 3872 Filaggrin 23.
FT CA_BIND 62 73 Potential.
FT COILED 186 216 Potential.
FT COMPBIAS 260 3955 Ser-rich.
FT COMPBIAS 4057 4060 Poly-Tyr.
FT VARIANT 332 332 G -> V (in dbSNP:rs41267154).
FT /FTId=VAR_061049.
FT VARIANT 444 444 G -> R (in dbSNP:rs11588170).
FT /FTId=VAR_061050.
FT VARIANT 454 454 T -> A (in dbSNP:rs2011331).
FT /FTId=VAR_059155.
FT VARIANT 478 478 P -> S (in dbSNP:rs11584340).
FT /FTId=VAR_059156.
FT VARIANT 725 725 T -> I (in dbSNP:rs3120655).
FT /FTId=VAR_059157.
FT VARIANT 742 742 S -> Y (in dbSNP:rs3120654).
FT /FTId=VAR_061051.
FT VARIANT 1184 1184 S -> L (in dbSNP:rs3120649).
FT /FTId=VAR_045968.
FT VARIANT 1376 1376 R -> G (in dbSNP:rs11581433).
FT /FTId=VAR_045969.
FT VARIANT 1437 1437 R -> C (in dbSNP:rs12750571).
FT /FTId=VAR_045970.
FT VARIANT 1482 1482 S -> Y (in dbSNP:rs11204978).
FT /FTId=VAR_059158.
FT VARIANT 1684 1684 R -> H (in dbSNP:rs12407807).
FT /FTId=VAR_061052.
FT VARIANT 1699 1699 R -> C (in dbSNP:rs12405278).
FT /FTId=VAR_059159.
FT VARIANT 1750 1750 S -> F (in dbSNP:rs3120647).
FT /FTId=VAR_059160.
FT VARIANT 1805 1805 A -> V (in dbSNP:rs12405241).
FT /FTId=VAR_045971.
FT VARIANT 1816 1816 H -> Q (in dbSNP:rs12073613).
FT /FTId=VAR_059161.
FT VARIANT 1891 1891 R -> Q (in dbSNP:rs12407748).
FT /FTId=VAR_059162.
FT VARIANT 1961 1961 H -> Q (in dbSNP:rs3126079).
FT /FTId=VAR_045972.
FT VARIANT 2022 2022 I -> T (in dbSNP:rs3120655).
FT /FTId=VAR_045973.
FT VARIANT 2108 2108 A -> V (in dbSNP:rs7522925).
FT /FTId=VAR_059163.
FT VARIANT 2119 2119 Y -> H (in dbSNP:rs7512553).
FT /FTId=VAR_059164.
FT VARIANT 2194 2194 Y -> H (in dbSNP:rs2184953).
FT /FTId=VAR_059165.
FT VARIANT 2507 2507 H -> Q (in dbSNP:rs3126074).
FT /FTId=VAR_045974.
FT VARIANT 2540 2540 R -> Q (in dbSNP:rs12407748).
FT /FTId=VAR_048472.
FT VARIANT 2545 2545 G -> R (in dbSNP:rs3126072).
FT /FTId=VAR_059166.
FT VARIANT 2781 2781 D -> Y (in dbSNP:rs2065958).
FT /FTId=VAR_048473.
FT VARIANT 3105 3105 Y -> D (in dbSNP:rs2065958).
FT /FTId=VAR_059167.
FT VARIANT 3179 3179 V -> G (in dbSNP:rs2065957).
FT /FTId=VAR_059168.
FT VARIANT 3371 3371 S -> F (in dbSNP:rs3120647).
FT /FTId=VAR_048474.
FT VARIANT 3396 3396 S -> P (in dbSNP:rs11584340).
FT /FTId=VAR_048475.
FT VARIANT 3415 3415 H -> Y (in dbSNP:rs7512553).
FT /FTId=VAR_048476.
FT VARIANT 3427 3427 S -> Y (in dbSNP:rs11204978).
FT /FTId=VAR_048477.
FT VARIANT 3436 3436 G -> A (in dbSNP:rs2065955).
FT /FTId=VAR_033931.
FT VARIANT 3437 3437 H -> Q (in dbSNP:rs12073613).
FT /FTId=VAR_048478.
FT VARIANT 3490 3490 R -> C (in dbSNP:rs2184953).
FT /FTId=VAR_048479.
FT VARIANT 3503 3503 W -> G (in dbSNP:rs12728908).
FT /FTId=VAR_059169.
FT VARIANT 3512 3512 Q -> R (in dbSNP:rs12407748).
FT /FTId=VAR_048480.
FT VARIANT 3564 3564 R -> H (in dbSNP:rs7518080).
FT /FTId=VAR_059170.
FT VARIANT 3584 3584 D -> N (in dbSNP:rs3814300).
FT /FTId=VAR_048481.
FT VARIANT 3593 3593 E -> D (in dbSNP:rs12083389).
FT /FTId=VAR_059171.
FT VARIANT 3630 3630 H -> Y (in dbSNP:rs9436065).
FT /FTId=VAR_059172.
FT VARIANT 3695 3695 S -> F (in dbSNP:rs3120647).
FT /FTId=VAR_048482.
FT VARIANT 3696 3696 T -> A (in dbSNP:rs2011331).
FT /FTId=VAR_048483.
FT VARIANT 3720 3720 S -> P (in dbSNP:rs11584340).
FT /FTId=VAR_048484.
FT VARIANT 3739 3739 H -> Y (in dbSNP:rs7512553).
FT /FTId=VAR_048485.
FT VARIANT 3751 3751 S -> Y (in dbSNP:rs11204978).
FT /FTId=VAR_048486.
FT VARIANT 3760 3760 G -> A (in dbSNP:rs2065955).
FT /FTId=VAR_048487.
FT VARIANT 3761 3761 H -> Q (in dbSNP:rs12073613).
FT /FTId=VAR_048488.
FT VARIANT 3814 3814 R -> C (in dbSNP:rs2184953).
FT /FTId=VAR_048489.
FT VARIANT 3827 3827 G -> W (in dbSNP:rs12728908).
FT /FTId=VAR_048490.
FT VARIANT 3908 3908 D -> N (in dbSNP:rs3814300).
FT /FTId=VAR_048491.
FT VARIANT 3935 3935 S -> P (in dbSNP:rs3126065).
FT /FTId=VAR_048492.
FT VARIANT 3970 3970 S -> L (in dbSNP:rs3814299).
FT /FTId=VAR_048493.
FT CONFLICT 2444 2444 K -> Q (in Ref. 3; AAA52454).
FT CONFLICT 2466 2466 P -> R (in Ref. 3; AAA52454).
FT CONFLICT 2652 2652 E -> D (in Ref. 3; AAA52454).
FT CONFLICT 2804 2804 H -> Q (in Ref. 3; AAA52454).
SQ SEQUENCE 4061 AA; 435170 MW; 3F4B1181F04AD9C0 CRC64;
MSTLLENIFA IINLFKQYSK KDKNTDTLSK KELKELLEKE FRQILKNPDD PDMVDVFMDH
LDIDHNKKID FTEFLLMVFK LAQAYYESTR KENLPISGHK HRKHSHHDKH EDNKQEENKE
NRKRPSSLER RNNRKGNKGR SKSPRETGGK RHESSSEKKE RKGYSPTHRE EEYGKNHHNS
SKKEKNKTEN TRLGDNRKRL SERLEEKEDN EEGVYDYENT GRMTQKWIQS GHIATYYTIQ
DEAYDTTDSL LEENKIYERS RSSDGKSSSQ VNRSRHENTS QVPLQESRTR KRRGSRVSQD
RDSEGHSEDS ERHSGSASRN HHGSAWEQSR DGSRHPRSHD EDRASHGHSA DSSRQSGTRH
AETSSRGQTA SSHEQARSSP GERHGSGHQQ SADSSRHSAT GRGQASSAVS DRGHRGSSGS
QASDSEGHSE NSDTQSVSGH GKAGLRQQSH QESTRGRSGE RSGRSGSSLY QVSTHEQPDS
AHGRTGTSTG GRQGSHHEQA RDSSRHSASQ EGQDTIRGHP GSSRGGRQGS HHEQSVNRSG
HSGSHHSHTT SQGRSDASHG QSGSRSASRQ TRNEEQSGDG TRHSGSRHHE ASSQADSSRH
SQVGQGQSSG PRTSRNQGSS VSQDSDSQGH SEDSERWSGS ASRNHHGSAQ EQSRDGSRHP
RSHHEDRAGH GHSADSSRKS GTRHTQNSSS GQAASSHEQA RSSAGERHGS RHQLQSADSS
RHSGTGHGQA SSAVRDSGHR GSSGSQATDS EGHSEDSDTQ SVSGHGQAGH HQQSHQESAR
DRSGERSRRS GSFLYQVSTH KQSESSHGWT GPSTGVRQGS HHEQARDNSR HSASQDGQDT
IRGHPGSSRR GRQGSHHEQS VDRSGHSGSH HSHTTSQGRS DASRGQSGSR SASRTTRNEE
QSRDGSRHSG SRHHEASSHA DISRHSQAGQ GQSEGSRTSR RQGSSVSQDS DSEGHSEDSE
RWSGSASRNH RGSAQEQSRH GSRHPRSHHE DRAGHGHSAD SSRQSGTPHA ETSSGGQAAS
SHEQARSSPG ERHGSRHQQS ADSSRHSGIP RRQASSAVRD SGHWGSSGSQ ASDSEGHSEE
SDTQSVSGHG QDGPHQQSHQ ESARDWSGGR SGRSGSFIYQ VSTHEQSESA HGRTRTSTGR
RQGSHHEQAR DSSRHSASQE GQDTIRAHPG SRRGGRQGSH HEQSVDRSGH SGSHHSHTTS
QGRSDASHGQ SGSRSASRQT RKDKQSGDGS RHSGSRHHEA ASWADSSRHS QVGQEQSSGS
RTSRHQGSSV SQDSDSERHS DDSERLSGSA SRNHHGSSRE QSRDGSRHPG FHQEDRASHG
HSADSSRQSG THHTESSSHG QAVSSHEQAR SSPGERHGSR HQQSADSSRH SGIGHRQASS
AVRDSGHRGS SGSQVTNSEG HSEDSDTQSV SAHGQAGPHQ QSHKESARGQ SGESSGRSRS
FLYQVSSHEQ SESTHGQTAP STGGRQGSRH EQARNSSRHS ASQDGQDTIR GHPGSSRGGR
QGSYHEQSVD RSGHSGYHHS HTTPQGRSDA SHGQSGPRSA SRQTRNEEQS GDGSRHSGSR
HHEPSTRAGS SRHSQVGQGE SAGSKTSRRQ GSSVSQDRDS EGHSEDSERR SESASRNHYG
SAREQSRHGS RNPRSHQEDR ASHGHSAESS RQSGTRHAET SSGGQAASSQ EQARSSPGER
HGSRHQQSAD SSTDSGTGRR QDSSVVGDSG NRGSSGSQAS DSEGHSEESD TQSVSAHGQA
GPHQQSHQES TRGQSGERSG RSGSFLYQVS THEQSESAHG RTGPSTGGRQ RSRHEQARDS
SRHSASQEGQ DTIRGHPGSS RGGRQGSHYE QSVDSSGHSG SHHSHTTSQE RSDVSRGQSG
SRSVSRQTRN EKQSGDGSRH SGSRHHEASS RADSSRHSQV GQGQSSGPRT SRNQGSSVSQ
DSDSQGHSED SERWSGSASR NHLGSAWEQS RDGSRHPGSH HEDRAGHGHS ADSSRQSGTR
HTESSSRGQA ASSHEQARSS AGERHGSHHQ LQSADSSRHS GIGHGQASSA VRDSGHRGYS
GSQASDSEGH SEDSDTQSVS AQGKAGPHQQ SHKESARGQS GESSGRSGSF LYQVSTHEQS
ESTHGQSAPS TGGRQGSHYD QAQDSSRHSA SQEGQDTIRG HPGPSRGGRQ GSHQEQSVDR
SGHSGSHHSH TTSQGRSDAS RGQSGSRSAS RKTYDKEQSG DGSRHSGSHH HEASSWADSS
RHSLVGQGQS SGPRTSRPRG SSVSQDSDSE GHSEDSERRS GSASRNHHGS AQEQSRDGSR
HPRSHHEDRA GHGHSAESSR QSGTHHAENS SGGQAASSHE QARSSAGERH GSHHQQSADS
SRHSGIGHGQ ASSAVRDSGH RGSSGSQASD SEGHSEDSDT QSVSAHGQAG PHQQSHQEST
RGRSAGRSGR SGSFLYQVST HEQSESAHGR TGTSTGGRQG SHHKQARDSS RHSTSQEGQD
TIHGHPGSSS GGRQGSHYEQ LVDRSGHSGS HHSHTTSQGR SDASHGHSGS RSASRQTRND
EQSGDGSRHS GSRHHEASSR ADSSGHSQVG QGQSEGPRTS RNWGSSFSQD SDSQGHSEDS
ERWSGSASRN HHGSAQEQLR DGSRHPRSHQ EDRAGHGHSA DSSRQSGTRH TQTSSGGQAA
SSHEQARSSA GERHGSHHQQ SADSSRHSGI GHGQASSAVR DSGHRGYSGS QASDNEGHSE
DSDTQSVSAH GQAGSHQQSH QESARGRSGE TSGHSGSFLY QVSTHEQSES SHGWTGPSTR
GRQGSRHEQA QDSSRHSASQ DGQDTIRGHP GSSRGGRQGY HHEHSVDSSG HSGSHHSHTT
SQGRSDASRG QSGSRSASRT TRNEEQSGDG SRHSGSRHHE ASTHADISRH SQAVQGQSEG
SRRSRRQGSS VSQDSDSEGH SEDSERWSGS ASRNHHGSAQ EQLRDGSRHP RSHQEDRAGH
GHSADSSRQS GTRHTQTSSG GQAASSHEQA RSSAGERHGS HHQQSADSSR HSGIGHGQAS
SAVRDSGHRG YSGSQASDNE GHSEDSDTQS VSAHGQAGSH QQSHQESARG RSGETSGHSG
SFLYQVSTHE QSESSHGWTG PSTRGRQGSR HEQAQDSSRH SASQYGQDTI RGHPGSSRGG
RQGYHHEHSV DSSGHSGSHH SHTTSQGRSD ASRGQSGSRS ASRTTRNEEQ SGDSSRHSVS
RHHEASTHAD ISRHSQAVQG QSEGSRRSRR QGSSVSQDSD SEGHSEDSER WSGSASRNHR
GSVQEQSRHG SRHPRSHHED RAGHGHSADR SRQSGTRHAE TSSGGQAASS HEQARSSPGE
RHGSRHQQSA DSSRHSGIPR GQASSAVRDS RHWGSSGSQA SDSEGHSEES DTQSVSGHGQ
AGPHQQSHQE SARDRSGGRS GRSGSFLYQV STHEQSESAH GRTRTSTGRR QGSHHEQARD
SSRHSASQEG QDTIRGHPGS SRRGRQGSHY EQSVDRSGHS GSHHSHTTSQ GRSDASRGQS
GSRSASRQTR NDEQSGDGSR HSWSHHHEAS TQADSSRHSQ SGQGQSAGPR TSRNQGSSVS
QDSDSQGHSE DSERWSGSAS RNHRGSAQEQ SRDGSRHPTS HHEDRAGHGH SAESSRQSGT
HHAENSSGGQ AASSHEQARS SAGERHGSHH QQSADSSRHS GIGHGQASSA VRDSGHRGSS
GSQASDSEGH SEDSDTQSVS AHGQAGPHQQ SHQESTRGRS AGRSGRSGSF LYQVSTHEQS
ESAHGRAGPS TGGRQGSRHE QARDSSRHSA SQEGQDTIRG HPGSRRGGRQ GSYHEQSVDR
SGHSGSHHSH TTSQGRSDAS HGQSGSRSAS RETRNEEQSG DGSRHSGSRH HEASTQADSS
RHSQSGQGES AGSRRSRRQG SSVSQDSDSE AYPEDSERRS ESASRNHHGS SREQSRDGSR
HPGSSHRDTA SHVQSSPVQS DSSTAKEHGH FSSLSQDSAY HSGIQSRGSP HSSSSYHYQS
EGTERQKGQS GLVWRHGSYG SADYDYGESG FRHSQHGSVS YNSNPVVFKE RSDICKASAF
GKDHPRYYAT YINKDPGLCG HSSDISKQLG FSQSQRYYYY E
//
ID FILA_HUMAN Reviewed; 4061 AA.
AC P20930; Q01720; Q5T583; Q9UC71;
DT 01-FEB-1991, integrated into UniProtKB/Swiss-Prot.
read moreDT 20-DEC-2005, sequence version 3.
DT 22-JAN-2014, entry version 121.
DE RecName: Full=Filaggrin;
GN Name=FLG;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-591, AND TISSUE SPECIFICITY.
RX PubMed=1429717;
RA Presland R.B., Haydock P.V., Fleckman P., Nirunsuksiri W., Dale B.A.;
RT "Characterization of the human epidermal profilaggrin gene. Genomic
RT organization and identification of an S-100-like calcium binding
RT domain at the amino terminus.";
RL J. Biol. Chem. 267:23772-23781(1992).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 2389-2804.
RX PubMed=2740331; DOI=10.1073/pnas.86.13.4848;
RA McKinley-Grant L.J., Idler W.W., Bernstein I.A., Parry D.A.D.,
RA Cannizzaro L., Croce C.M., Huebner K., Lessin S.R., Steinert P.M.;
RT "Characterization of a cDNA clone encoding human filaggrin and
RT localization of the gene to chromosome region 1q21.";
RL Proc. Natl. Acad. Sci. U.S.A. 86:4848-4852(1989).
RN [4]
RP PROTEIN SEQUENCE OF 2741-2760 AND 3065-3084, AND N-TERMINAL
RP PROCESSING.
RC TISSUE=Foreskin;
RX PubMed=7612609; DOI=10.1021/bi00027a018;
RA Thulin C.D., Walsh K.A.;
RT "Identification of the amino terminus of human filaggrin using
RT differential LC/MS techniques: implications for profilaggrin
RT processing.";
RL Biochemistry 34:8687-8692(1995).
RN [5]
RP CITRULLINATION.
RX PubMed=8780679; DOI=10.1006/bbrc.1996.1240;
RA Senshu T., Kan S., Ogawa H., Manabe M., Asaga H.;
RT "Preferential deimination of keratin K1 and filaggrin during the
RT terminal differentiation of human epidermis.";
RL Biochem. Biophys. Res. Commun. 225:712-719(1996).
RN [6]
RP INVOLVEMENT IN SUSCEPTIBILITY TO ATOD2.
RX PubMed=16815158; DOI=10.1016/j.jaci.2006.05.004;
RA Weidinger S., Illig T., Baurecht H., Irvine A.D., Rodriguez E.,
RA Diaz-Lacava A., Klopp N., Wagenpfeil S., Zhao Y., Liao H., Lee S.P.,
RA Palmer C.N.A., Jenneck C., Maintz L., Hagemann T., Behrendt H.,
RA Ring J., Nothen M.M., McLean W.H.I., Novak N.;
RT "Loss-of-function variations within the filaggrin gene predispose for
RT atopic dermatitis with allergic sensitizations.";
RL J. Allergy Clin. Immunol. 118:214-219(2006).
RN [7]
RP INVOLVEMENT IN SUSCEPTIBILITY TO ATOD2.
RX PubMed=17030239; DOI=10.1016/j.jaci.2006.07.026;
RA Marenholz I., Nickel R., Rueschendorf F., Schulz F.,
RA Esparza-Gordillo J., Kerscher T., Grueber C., Lau S., Worm M.,
RA Keil T., Kurek M., Zaluga E., Wahn U., Lee Y.-A.;
RT "Filaggrin loss-of-function mutations predispose to phenotypes
RT involved in the atopic march.";
RL J. Allergy Clin. Immunol. 118:866-871(2006).
RN [8]
RP INVOLVEMENT IN ICHTHYOSIS VULGARIS.
RX PubMed=16444271; DOI=10.1038/ng1743;
RA Smith F.J.D., Irvine A.D., Terron-Kwiatkowski A., Sandilands A.,
RA Campbell L.E., Zhao Y., Liao H., Evans A.T., Goudie D.R.,
RA Lewis-Jones S., Arseculeratne G., Munro C.S., Sergeant A., O'Regan G.,
RA Bale S.J., Compton J.G., DiGiovanna J.J., Presland R.B., Fleckman P.,
RA McLean W.H.I.;
RT "Loss-of-function mutations in the gene encoding filaggrin cause
RT ichthyosis vulgaris.";
RL Nat. Genet. 38:337-342(2006).
RN [9]
RP INVOLVEMENT IN SUSCEPTIBILITY TO ATOD2.
RX PubMed=16550169; DOI=10.1038/ng1767;
RA Palmer C.N.A., Irvine A.D., Terron-Kwiatkowski A., Zhao Y., Liao H.,
RA Lee S.P., Goudie D.R., Sandilands A., Campbell L.E., Smith F.J.D.,
RA O'Regan G.M., Watson R.M., Cecil J.E., Bale S.J., Compton J.G.,
RA DiGiovanna J.J., Fleckman P., Lewis-Jones S., Arseculeratne G.,
RA Sergeant A., Munro C.S., El Houate B., McElreavey K., Halkjaer L.B.,
RA Bisgaard H., Mukhopadhyay S., McLean W.H.I.;
RT "Common loss-of-function variants of the epidermal barrier protein
RT filaggrin are a major predisposing factor for atopic dermatitis.";
RL Nat. Genet. 38:441-446(2006).
RN [10]
RP INVOLVEMENT IN SUSCEPTIBILITY TO ATOD2.
RX PubMed=17291859; DOI=10.1016/j.jaci.2006.12.646;
RA Nomura T., Sandilands A., Akiyama M., Liao H., Evans A.T., Sakai K.,
RA Ota M., Sugiura H., Yamamoto K., Sato H., Palmer C.N.A., Smith F.J.D.,
RA McLean W.H.I., Shimizu H.;
RT "Unique mutations in the filaggrin gene in Japanese patients with
RT ichthyosis vulgaris and atopic dermatitis.";
RL J. Allergy Clin. Immunol. 119:434-440(2007).
CC -!- FUNCTION: Aggregates keratin intermediate filaments and promotes
CC disulfide-bond formation among the intermediate filaments during
CC terminal differentiation of mammalian epidermis.
CC -!- TISSUE SPECIFICITY: Keratohyalin granules.
CC -!- PTM: Filaggrin is initially synthesized as a large, insoluble,
CC highly phosphorylated precursor containing many tandem copies of
CC 324 AA, which are not separated by large linker sequences. During
CC terminal differentiation it is dephosphorylated and
CC proteolytically cleaved. The N-terminal of the mature protein is
CC heterogeneous, and is blocked by the formation of pyroglutamate.
CC -!- PTM: Undergoes deimination of some arginine residues
CC (citrullination).
CC -!- DISEASE: Ichthyosis vulgaris (VI) [MIM:146700]: The most common
CC form of ichthyosis inherited as an autosomal dominant trait. It is
CC characterized by palmar hyperlinearity, keratosis pilaris and a
CC fine scale that is most prominent over the lower abdomen, arms,
CC and legs. Ichthyosis vulgaris is characterized histologically by
CC absent or reduced keratohyalin granules in the epidermis and mild
CC hyperkeratosis. The disease can be associated with frequent
CC asthma, eczema or hay fever. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- DISEASE: Dermatitis atopic 2 (ATOD2) [MIM:605803]: Atopic
CC dermatitis is a complex, inflammatory disease with multiple
CC alleles at several loci thought to be involved in the
CC pathogenesis. It commonly begins in infancy or early childhood and
CC is characterized by a chronic relapsing form of skin inflammation,
CC a disturbance of epidermal barrier function that culminates in dry
CC skin, and IgE-mediated sensitization to food and environmental
CC allergens. It is manifested by lichenification, excoriation, and
CC crusting, mainly on the flexural surfaces of the elbow and knee.
CC Note=Disease susceptibility is associated with variations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the S100-fused protein family.
CC -!- SIMILARITY: Contains 2 EF-hand domains.
CC -!- SIMILARITY: Contains 23 filaggrin repeats.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/FLG";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; AL356504; CAI19595.1; -; Genomic_DNA.
DR EMBL; L01089; AAA60177.1; -; Genomic_DNA.
DR EMBL; M24355; AAA52454.1; -; mRNA.
DR PIR; A32947; A32947.
DR PIR; A45135; A45135.
DR PIR; A48118; A48118.
DR RefSeq; NP_002007.1; NM_002016.1.
DR UniGene; Hs.654510; -.
DR ProteinModelPortal; P20930; -.
DR SMR; P20930; 11-84.
DR IntAct; P20930; 4.
DR STRING; 9606.ENSP00000357789; -.
DR PhosphoSite; P20930; -.
DR DMDM; 84028206; -.
DR PaxDb; P20930; -.
DR PeptideAtlas; P20930; -.
DR PRIDE; P20930; -.
DR Ensembl; ENST00000368799; ENSP00000357789; ENSG00000143631.
DR GeneID; 2312; -.
DR KEGG; hsa:2312; -.
DR UCSC; uc001ezu.1; human.
DR CTD; 2312; -.
DR GeneCards; GC01M152274; -.
DR H-InvDB; HIX0022704; -.
DR HGNC; HGNC:3748; FLG.
DR HPA; CAB002210; -.
DR HPA; HPA030188; -.
DR HPA; HPA030189; -.
DR MIM; 135940; gene.
DR MIM; 146700; phenotype.
DR MIM; 605803; phenotype.
DR neXtProt; NX_P20930; -.
DR Orphanet; 462; Autosomal dominant ichthyosis vulgaris.
DR PharmGKB; PA28169; -.
DR eggNOG; NOG12793; -.
DR HOGENOM; HOG000112591; -.
DR InParanoid; P20930; -.
DR OMA; HGSRHPR; -.
DR OrthoDB; EOG7ZWD1D; -.
DR GeneWiki; Filaggrin; -.
DR GenomeRNAi; 2312; -.
DR NextBio; 9389; -.
DR PRO; PR:P20930; -.
DR ArrayExpress; P20930; -.
DR Bgee; P20930; -.
DR CleanEx; HS_FLG; -.
DR Genevestigator; P20930; -.
DR GO; GO:0016023; C:cytoplasmic membrane-bounded vesicle; IDA:UniProtKB.
DR GO; GO:0005882; C:intermediate filament; NAS:UniProtKB.
DR GO; GO:0005509; F:calcium ion binding; IEA:InterPro.
DR GO; GO:0005198; F:structural molecule activity; NAS:UniProtKB.
DR GO; GO:0030216; P:keratinocyte differentiation; TAS:BHF-UCL.
DR Gene3D; 1.10.238.10; -; 1.
DR InterPro; IPR011992; EF-hand-dom_pair.
DR InterPro; IPR018247; EF_Hand_1_Ca_BS.
DR InterPro; IPR002048; EF_hand_dom.
DR InterPro; IPR003303; Filaggrin.
DR InterPro; IPR001751; S100/CaBP-9k_CS.
DR InterPro; IPR013787; S100_Ca-bd_sub.
DR Pfam; PF03516; Filaggrin; 23.
DR Pfam; PF01023; S_100; 1.
DR PRINTS; PR00487; FILAGGRIN.
DR PROSITE; PS00018; EF_HAND_1; 1.
DR PROSITE; PS50222; EF_HAND_2; 2.
DR PROSITE; PS00303; S100_CABP; 1.
PE 1: Evidence at protein level;
KW Calcium; Citrullination; Coiled coil; Complete proteome;
KW Developmental protein; Direct protein sequencing; Ichthyosis;
KW Metal-binding; Phosphoprotein; Polymorphism; Reference proteome;
KW Repeat.
FT CHAIN 1 4061 Filaggrin.
FT /FTId=PRO_0000144036.
FT DOMAIN 6 43 EF-hand 1.
FT DOMAIN 49 84 EF-hand 2.
FT REPEAT 258 306 Filaggrin 1.
FT REPEAT 374 428 Filaggrin 2.
FT REPEAT 579 630 Filaggrin 3.
FT REPEAT 698 753 Filaggrin 4.
FT REPEAT 904 955 Filaggrin 5.
FT REPEAT 1023 1077 Filaggrin 6.
FT REPEAT 1228 1279 Filaggrin 7.
FT REPEAT 1347 1401 Filaggrin 8.
FT REPEAT 1552 1603 Filaggrin 9.
FT REPEAT 1671 1725 Filaggrin 10.
FT REPEAT 1876 1927 Filaggrin 11.
FT REPEAT 1995 2050 Filaggrin 12.
FT REPEAT 2201 2252 Filaggrin 13.
FT REPEAT 2320 2374 Filaggrin 14.
FT REPEAT 2525 2576 Filaggrin 15.
FT REPEAT 2644 2698 Filaggrin 16.
FT REPEAT 2849 2900 Filaggrin 17.
FT REPEAT 2968 3022 Filaggrin 18.
FT REPEAT 3173 3224 Filaggrin 19.
FT REPEAT 3292 3346 Filaggrin 20.
FT REPEAT 3497 3548 Filaggrin 21.
FT REPEAT 3616 3670 Filaggrin 22.
FT REPEAT 3821 3872 Filaggrin 23.
FT CA_BIND 62 73 Potential.
FT COILED 186 216 Potential.
FT COMPBIAS 260 3955 Ser-rich.
FT COMPBIAS 4057 4060 Poly-Tyr.
FT VARIANT 332 332 G -> V (in dbSNP:rs41267154).
FT /FTId=VAR_061049.
FT VARIANT 444 444 G -> R (in dbSNP:rs11588170).
FT /FTId=VAR_061050.
FT VARIANT 454 454 T -> A (in dbSNP:rs2011331).
FT /FTId=VAR_059155.
FT VARIANT 478 478 P -> S (in dbSNP:rs11584340).
FT /FTId=VAR_059156.
FT VARIANT 725 725 T -> I (in dbSNP:rs3120655).
FT /FTId=VAR_059157.
FT VARIANT 742 742 S -> Y (in dbSNP:rs3120654).
FT /FTId=VAR_061051.
FT VARIANT 1184 1184 S -> L (in dbSNP:rs3120649).
FT /FTId=VAR_045968.
FT VARIANT 1376 1376 R -> G (in dbSNP:rs11581433).
FT /FTId=VAR_045969.
FT VARIANT 1437 1437 R -> C (in dbSNP:rs12750571).
FT /FTId=VAR_045970.
FT VARIANT 1482 1482 S -> Y (in dbSNP:rs11204978).
FT /FTId=VAR_059158.
FT VARIANT 1684 1684 R -> H (in dbSNP:rs12407807).
FT /FTId=VAR_061052.
FT VARIANT 1699 1699 R -> C (in dbSNP:rs12405278).
FT /FTId=VAR_059159.
FT VARIANT 1750 1750 S -> F (in dbSNP:rs3120647).
FT /FTId=VAR_059160.
FT VARIANT 1805 1805 A -> V (in dbSNP:rs12405241).
FT /FTId=VAR_045971.
FT VARIANT 1816 1816 H -> Q (in dbSNP:rs12073613).
FT /FTId=VAR_059161.
FT VARIANT 1891 1891 R -> Q (in dbSNP:rs12407748).
FT /FTId=VAR_059162.
FT VARIANT 1961 1961 H -> Q (in dbSNP:rs3126079).
FT /FTId=VAR_045972.
FT VARIANT 2022 2022 I -> T (in dbSNP:rs3120655).
FT /FTId=VAR_045973.
FT VARIANT 2108 2108 A -> V (in dbSNP:rs7522925).
FT /FTId=VAR_059163.
FT VARIANT 2119 2119 Y -> H (in dbSNP:rs7512553).
FT /FTId=VAR_059164.
FT VARIANT 2194 2194 Y -> H (in dbSNP:rs2184953).
FT /FTId=VAR_059165.
FT VARIANT 2507 2507 H -> Q (in dbSNP:rs3126074).
FT /FTId=VAR_045974.
FT VARIANT 2540 2540 R -> Q (in dbSNP:rs12407748).
FT /FTId=VAR_048472.
FT VARIANT 2545 2545 G -> R (in dbSNP:rs3126072).
FT /FTId=VAR_059166.
FT VARIANT 2781 2781 D -> Y (in dbSNP:rs2065958).
FT /FTId=VAR_048473.
FT VARIANT 3105 3105 Y -> D (in dbSNP:rs2065958).
FT /FTId=VAR_059167.
FT VARIANT 3179 3179 V -> G (in dbSNP:rs2065957).
FT /FTId=VAR_059168.
FT VARIANT 3371 3371 S -> F (in dbSNP:rs3120647).
FT /FTId=VAR_048474.
FT VARIANT 3396 3396 S -> P (in dbSNP:rs11584340).
FT /FTId=VAR_048475.
FT VARIANT 3415 3415 H -> Y (in dbSNP:rs7512553).
FT /FTId=VAR_048476.
FT VARIANT 3427 3427 S -> Y (in dbSNP:rs11204978).
FT /FTId=VAR_048477.
FT VARIANT 3436 3436 G -> A (in dbSNP:rs2065955).
FT /FTId=VAR_033931.
FT VARIANT 3437 3437 H -> Q (in dbSNP:rs12073613).
FT /FTId=VAR_048478.
FT VARIANT 3490 3490 R -> C (in dbSNP:rs2184953).
FT /FTId=VAR_048479.
FT VARIANT 3503 3503 W -> G (in dbSNP:rs12728908).
FT /FTId=VAR_059169.
FT VARIANT 3512 3512 Q -> R (in dbSNP:rs12407748).
FT /FTId=VAR_048480.
FT VARIANT 3564 3564 R -> H (in dbSNP:rs7518080).
FT /FTId=VAR_059170.
FT VARIANT 3584 3584 D -> N (in dbSNP:rs3814300).
FT /FTId=VAR_048481.
FT VARIANT 3593 3593 E -> D (in dbSNP:rs12083389).
FT /FTId=VAR_059171.
FT VARIANT 3630 3630 H -> Y (in dbSNP:rs9436065).
FT /FTId=VAR_059172.
FT VARIANT 3695 3695 S -> F (in dbSNP:rs3120647).
FT /FTId=VAR_048482.
FT VARIANT 3696 3696 T -> A (in dbSNP:rs2011331).
FT /FTId=VAR_048483.
FT VARIANT 3720 3720 S -> P (in dbSNP:rs11584340).
FT /FTId=VAR_048484.
FT VARIANT 3739 3739 H -> Y (in dbSNP:rs7512553).
FT /FTId=VAR_048485.
FT VARIANT 3751 3751 S -> Y (in dbSNP:rs11204978).
FT /FTId=VAR_048486.
FT VARIANT 3760 3760 G -> A (in dbSNP:rs2065955).
FT /FTId=VAR_048487.
FT VARIANT 3761 3761 H -> Q (in dbSNP:rs12073613).
FT /FTId=VAR_048488.
FT VARIANT 3814 3814 R -> C (in dbSNP:rs2184953).
FT /FTId=VAR_048489.
FT VARIANT 3827 3827 G -> W (in dbSNP:rs12728908).
FT /FTId=VAR_048490.
FT VARIANT 3908 3908 D -> N (in dbSNP:rs3814300).
FT /FTId=VAR_048491.
FT VARIANT 3935 3935 S -> P (in dbSNP:rs3126065).
FT /FTId=VAR_048492.
FT VARIANT 3970 3970 S -> L (in dbSNP:rs3814299).
FT /FTId=VAR_048493.
FT CONFLICT 2444 2444 K -> Q (in Ref. 3; AAA52454).
FT CONFLICT 2466 2466 P -> R (in Ref. 3; AAA52454).
FT CONFLICT 2652 2652 E -> D (in Ref. 3; AAA52454).
FT CONFLICT 2804 2804 H -> Q (in Ref. 3; AAA52454).
SQ SEQUENCE 4061 AA; 435170 MW; 3F4B1181F04AD9C0 CRC64;
MSTLLENIFA IINLFKQYSK KDKNTDTLSK KELKELLEKE FRQILKNPDD PDMVDVFMDH
LDIDHNKKID FTEFLLMVFK LAQAYYESTR KENLPISGHK HRKHSHHDKH EDNKQEENKE
NRKRPSSLER RNNRKGNKGR SKSPRETGGK RHESSSEKKE RKGYSPTHRE EEYGKNHHNS
SKKEKNKTEN TRLGDNRKRL SERLEEKEDN EEGVYDYENT GRMTQKWIQS GHIATYYTIQ
DEAYDTTDSL LEENKIYERS RSSDGKSSSQ VNRSRHENTS QVPLQESRTR KRRGSRVSQD
RDSEGHSEDS ERHSGSASRN HHGSAWEQSR DGSRHPRSHD EDRASHGHSA DSSRQSGTRH
AETSSRGQTA SSHEQARSSP GERHGSGHQQ SADSSRHSAT GRGQASSAVS DRGHRGSSGS
QASDSEGHSE NSDTQSVSGH GKAGLRQQSH QESTRGRSGE RSGRSGSSLY QVSTHEQPDS
AHGRTGTSTG GRQGSHHEQA RDSSRHSASQ EGQDTIRGHP GSSRGGRQGS HHEQSVNRSG
HSGSHHSHTT SQGRSDASHG QSGSRSASRQ TRNEEQSGDG TRHSGSRHHE ASSQADSSRH
SQVGQGQSSG PRTSRNQGSS VSQDSDSQGH SEDSERWSGS ASRNHHGSAQ EQSRDGSRHP
RSHHEDRAGH GHSADSSRKS GTRHTQNSSS GQAASSHEQA RSSAGERHGS RHQLQSADSS
RHSGTGHGQA SSAVRDSGHR GSSGSQATDS EGHSEDSDTQ SVSGHGQAGH HQQSHQESAR
DRSGERSRRS GSFLYQVSTH KQSESSHGWT GPSTGVRQGS HHEQARDNSR HSASQDGQDT
IRGHPGSSRR GRQGSHHEQS VDRSGHSGSH HSHTTSQGRS DASRGQSGSR SASRTTRNEE
QSRDGSRHSG SRHHEASSHA DISRHSQAGQ GQSEGSRTSR RQGSSVSQDS DSEGHSEDSE
RWSGSASRNH RGSAQEQSRH GSRHPRSHHE DRAGHGHSAD SSRQSGTPHA ETSSGGQAAS
SHEQARSSPG ERHGSRHQQS ADSSRHSGIP RRQASSAVRD SGHWGSSGSQ ASDSEGHSEE
SDTQSVSGHG QDGPHQQSHQ ESARDWSGGR SGRSGSFIYQ VSTHEQSESA HGRTRTSTGR
RQGSHHEQAR DSSRHSASQE GQDTIRAHPG SRRGGRQGSH HEQSVDRSGH SGSHHSHTTS
QGRSDASHGQ SGSRSASRQT RKDKQSGDGS RHSGSRHHEA ASWADSSRHS QVGQEQSSGS
RTSRHQGSSV SQDSDSERHS DDSERLSGSA SRNHHGSSRE QSRDGSRHPG FHQEDRASHG
HSADSSRQSG THHTESSSHG QAVSSHEQAR SSPGERHGSR HQQSADSSRH SGIGHRQASS
AVRDSGHRGS SGSQVTNSEG HSEDSDTQSV SAHGQAGPHQ QSHKESARGQ SGESSGRSRS
FLYQVSSHEQ SESTHGQTAP STGGRQGSRH EQARNSSRHS ASQDGQDTIR GHPGSSRGGR
QGSYHEQSVD RSGHSGYHHS HTTPQGRSDA SHGQSGPRSA SRQTRNEEQS GDGSRHSGSR
HHEPSTRAGS SRHSQVGQGE SAGSKTSRRQ GSSVSQDRDS EGHSEDSERR SESASRNHYG
SAREQSRHGS RNPRSHQEDR ASHGHSAESS RQSGTRHAET SSGGQAASSQ EQARSSPGER
HGSRHQQSAD SSTDSGTGRR QDSSVVGDSG NRGSSGSQAS DSEGHSEESD TQSVSAHGQA
GPHQQSHQES TRGQSGERSG RSGSFLYQVS THEQSESAHG RTGPSTGGRQ RSRHEQARDS
SRHSASQEGQ DTIRGHPGSS RGGRQGSHYE QSVDSSGHSG SHHSHTTSQE RSDVSRGQSG
SRSVSRQTRN EKQSGDGSRH SGSRHHEASS RADSSRHSQV GQGQSSGPRT SRNQGSSVSQ
DSDSQGHSED SERWSGSASR NHLGSAWEQS RDGSRHPGSH HEDRAGHGHS ADSSRQSGTR
HTESSSRGQA ASSHEQARSS AGERHGSHHQ LQSADSSRHS GIGHGQASSA VRDSGHRGYS
GSQASDSEGH SEDSDTQSVS AQGKAGPHQQ SHKESARGQS GESSGRSGSF LYQVSTHEQS
ESTHGQSAPS TGGRQGSHYD QAQDSSRHSA SQEGQDTIRG HPGPSRGGRQ GSHQEQSVDR
SGHSGSHHSH TTSQGRSDAS RGQSGSRSAS RKTYDKEQSG DGSRHSGSHH HEASSWADSS
RHSLVGQGQS SGPRTSRPRG SSVSQDSDSE GHSEDSERRS GSASRNHHGS AQEQSRDGSR
HPRSHHEDRA GHGHSAESSR QSGTHHAENS SGGQAASSHE QARSSAGERH GSHHQQSADS
SRHSGIGHGQ ASSAVRDSGH RGSSGSQASD SEGHSEDSDT QSVSAHGQAG PHQQSHQEST
RGRSAGRSGR SGSFLYQVST HEQSESAHGR TGTSTGGRQG SHHKQARDSS RHSTSQEGQD
TIHGHPGSSS GGRQGSHYEQ LVDRSGHSGS HHSHTTSQGR SDASHGHSGS RSASRQTRND
EQSGDGSRHS GSRHHEASSR ADSSGHSQVG QGQSEGPRTS RNWGSSFSQD SDSQGHSEDS
ERWSGSASRN HHGSAQEQLR DGSRHPRSHQ EDRAGHGHSA DSSRQSGTRH TQTSSGGQAA
SSHEQARSSA GERHGSHHQQ SADSSRHSGI GHGQASSAVR DSGHRGYSGS QASDNEGHSE
DSDTQSVSAH GQAGSHQQSH QESARGRSGE TSGHSGSFLY QVSTHEQSES SHGWTGPSTR
GRQGSRHEQA QDSSRHSASQ DGQDTIRGHP GSSRGGRQGY HHEHSVDSSG HSGSHHSHTT
SQGRSDASRG QSGSRSASRT TRNEEQSGDG SRHSGSRHHE ASTHADISRH SQAVQGQSEG
SRRSRRQGSS VSQDSDSEGH SEDSERWSGS ASRNHHGSAQ EQLRDGSRHP RSHQEDRAGH
GHSADSSRQS GTRHTQTSSG GQAASSHEQA RSSAGERHGS HHQQSADSSR HSGIGHGQAS
SAVRDSGHRG YSGSQASDNE GHSEDSDTQS VSAHGQAGSH QQSHQESARG RSGETSGHSG
SFLYQVSTHE QSESSHGWTG PSTRGRQGSR HEQAQDSSRH SASQYGQDTI RGHPGSSRGG
RQGYHHEHSV DSSGHSGSHH SHTTSQGRSD ASRGQSGSRS ASRTTRNEEQ SGDSSRHSVS
RHHEASTHAD ISRHSQAVQG QSEGSRRSRR QGSSVSQDSD SEGHSEDSER WSGSASRNHR
GSVQEQSRHG SRHPRSHHED RAGHGHSADR SRQSGTRHAE TSSGGQAASS HEQARSSPGE
RHGSRHQQSA DSSRHSGIPR GQASSAVRDS RHWGSSGSQA SDSEGHSEES DTQSVSGHGQ
AGPHQQSHQE SARDRSGGRS GRSGSFLYQV STHEQSESAH GRTRTSTGRR QGSHHEQARD
SSRHSASQEG QDTIRGHPGS SRRGRQGSHY EQSVDRSGHS GSHHSHTTSQ GRSDASRGQS
GSRSASRQTR NDEQSGDGSR HSWSHHHEAS TQADSSRHSQ SGQGQSAGPR TSRNQGSSVS
QDSDSQGHSE DSERWSGSAS RNHRGSAQEQ SRDGSRHPTS HHEDRAGHGH SAESSRQSGT
HHAENSSGGQ AASSHEQARS SAGERHGSHH QQSADSSRHS GIGHGQASSA VRDSGHRGSS
GSQASDSEGH SEDSDTQSVS AHGQAGPHQQ SHQESTRGRS AGRSGRSGSF LYQVSTHEQS
ESAHGRAGPS TGGRQGSRHE QARDSSRHSA SQEGQDTIRG HPGSRRGGRQ GSYHEQSVDR
SGHSGSHHSH TTSQGRSDAS HGQSGSRSAS RETRNEEQSG DGSRHSGSRH HEASTQADSS
RHSQSGQGES AGSRRSRRQG SSVSQDSDSE AYPEDSERRS ESASRNHHGS SREQSRDGSR
HPGSSHRDTA SHVQSSPVQS DSSTAKEHGH FSSLSQDSAY HSGIQSRGSP HSSSSYHYQS
EGTERQKGQS GLVWRHGSYG SADYDYGESG FRHSQHGSVS YNSNPVVFKE RSDICKASAF
GKDHPRYYAT YINKDPGLCG HSSDISKQLG FSQSQRYYYY E
//
MIM
135940
*RECORD*
*FIELD* NO
135940
*FIELD* TI
*135940 FILAGGRIN; FLG
PROFILAGGRIN, INCLUDED
*FIELD* TX
DESCRIPTION
Profilaggrin is a major protein component of the keratohyalin granules
read moreof mammalian epidermis. It is initially expressed as a large polyprotein
precursor which is subsequently proteolytically processed into
individual functional filaggrin molecules. The filaggrins show wide
species variations and their aberrant expression has been implicated in
a number of keratinizing disorders (Baden et al., 1974; Holbrook et al.,
1982; Sybert et al., 1985).
CLONING
McKinley-Grant et al. (1989) isolated a cDNA clone encoding human
filaggrin. They demonstrated that the human gene encodes a polyprotein
precursor containing numerous tandem filaggrin repeats. This structure
is similar to that of the mouse; however, the human filaggrin repeat is
much longer (972 basepairs; 324 amino acids) and shows little sequence
homology to the mouse protein. They found furthermore that the human
filaggrin repeats show considerable sequence variations; such
polymorphism is not found in the mouse. By peptide mapping, they defined
a short linker sequence within the human filaggrin repeat that is
excised by proteolysis to yield functional molecules. They showed by in
situ hybridization that the expression of the gene for the human
filaggrin precursor is tightly regulated at the transcriptional level in
terminally differentiating epidermis.
Gan et al. (1990) isolated genomic DNA and cDNA clones encoding the
5-prime and 3-prime ends of the human gene and mRNA. They found evidence
of likely CAT and TATA sequences, an intron in the 5-prime untranslated
region, and several potential regulatory sequences. The gene is made up
of repeats, all of the same length. Sequences showed considerable
variation, most attributable to single-base changes. Thus, human
filaggrin consists of a heterogeneous population of molecules of
different sizes, charges, and sequences. Amino acid sequences encoding
the amino and carboxyl termini were more conserved, as were the 5-prime
and 3-prime DNA sequences flanking the coding portions of the gene. The
presence of unique restriction enzyme sites in these conserved flanking
sequences enabled Gan et al. (1990) to calculate the size of the
full-length gene and the number of repeats in it; depending on the
source of genomic DNA, the gene contains 10, 11, or 12 filaggrin repeats
that segregate in families in a normal mendelian manner. Thus, the human
profilaggrin gene is polymorphic with respect to size due to simple
allelic differences between individuals.
GENE STRUCTURE
The FLG gene comprises 3 exons (Presland et al., 1992).
MAPPING
Using a cDNA clone as a probe in the study of a panel of mouse-human
somatic cell hybrids retaining overlapping subsets of human chromosomal
regions and for chromosomal in situ hybridization, McKinley-Grant et al.
(1989) demonstrated that the human filaggrin gene maps to 1q21.
Rothnagel et al. (1994) mapped the homologous gene to mouse chromosome 3
by PCR analyses of DNAs isolated from mouse/Chinese hamster somatic cell
hybrids.
Genes of 3 protein families that are specifically expressed in the
course of terminal differentiation of human epidermis have been mapped
to 1q21. Volz et al. (1993) showed that these genes are physically
linked within 2.05 Mb of DNA in the following order: calpactin I light
chain (CAL1L; 114085), trichohyalin (THL; 190370), profilaggrin,
involucrin (IVL; 147360), small proline-rich protein (SPRR1A; 182265),
loricrin (LOR; 152445), and calcyclin (CACY; 114110).
GENE FUNCTION
Smith et al. (2006) reviewed the function of filaggrin, also known as
filament-aggregating protein, in the formation of the stratum corneum.
Keratohyalin granules in the granular layer of interfollicular epidermis
are predominantly composed of the 400-kD protein profilaggrin. Following
a short, unique N-terminal domain, most of the profilaggrin molecule
consists of 10 to 12 repeats of the 324-residue filaggrin sequence (Gan
et al., 1990). Upon terminal differentiation of granular cells,
profilaggrin is proteolytically cleaved into filaggrin peptides of
approximately 37 kD and the N-terminal domain containing an S100-like
calcium-binding domain. Filaggrin rapidly aggregates the keratin
cytoskeleton, causing collapse of the granular cells into flattened
anuclear squames. This condensed cytoskeleton is crosslinked by
transglutaminases during formation of the cornified cell envelope (CCE).
The CCE is the outermost barrier layer of the skin which not only
prevents water loss but also impedes the entry of allergens and
infectious agents. Filaggrin is therefore a key protein in facilitating
epidermal differentiation and maintaining barrier function.
MOLECULAR GENETICS
In 15 kindreds with ichthyosis vulgaris (146700), Smith et al. (2006)
identified homozygous or compound heterozygous mutations R501X
(135940.0001) and 2282del4 (135940.0002) in the FLG gene in individuals
with a moderate or severe phenotype. They concluded that these mutations
are semidominant; heterozygotes show a very mild phenotype with
incomplete penetrance. The mutations showed a combined allele frequency
of approximately 4% in populations of European ancestry, explaining the
high incidence of ichthyosis vulgaris. Profilaggrin is the major protein
of keratohyalin granules in the epidermis. During terminal
differentiation, it is cleaved into multiple filaggrin peptides that
aggregate keratin filaments. The resultant matrix is crosslinked to form
a major component of the cornified cell envelope. Smith et al. (2006)
found that loss or reduction of this major structural protein leads to
varying degrees of impaired keratinization.
Twin and family studies have indicated a highly heritable predisposition
to atopic disease, including atopic dermatitis (see 603165), allergy,
and asthma (see 600807). Although genetic studies have focused on
immunologic mechanisms of atopic dermatitis, a primary epithelial
barrier defect has been anticipated (Cookson and Moffatt, 2002).
Filaggrin is a key protein that facilitates terminal differentiation of
the epidermis and formation of the skin barrier. Palmer et al. (2006)
showed that 2 independent loss-of-function genetic variants, R501X
(135940.0001) and 2282del4 (135940.0002), in the FLG gene are very
strong predisposing factors for atopic dermatitis (605803). These
mutations had been shown to be the cause of ichthyosis vulgaris in 15
families and isolated cases (Smith et al., 2006). The R501X and 2282del4
variants, carried by approximately 9% of people of European origin, also
showed highly significant association with asthma occurring in the
context of atopic dermatitis. This work established a key role for
impaired skin barrier function in the development of atopic disease.
Sandilands et al. (2007) showed that the 2 common filaggrin-null
mutations reported by Smith et al. (2006) and Palmer et al. (2006) are
ancestral European variants carried on conserved haplotypes. To
facilitate comprehensive analysis in other populations, they reported a
strategy for full sequencing of this large, highly repetitive gene, and
described 15 variants, including 7 that are prevalent. All the variants
were either nonsense or frameshift mutations that, in representative
cases, resulted in loss of filaggrin production in the epidermis. In an
Irish case-control study, the 5 most common European mutations showed a
strong association with moderate to severe childhood eczema. They found
3 additional rare null mutations in this case series, suggesting that
the genetic architecture of filaggrin-related atopic dermatitis consists
of both prevalent and rare risk alleles.
Using the transmission-disequilibrium test in 476 German
parent-offspring trios with atopic dermatitis, Weidinger et al. (2006)
found a significant association between the loss-of-function mutations
R501X and 2282del4 in the FLG gene and extrinsic atopic dermatitis,
allergic sensitization, total IgE level, asthma, and palmar
hyperlinearity; there was no significant association with intrinsic
atopic dermatitis.
Marenholz et al. (2006) genotyped 1092 children with eczema (atopic
dermatitis) from 2 large European populations for the R501X and 2282del4
mutations in the FLG gene and confirmed a highly significant association
between the null mutations and eczema and concomitant asthma. Moreover,
the authors found that these mutations predisposed to asthma, allergic
rhinitis, and allergic sensitization only in the presence of eczema,
highlighting the importance of the epidermal barrier in the pathogenesis
of these disorders (the so-called 'atopic march').
Nomura et al. (2007) sequenced the entire FLG gene in 7 Japanese
patients with ichthyosis vulgaris from 4 unrelated families who were
negative for the R501X and 2282del4 mutations, and identified
heterozygosity for 2 novel mutations, S2554X (135940.0003) and 3321delA
(135940.0004), respectively. The authors then screened 143 Japanese
patients with atopic dermatitis from 140 unrelated families for the
novel null mutations and identified S2554X in 6 patients and 3321delA in
2 patients; they were not found in 156 unrelated Japanese nonatopic and
nonichthyotic controls, yielding a chi-square p value of 0.0015. Noting
that the R501X and 2282del4 mutations were absent from a total of 253
Japanese individuals, including their patients with ichthyosis vulgaris
and atopic dermatitis, Nomura et al. (2007) concluded that FLG mutations
in Japan are different from those found in European-origin populations.
ANIMAL MODEL
Netherton syndrome (256500) is an autosomal recessive multisystemic
disorder characterized by congenital ichthyosiform erythroderma, hair
shaft defects and atopy, caused by mutation in the SPINK5 gene (605010).
Hewett et al. (2005) created mice with an R820X mutation in the Spink5
gene. Newborn homozygotes developed a severe ichthyosis with a loss of
skin barrier function and dehydration, resulting in death within a few
hours. Biochemical analysis of skin revealed a substantial increase in
the proteolytic processing of profilaggrin into its constituent
filaggrin monomers. The authors suggested that in the absence of SPINK5
there is an abnormal increase in the processing of profilaggrin, and
that this may play a direct role in the observed deficit in the adhesion
of the stratum corneum and the severely compromised epidermal barrier
function.
Fallon et al. (2009) reported a 1-bp deletion mutation, 5303delA,
analogous to common human FLG mutations, within the murine Flg gene in
the spontaneous mouse mutant 'flaky tail' (ft). Fallon et al. (2009)
demonstrated that topical application of allergen to mice homozygous for
this mutation resulted in cutaneous inflammatory infiltrates and
enhanced cutaneous allergen priming with development of
allergen-specific antibody responses. These data validated flaky tail as
a useful model of filaggrin deficiency and provided experimental
evidence for the hypothesis that antigen transfer through a defective
epidermal barrier is a key mechanism underlying elevated IgE
sensitization and initiation of cutaneous inflammation in humans with
filaggrin-related atopic disease.
*FIELD* AV
.0001
ICHTHYOSIS VULGARIS
DERMATITIS, ATOPIC, 2, SUSCEPTIBILITY TO, INCLUDED
FLG, ARG501TER
In 7 unrelated ichthyosis vulgaris (146700) families and 8 additional
'sporadic' cases from Ireland, Scotland, and the U.S., Smith et al.
(2006) found that ichthyosis vulgaris was associated with an
arg501-to-stop (R501X) mutation arising from a 1501C-to-T transition
near the start of repeat 1 in exon 3 of the FLG gene. In 3 families,
ichthyosis vulgaris patients with a very pronounced phenotype were
homozygous for R501X. In other families and isolated cases, they found
individuals with the marked ichthyosis vulgaris phenotype to be compound
heterozygous for R501X and a second mutation, 2282del4, in exon 3
(135940.0002).
Ichthyosis vulgaris is semidominant: that is, heterozygotes had either
no discernible phenotype or milder ichthyosis, whereas homozygotes or
compound heterozygotes had marked ichthyosis and an overt histologic
skin barrier defect. In an extension of the work of Smith et al. (2006),
Palmer et al. (2006) noted that in their families with ichthyosis
vulgaris, many individuals null or heterozygous for filaggrin also had
atopic dermatitis (605803) (eczema) and, in a few cases, also had asthma
(see 600807). Specifically, atopic dermatitis was prevalent in the
individuals with mild ichthyosis vulgaris, all of whom were heterozygous
for either the R501X or 2282del4 FLG-null allele (13/29; 44%). Atopic
dermatitis was particularly common in individuals with severe ichthyosis
vulgaris, all of whom were homozygous or compound heterozygous for
FLG-null alleles (16/21; 76%). None of the individuals in these families
who lacked an FLG-null allele had atopic dermatitis (n = 13). Thus,
atopic dermatitis is inherited as a semidominant trait in these
families, with high penetrance in FLG-null homozygotes or compound
heterozygotes and reduced penetrance in heterozygotes.
Using the transmission-disequilibrium test in 476 German
parent-offspring trios with atopic dermatitis, Weidinger et al. (2006)
found a significant association between the loss-of-function mutations
R501X and 2282del4 in the FLG gene and extrinsic atopic dermatitis,
allergic sensitization, total IgE level, asthma, and palmar
hyperlinearity; there was no significant association with intrinsic
atopic dermatitis.
Marenholz et al. (2006) genotyped 1092 children with eczema (atopic
dermatitis) from 2 large European populations for the R501X and 2282del4
mutations in the FLG gene and replicated the highly significant
association between the null mutations and eczema and concomitant
asthma. Moreover, the authors found that these mutations predisposed to
asthma, allergic rhinitis, and allergic sensitization only in the
presence of eczema, and that the mutations predisposed equally to atopic
(intrinsic) and nonatopic (extrinsic) forms of eczema. They demonstrated
that the presence of 2 null alleles is an independent risk factor for
asthma in children with eczema (OR, 11.76, p = 0.0085). Together, the 2
mutations accounted for approximately 11% of eczema cases in the German
population.
.0002
ICHTHYOSIS VULGARIS
DERMATITIS, ATOPIC, 2, SUSCEPTIBILITY TO, INCLUDED
FLG, 4-BP DEL, 2282CAGT
See 135940.0001 and Smith et al. (2006). The 2282del4 mutation leads to
a premature termination codon 107 bp downstream and, like R501X, stops
protein translation within the first filaggrin repeat.
Palmer et al. (2006) found an association of the 2282del4 and R501X
genetic variants of the FLG gene with atopic dermatitis; see
135940.0001.
Weidinger et al. (2006) found a significant association between atopic
dermatitis, in particular the extrinsic type, and the R501X and 2282del4
mutations; Marenholz et al. (2006) replicated the association and also
found that the presence of 2 null alleles was an independent risk factor
for asthma in children with eczema. See 135940.0001.
.0003
ICHTHYOSIS VULGARIS
DERMATITIS, ATOPIC, 2, SUSCEPTIBILITY TO, INCLUDED
FLG, SER2554TER
In affected members of 2 unrelated Japanese families with ichthyosis
vulgaris (146700) who were negative for previously identified null
mutations in the FLG gene, Nomura et al. (2007) identified
heterozygosity for a 7661C-G transversion in exon 3 of the FLG gene,
resulting in a ser2554-to-ter (S2554X) substitution, predicted to cause
premature termination of profilaggrin translation in the filaggrin
repeat domain 7. The older sister of 1 proband, who had a severe
presentation of the disease, was found to be homozygous for S2554X. The
authors then screened 143 Japanese patients with atopic dermatitis
(605803) from 140 unrelated families for this null mutation and
identified S2554X in 6 patients. The mutation was not found in 156
unrelated nonatopic and nonichthyotic Japanese controls.
.0004
ICHTHYOSIS VULGARIS
DERMATITIS, ATOPIC, 2, SUSCEPTIBILITY TO, INCLUDED
FLG, 1-BP DEL, 3321A
In 2 probands from 2 unrelated Japanese families with ichthyosis
vulgaris (146700), who were negative for previously identified null
mutations in the FLG gene, Nomura et al. (2007) identified
heterozygosity for a 1-bp deletion (3321delA) in exon 3 of the FLG gene,
resulting in a premature termination of profilaggrin translation in
filaggrin repeat domain 2. The authors then screened 143 Japanese
patients with atopic dermatitis (605803) from 140 unrelated families for
this deletion and identified 3321delA in 2 patients. The deletion was
not found in 156 unrelated nonatopic and nonichthyotic Japanese
controls.
*FIELD* RF
1. Baden, H. P.; Roth, S. I.; Goldsmith, L. A.; Lee, L. D.: Keratohyalin
protein in disorders of keratinization. J. Invest. Derm. 62: 411-414,
1974.
2. Cookson, W. O. C. M.; Moffatt, M. F.: The genetics of atopic dermatitis. Curr.
Opin. Allergy Clin. Immun. 2: 383-387, 2002.
3. Fallon, P. G.; Sasaki, T.; Sandilands, A.; Campbell, L. E.; Saunders,
S. P.; Mangan, N. E.; Callanan, J. J.; Kawasaki, H.; Shiohama, A.;
Kubo, A.; Sundberg, J. P.; Presland, R. B.; Fleckman, P.; Shimizu,
N.; Kudoh, J.; Irvine, A. D.; Amagai, M.; McLean, W. H. I.: A homozygous
frameshift mutation in the mouse Flg gene facilitates enhanced percutaneous
allergen priming. Nature Genet. 41: 602-608, 2009.
4. Gan, S.-Q.; McBride, O. W.; Idler, W. W.; Markova, N.; Steinert,
P. M.: Organization, structure, and polymorphisms of the human profilaggrin
gene. Biochemistry 29: 9432-9440, 1990. Note: Erratum: Biochemistry:
30: 5814 only, 1991.
5. Hewett, D. R.; Simons, A. L.; Mangan, N. E.; Jolin, H. E.; Green,
S. M.; Fallon, P. G.; McKenzie, A. N. J.: Lethal, neonatal ichthyosis
with increased proteolytic processing of filaggrin in a mouse model
of Netherton syndrome. Hum. Molec. Genet. 14: 335-346, 2005.
6. Holbrook, K. A.; Dale, B. A.; Brown, K. S.: Abnormal epidermal
keratinization in the repeated epilation mutant mouse. J. Cell Biol. 92:
387-397, 1982.
7. Marenholz, I.; Nickel, R.; Ruschendorf, F.; Schulz, F.; Esparza-Gordillo,
J.; Kerscher, T.; Gruber, C.; Lau, S.; Worm, M.; Keil, T.; Kurek,
M.; Zaluga, E.; Wahn, U.; Lee, Y.-A.: Filaggrin loss-of-function
mutations predispose to phenotypes involved in the atopic march. J.
Allergy Clin. Immun. 118: 866-871, 2006.
8. McKinley-Grant, L. J.; Idler, W. W.; Bernstein, I. A.; Parry, D.
A. D.; Cannizzaro, L.; Croce, C. M.; Huebner, K.; Lessin, S. R.; Steinert,
P. M.: Characterization of a cDNA clone encoding human filaggrin
and localization of the gene to chromosome region 1q21. Proc. Nat.
Acad. Sci. 86: 4848-4852, 1989.
9. Nomura, T.; Sandilands, A.; Akiyama, M.; Liao, H.; Evans, A. T.;
Sakai, K.; Ota, M.; Sugiura, H.; Yamamoto, K.; Sato, H.; Palmer, C.
N. A.; Smith, F. J. D.; McLean, W. H. I.; Shimizu, H.: Unique mutations
in the filaggrin gene in Japanese patients with ichthyosis vulgaris
and atopic dermatitis. J. Allergy Clin. Immun. 119: 434-440, 2007.
10. Palmer, C. N. A.; Irvine, A. D.; Terron-Kwiatkowski, A.; Zhao,
Y.; Liao, H.; Lee, S. P.; Goudie, D. R.; Sandilands, A.; Campbell,
L. E.; Smith, F. J. D.; O'Regan, G. M.; Watson, R. M.; and 15 others
: Common loss-of-function variants of the epidermal barrier protein
filaggrin are a major predisposing factor for atopic dermatitis. Nature
Genet. 38: 441-446, 2006.
11. Presland, R. B.; Haydock, P. V.; Fleckman, P.; Nirunsuksiri, W.;
Dale, B. A.: Characterization of the human epidermal profilaggrin
gene: genomic organization and identification of an S-100-like calcium
binding domain at the amino terminus. J. Biol. Chem. 267: 23772-23781,
1992.
12. Rothnagel, J. A.; Longley, M. A.; Bundman, D. S.; Naylor, S. L.;
Lalley, P. A.; Jenkins, N. A.; Gilbert, D. J.; Copeland, N. G.; Roop,
D. R.: Characterization of the mouse loricrin gene: linkage with
profilaggrin and the flaky tail and soft coat mutant loci on chromosome
3. Genomics 23: 450-456, 1994.
13. Sandilands, A.; Terron-Kwiatkowski, A.; Hull, P. R.; O'Regan,
G. M.; Clayton, T. H.; Watson, R. M.; Carrick, T.; Evans, A. T.; Liao,
H.; Zhao, Y.; Campbell, L. E.; Schmuth, M.; and 13 others: Comprehensive
analysis of the gene encoding filaggrin uncovers prevalent and rare
mutations in ichthyosis vulgaris and atopic eczema. Nature Genet. 39:
650-654, 2007.
14. Smith, F. J. D.; Irvine, A. D.; Terron-Kwiatkowski, A.; Sandilands,
A.; Campbell, L. E.; Zhao, Y.; Liao, H.; Evans, A. T.; Goudie, D.
R.; Lewis-Jones, S.; Arseculeratne, G.; Munro, C. S.; Sergeant, A.;
O'Regan, G.; Bale, S. J.; Compton, J. G.; DiGiovanna, J. J.; Presland,
R. B.; Fleckman, P.; McLean, W. H. I.: Loss-of-function mutations
in the gene encoding filaggrin cause ichthyosis vulgaris. Nature
Genet. 38: 337-342, 2006.
15. Sybert, V. P.; Dale, B. A.; Holbrook, K. A.: Ichthyosis vulgaris:
identification of a defect in synthesis of filaggrin correlated with
an absence of keratohyaline granules. J. Invest. Derm. 84: 191-194,
1985.
16. Volz, A.; Korge, B. P.; Compton, J. G.; Ziegler, A.; Steinert,
P. M.; Mischke, D.: Physical mapping of a functional cluster of epidermal
differentiation genes on chromosome 1q21. Genomics 18: 92-99, 1993.
17. Weidinger, S.; Illig, T.; Baurecht, H.; Irvine, A. D.; Rodriquez,
E.; Diaz-Lacava, A.; Klopp, N.; Wagenpfeil, S.; Zhao, Y.; Liao, H.;
Lee, S. P.; Palmer, C. N. A.; Jenneck, C.; Maintz, L.; Hagemann, T.;
Behrendt, H.; Ring, J.; Nothen, M. M.; McLean, W. H. I.; Novak, N.
: Loss-of-function variations within the filaggrin gene predispose
for atopic dermatitis with allergic sensitizations. J. Allergy Clin.
Immun. 118: 214-219, 2006. Note: Erratum: J. Allergy Clin. Immun.
118: 922 only, 2006. Erratum: J. Allergy Clin. Immun. 118: 724 only,
2006.
*FIELD* CN
Ada Hamosh - updated: 10/2/2009
Marla J. F. O'Neill - updated: 4/18/2008
George E. Tiller - updated: 11/8/2007
Victor A. McKusick - updated: 5/24/2007
Victor A. McKusick - updated: 4/27/2006
Victor A. McKusick - updated: 2/24/2006
*FIELD* CD
Victor A. McKusick: 11/8/1987
*FIELD* ED
terry: 04/04/2013
terry: 3/28/2013
wwang: 2/7/2011
alopez: 10/8/2009
terry: 10/2/2009
terry: 7/18/2008
carol: 4/18/2008
carol: 4/14/2008
wwang: 12/3/2007
terry: 11/8/2007
terry: 8/9/2007
alopez: 6/6/2007
terry: 5/24/2007
alopez: 5/2/2006
terry: 4/27/2006
alopez: 3/2/2006
terry: 2/24/2006
dkim: 12/16/1998
terry: 6/18/1998
alopez: 7/29/1997
alopez: 7/7/1997
carol: 12/1/1994
carol: 10/14/1993
supermim: 3/16/1992
carol: 3/4/1992
carol: 1/31/1991
carol: 12/17/1990
*RECORD*
*FIELD* NO
135940
*FIELD* TI
*135940 FILAGGRIN; FLG
PROFILAGGRIN, INCLUDED
*FIELD* TX
DESCRIPTION
Profilaggrin is a major protein component of the keratohyalin granules
read moreof mammalian epidermis. It is initially expressed as a large polyprotein
precursor which is subsequently proteolytically processed into
individual functional filaggrin molecules. The filaggrins show wide
species variations and their aberrant expression has been implicated in
a number of keratinizing disorders (Baden et al., 1974; Holbrook et al.,
1982; Sybert et al., 1985).
CLONING
McKinley-Grant et al. (1989) isolated a cDNA clone encoding human
filaggrin. They demonstrated that the human gene encodes a polyprotein
precursor containing numerous tandem filaggrin repeats. This structure
is similar to that of the mouse; however, the human filaggrin repeat is
much longer (972 basepairs; 324 amino acids) and shows little sequence
homology to the mouse protein. They found furthermore that the human
filaggrin repeats show considerable sequence variations; such
polymorphism is not found in the mouse. By peptide mapping, they defined
a short linker sequence within the human filaggrin repeat that is
excised by proteolysis to yield functional molecules. They showed by in
situ hybridization that the expression of the gene for the human
filaggrin precursor is tightly regulated at the transcriptional level in
terminally differentiating epidermis.
Gan et al. (1990) isolated genomic DNA and cDNA clones encoding the
5-prime and 3-prime ends of the human gene and mRNA. They found evidence
of likely CAT and TATA sequences, an intron in the 5-prime untranslated
region, and several potential regulatory sequences. The gene is made up
of repeats, all of the same length. Sequences showed considerable
variation, most attributable to single-base changes. Thus, human
filaggrin consists of a heterogeneous population of molecules of
different sizes, charges, and sequences. Amino acid sequences encoding
the amino and carboxyl termini were more conserved, as were the 5-prime
and 3-prime DNA sequences flanking the coding portions of the gene. The
presence of unique restriction enzyme sites in these conserved flanking
sequences enabled Gan et al. (1990) to calculate the size of the
full-length gene and the number of repeats in it; depending on the
source of genomic DNA, the gene contains 10, 11, or 12 filaggrin repeats
that segregate in families in a normal mendelian manner. Thus, the human
profilaggrin gene is polymorphic with respect to size due to simple
allelic differences between individuals.
GENE STRUCTURE
The FLG gene comprises 3 exons (Presland et al., 1992).
MAPPING
Using a cDNA clone as a probe in the study of a panel of mouse-human
somatic cell hybrids retaining overlapping subsets of human chromosomal
regions and for chromosomal in situ hybridization, McKinley-Grant et al.
(1989) demonstrated that the human filaggrin gene maps to 1q21.
Rothnagel et al. (1994) mapped the homologous gene to mouse chromosome 3
by PCR analyses of DNAs isolated from mouse/Chinese hamster somatic cell
hybrids.
Genes of 3 protein families that are specifically expressed in the
course of terminal differentiation of human epidermis have been mapped
to 1q21. Volz et al. (1993) showed that these genes are physically
linked within 2.05 Mb of DNA in the following order: calpactin I light
chain (CAL1L; 114085), trichohyalin (THL; 190370), profilaggrin,
involucrin (IVL; 147360), small proline-rich protein (SPRR1A; 182265),
loricrin (LOR; 152445), and calcyclin (CACY; 114110).
GENE FUNCTION
Smith et al. (2006) reviewed the function of filaggrin, also known as
filament-aggregating protein, in the formation of the stratum corneum.
Keratohyalin granules in the granular layer of interfollicular epidermis
are predominantly composed of the 400-kD protein profilaggrin. Following
a short, unique N-terminal domain, most of the profilaggrin molecule
consists of 10 to 12 repeats of the 324-residue filaggrin sequence (Gan
et al., 1990). Upon terminal differentiation of granular cells,
profilaggrin is proteolytically cleaved into filaggrin peptides of
approximately 37 kD and the N-terminal domain containing an S100-like
calcium-binding domain. Filaggrin rapidly aggregates the keratin
cytoskeleton, causing collapse of the granular cells into flattened
anuclear squames. This condensed cytoskeleton is crosslinked by
transglutaminases during formation of the cornified cell envelope (CCE).
The CCE is the outermost barrier layer of the skin which not only
prevents water loss but also impedes the entry of allergens and
infectious agents. Filaggrin is therefore a key protein in facilitating
epidermal differentiation and maintaining barrier function.
MOLECULAR GENETICS
In 15 kindreds with ichthyosis vulgaris (146700), Smith et al. (2006)
identified homozygous or compound heterozygous mutations R501X
(135940.0001) and 2282del4 (135940.0002) in the FLG gene in individuals
with a moderate or severe phenotype. They concluded that these mutations
are semidominant; heterozygotes show a very mild phenotype with
incomplete penetrance. The mutations showed a combined allele frequency
of approximately 4% in populations of European ancestry, explaining the
high incidence of ichthyosis vulgaris. Profilaggrin is the major protein
of keratohyalin granules in the epidermis. During terminal
differentiation, it is cleaved into multiple filaggrin peptides that
aggregate keratin filaments. The resultant matrix is crosslinked to form
a major component of the cornified cell envelope. Smith et al. (2006)
found that loss or reduction of this major structural protein leads to
varying degrees of impaired keratinization.
Twin and family studies have indicated a highly heritable predisposition
to atopic disease, including atopic dermatitis (see 603165), allergy,
and asthma (see 600807). Although genetic studies have focused on
immunologic mechanisms of atopic dermatitis, a primary epithelial
barrier defect has been anticipated (Cookson and Moffatt, 2002).
Filaggrin is a key protein that facilitates terminal differentiation of
the epidermis and formation of the skin barrier. Palmer et al. (2006)
showed that 2 independent loss-of-function genetic variants, R501X
(135940.0001) and 2282del4 (135940.0002), in the FLG gene are very
strong predisposing factors for atopic dermatitis (605803). These
mutations had been shown to be the cause of ichthyosis vulgaris in 15
families and isolated cases (Smith et al., 2006). The R501X and 2282del4
variants, carried by approximately 9% of people of European origin, also
showed highly significant association with asthma occurring in the
context of atopic dermatitis. This work established a key role for
impaired skin barrier function in the development of atopic disease.
Sandilands et al. (2007) showed that the 2 common filaggrin-null
mutations reported by Smith et al. (2006) and Palmer et al. (2006) are
ancestral European variants carried on conserved haplotypes. To
facilitate comprehensive analysis in other populations, they reported a
strategy for full sequencing of this large, highly repetitive gene, and
described 15 variants, including 7 that are prevalent. All the variants
were either nonsense or frameshift mutations that, in representative
cases, resulted in loss of filaggrin production in the epidermis. In an
Irish case-control study, the 5 most common European mutations showed a
strong association with moderate to severe childhood eczema. They found
3 additional rare null mutations in this case series, suggesting that
the genetic architecture of filaggrin-related atopic dermatitis consists
of both prevalent and rare risk alleles.
Using the transmission-disequilibrium test in 476 German
parent-offspring trios with atopic dermatitis, Weidinger et al. (2006)
found a significant association between the loss-of-function mutations
R501X and 2282del4 in the FLG gene and extrinsic atopic dermatitis,
allergic sensitization, total IgE level, asthma, and palmar
hyperlinearity; there was no significant association with intrinsic
atopic dermatitis.
Marenholz et al. (2006) genotyped 1092 children with eczema (atopic
dermatitis) from 2 large European populations for the R501X and 2282del4
mutations in the FLG gene and confirmed a highly significant association
between the null mutations and eczema and concomitant asthma. Moreover,
the authors found that these mutations predisposed to asthma, allergic
rhinitis, and allergic sensitization only in the presence of eczema,
highlighting the importance of the epidermal barrier in the pathogenesis
of these disorders (the so-called 'atopic march').
Nomura et al. (2007) sequenced the entire FLG gene in 7 Japanese
patients with ichthyosis vulgaris from 4 unrelated families who were
negative for the R501X and 2282del4 mutations, and identified
heterozygosity for 2 novel mutations, S2554X (135940.0003) and 3321delA
(135940.0004), respectively. The authors then screened 143 Japanese
patients with atopic dermatitis from 140 unrelated families for the
novel null mutations and identified S2554X in 6 patients and 3321delA in
2 patients; they were not found in 156 unrelated Japanese nonatopic and
nonichthyotic controls, yielding a chi-square p value of 0.0015. Noting
that the R501X and 2282del4 mutations were absent from a total of 253
Japanese individuals, including their patients with ichthyosis vulgaris
and atopic dermatitis, Nomura et al. (2007) concluded that FLG mutations
in Japan are different from those found in European-origin populations.
ANIMAL MODEL
Netherton syndrome (256500) is an autosomal recessive multisystemic
disorder characterized by congenital ichthyosiform erythroderma, hair
shaft defects and atopy, caused by mutation in the SPINK5 gene (605010).
Hewett et al. (2005) created mice with an R820X mutation in the Spink5
gene. Newborn homozygotes developed a severe ichthyosis with a loss of
skin barrier function and dehydration, resulting in death within a few
hours. Biochemical analysis of skin revealed a substantial increase in
the proteolytic processing of profilaggrin into its constituent
filaggrin monomers. The authors suggested that in the absence of SPINK5
there is an abnormal increase in the processing of profilaggrin, and
that this may play a direct role in the observed deficit in the adhesion
of the stratum corneum and the severely compromised epidermal barrier
function.
Fallon et al. (2009) reported a 1-bp deletion mutation, 5303delA,
analogous to common human FLG mutations, within the murine Flg gene in
the spontaneous mouse mutant 'flaky tail' (ft). Fallon et al. (2009)
demonstrated that topical application of allergen to mice homozygous for
this mutation resulted in cutaneous inflammatory infiltrates and
enhanced cutaneous allergen priming with development of
allergen-specific antibody responses. These data validated flaky tail as
a useful model of filaggrin deficiency and provided experimental
evidence for the hypothesis that antigen transfer through a defective
epidermal barrier is a key mechanism underlying elevated IgE
sensitization and initiation of cutaneous inflammation in humans with
filaggrin-related atopic disease.
*FIELD* AV
.0001
ICHTHYOSIS VULGARIS
DERMATITIS, ATOPIC, 2, SUSCEPTIBILITY TO, INCLUDED
FLG, ARG501TER
In 7 unrelated ichthyosis vulgaris (146700) families and 8 additional
'sporadic' cases from Ireland, Scotland, and the U.S., Smith et al.
(2006) found that ichthyosis vulgaris was associated with an
arg501-to-stop (R501X) mutation arising from a 1501C-to-T transition
near the start of repeat 1 in exon 3 of the FLG gene. In 3 families,
ichthyosis vulgaris patients with a very pronounced phenotype were
homozygous for R501X. In other families and isolated cases, they found
individuals with the marked ichthyosis vulgaris phenotype to be compound
heterozygous for R501X and a second mutation, 2282del4, in exon 3
(135940.0002).
Ichthyosis vulgaris is semidominant: that is, heterozygotes had either
no discernible phenotype or milder ichthyosis, whereas homozygotes or
compound heterozygotes had marked ichthyosis and an overt histologic
skin barrier defect. In an extension of the work of Smith et al. (2006),
Palmer et al. (2006) noted that in their families with ichthyosis
vulgaris, many individuals null or heterozygous for filaggrin also had
atopic dermatitis (605803) (eczema) and, in a few cases, also had asthma
(see 600807). Specifically, atopic dermatitis was prevalent in the
individuals with mild ichthyosis vulgaris, all of whom were heterozygous
for either the R501X or 2282del4 FLG-null allele (13/29; 44%). Atopic
dermatitis was particularly common in individuals with severe ichthyosis
vulgaris, all of whom were homozygous or compound heterozygous for
FLG-null alleles (16/21; 76%). None of the individuals in these families
who lacked an FLG-null allele had atopic dermatitis (n = 13). Thus,
atopic dermatitis is inherited as a semidominant trait in these
families, with high penetrance in FLG-null homozygotes or compound
heterozygotes and reduced penetrance in heterozygotes.
Using the transmission-disequilibrium test in 476 German
parent-offspring trios with atopic dermatitis, Weidinger et al. (2006)
found a significant association between the loss-of-function mutations
R501X and 2282del4 in the FLG gene and extrinsic atopic dermatitis,
allergic sensitization, total IgE level, asthma, and palmar
hyperlinearity; there was no significant association with intrinsic
atopic dermatitis.
Marenholz et al. (2006) genotyped 1092 children with eczema (atopic
dermatitis) from 2 large European populations for the R501X and 2282del4
mutations in the FLG gene and replicated the highly significant
association between the null mutations and eczema and concomitant
asthma. Moreover, the authors found that these mutations predisposed to
asthma, allergic rhinitis, and allergic sensitization only in the
presence of eczema, and that the mutations predisposed equally to atopic
(intrinsic) and nonatopic (extrinsic) forms of eczema. They demonstrated
that the presence of 2 null alleles is an independent risk factor for
asthma in children with eczema (OR, 11.76, p = 0.0085). Together, the 2
mutations accounted for approximately 11% of eczema cases in the German
population.
.0002
ICHTHYOSIS VULGARIS
DERMATITIS, ATOPIC, 2, SUSCEPTIBILITY TO, INCLUDED
FLG, 4-BP DEL, 2282CAGT
See 135940.0001 and Smith et al. (2006). The 2282del4 mutation leads to
a premature termination codon 107 bp downstream and, like R501X, stops
protein translation within the first filaggrin repeat.
Palmer et al. (2006) found an association of the 2282del4 and R501X
genetic variants of the FLG gene with atopic dermatitis; see
135940.0001.
Weidinger et al. (2006) found a significant association between atopic
dermatitis, in particular the extrinsic type, and the R501X and 2282del4
mutations; Marenholz et al. (2006) replicated the association and also
found that the presence of 2 null alleles was an independent risk factor
for asthma in children with eczema. See 135940.0001.
.0003
ICHTHYOSIS VULGARIS
DERMATITIS, ATOPIC, 2, SUSCEPTIBILITY TO, INCLUDED
FLG, SER2554TER
In affected members of 2 unrelated Japanese families with ichthyosis
vulgaris (146700) who were negative for previously identified null
mutations in the FLG gene, Nomura et al. (2007) identified
heterozygosity for a 7661C-G transversion in exon 3 of the FLG gene,
resulting in a ser2554-to-ter (S2554X) substitution, predicted to cause
premature termination of profilaggrin translation in the filaggrin
repeat domain 7. The older sister of 1 proband, who had a severe
presentation of the disease, was found to be homozygous for S2554X. The
authors then screened 143 Japanese patients with atopic dermatitis
(605803) from 140 unrelated families for this null mutation and
identified S2554X in 6 patients. The mutation was not found in 156
unrelated nonatopic and nonichthyotic Japanese controls.
.0004
ICHTHYOSIS VULGARIS
DERMATITIS, ATOPIC, 2, SUSCEPTIBILITY TO, INCLUDED
FLG, 1-BP DEL, 3321A
In 2 probands from 2 unrelated Japanese families with ichthyosis
vulgaris (146700), who were negative for previously identified null
mutations in the FLG gene, Nomura et al. (2007) identified
heterozygosity for a 1-bp deletion (3321delA) in exon 3 of the FLG gene,
resulting in a premature termination of profilaggrin translation in
filaggrin repeat domain 2. The authors then screened 143 Japanese
patients with atopic dermatitis (605803) from 140 unrelated families for
this deletion and identified 3321delA in 2 patients. The deletion was
not found in 156 unrelated nonatopic and nonichthyotic Japanese
controls.
*FIELD* RF
1. Baden, H. P.; Roth, S. I.; Goldsmith, L. A.; Lee, L. D.: Keratohyalin
protein in disorders of keratinization. J. Invest. Derm. 62: 411-414,
1974.
2. Cookson, W. O. C. M.; Moffatt, M. F.: The genetics of atopic dermatitis. Curr.
Opin. Allergy Clin. Immun. 2: 383-387, 2002.
3. Fallon, P. G.; Sasaki, T.; Sandilands, A.; Campbell, L. E.; Saunders,
S. P.; Mangan, N. E.; Callanan, J. J.; Kawasaki, H.; Shiohama, A.;
Kubo, A.; Sundberg, J. P.; Presland, R. B.; Fleckman, P.; Shimizu,
N.; Kudoh, J.; Irvine, A. D.; Amagai, M.; McLean, W. H. I.: A homozygous
frameshift mutation in the mouse Flg gene facilitates enhanced percutaneous
allergen priming. Nature Genet. 41: 602-608, 2009.
4. Gan, S.-Q.; McBride, O. W.; Idler, W. W.; Markova, N.; Steinert,
P. M.: Organization, structure, and polymorphisms of the human profilaggrin
gene. Biochemistry 29: 9432-9440, 1990. Note: Erratum: Biochemistry:
30: 5814 only, 1991.
5. Hewett, D. R.; Simons, A. L.; Mangan, N. E.; Jolin, H. E.; Green,
S. M.; Fallon, P. G.; McKenzie, A. N. J.: Lethal, neonatal ichthyosis
with increased proteolytic processing of filaggrin in a mouse model
of Netherton syndrome. Hum. Molec. Genet. 14: 335-346, 2005.
6. Holbrook, K. A.; Dale, B. A.; Brown, K. S.: Abnormal epidermal
keratinization in the repeated epilation mutant mouse. J. Cell Biol. 92:
387-397, 1982.
7. Marenholz, I.; Nickel, R.; Ruschendorf, F.; Schulz, F.; Esparza-Gordillo,
J.; Kerscher, T.; Gruber, C.; Lau, S.; Worm, M.; Keil, T.; Kurek,
M.; Zaluga, E.; Wahn, U.; Lee, Y.-A.: Filaggrin loss-of-function
mutations predispose to phenotypes involved in the atopic march. J.
Allergy Clin. Immun. 118: 866-871, 2006.
8. McKinley-Grant, L. J.; Idler, W. W.; Bernstein, I. A.; Parry, D.
A. D.; Cannizzaro, L.; Croce, C. M.; Huebner, K.; Lessin, S. R.; Steinert,
P. M.: Characterization of a cDNA clone encoding human filaggrin
and localization of the gene to chromosome region 1q21. Proc. Nat.
Acad. Sci. 86: 4848-4852, 1989.
9. Nomura, T.; Sandilands, A.; Akiyama, M.; Liao, H.; Evans, A. T.;
Sakai, K.; Ota, M.; Sugiura, H.; Yamamoto, K.; Sato, H.; Palmer, C.
N. A.; Smith, F. J. D.; McLean, W. H. I.; Shimizu, H.: Unique mutations
in the filaggrin gene in Japanese patients with ichthyosis vulgaris
and atopic dermatitis. J. Allergy Clin. Immun. 119: 434-440, 2007.
10. Palmer, C. N. A.; Irvine, A. D.; Terron-Kwiatkowski, A.; Zhao,
Y.; Liao, H.; Lee, S. P.; Goudie, D. R.; Sandilands, A.; Campbell,
L. E.; Smith, F. J. D.; O'Regan, G. M.; Watson, R. M.; and 15 others
: Common loss-of-function variants of the epidermal barrier protein
filaggrin are a major predisposing factor for atopic dermatitis. Nature
Genet. 38: 441-446, 2006.
11. Presland, R. B.; Haydock, P. V.; Fleckman, P.; Nirunsuksiri, W.;
Dale, B. A.: Characterization of the human epidermal profilaggrin
gene: genomic organization and identification of an S-100-like calcium
binding domain at the amino terminus. J. Biol. Chem. 267: 23772-23781,
1992.
12. Rothnagel, J. A.; Longley, M. A.; Bundman, D. S.; Naylor, S. L.;
Lalley, P. A.; Jenkins, N. A.; Gilbert, D. J.; Copeland, N. G.; Roop,
D. R.: Characterization of the mouse loricrin gene: linkage with
profilaggrin and the flaky tail and soft coat mutant loci on chromosome
3. Genomics 23: 450-456, 1994.
13. Sandilands, A.; Terron-Kwiatkowski, A.; Hull, P. R.; O'Regan,
G. M.; Clayton, T. H.; Watson, R. M.; Carrick, T.; Evans, A. T.; Liao,
H.; Zhao, Y.; Campbell, L. E.; Schmuth, M.; and 13 others: Comprehensive
analysis of the gene encoding filaggrin uncovers prevalent and rare
mutations in ichthyosis vulgaris and atopic eczema. Nature Genet. 39:
650-654, 2007.
14. Smith, F. J. D.; Irvine, A. D.; Terron-Kwiatkowski, A.; Sandilands,
A.; Campbell, L. E.; Zhao, Y.; Liao, H.; Evans, A. T.; Goudie, D.
R.; Lewis-Jones, S.; Arseculeratne, G.; Munro, C. S.; Sergeant, A.;
O'Regan, G.; Bale, S. J.; Compton, J. G.; DiGiovanna, J. J.; Presland,
R. B.; Fleckman, P.; McLean, W. H. I.: Loss-of-function mutations
in the gene encoding filaggrin cause ichthyosis vulgaris. Nature
Genet. 38: 337-342, 2006.
15. Sybert, V. P.; Dale, B. A.; Holbrook, K. A.: Ichthyosis vulgaris:
identification of a defect in synthesis of filaggrin correlated with
an absence of keratohyaline granules. J. Invest. Derm. 84: 191-194,
1985.
16. Volz, A.; Korge, B. P.; Compton, J. G.; Ziegler, A.; Steinert,
P. M.; Mischke, D.: Physical mapping of a functional cluster of epidermal
differentiation genes on chromosome 1q21. Genomics 18: 92-99, 1993.
17. Weidinger, S.; Illig, T.; Baurecht, H.; Irvine, A. D.; Rodriquez,
E.; Diaz-Lacava, A.; Klopp, N.; Wagenpfeil, S.; Zhao, Y.; Liao, H.;
Lee, S. P.; Palmer, C. N. A.; Jenneck, C.; Maintz, L.; Hagemann, T.;
Behrendt, H.; Ring, J.; Nothen, M. M.; McLean, W. H. I.; Novak, N.
: Loss-of-function variations within the filaggrin gene predispose
for atopic dermatitis with allergic sensitizations. J. Allergy Clin.
Immun. 118: 214-219, 2006. Note: Erratum: J. Allergy Clin. Immun.
118: 922 only, 2006. Erratum: J. Allergy Clin. Immun. 118: 724 only,
2006.
*FIELD* CN
Ada Hamosh - updated: 10/2/2009
Marla J. F. O'Neill - updated: 4/18/2008
George E. Tiller - updated: 11/8/2007
Victor A. McKusick - updated: 5/24/2007
Victor A. McKusick - updated: 4/27/2006
Victor A. McKusick - updated: 2/24/2006
*FIELD* CD
Victor A. McKusick: 11/8/1987
*FIELD* ED
terry: 04/04/2013
terry: 3/28/2013
wwang: 2/7/2011
alopez: 10/8/2009
terry: 10/2/2009
terry: 7/18/2008
carol: 4/18/2008
carol: 4/14/2008
wwang: 12/3/2007
terry: 11/8/2007
terry: 8/9/2007
alopez: 6/6/2007
terry: 5/24/2007
alopez: 5/2/2006
terry: 4/27/2006
alopez: 3/2/2006
terry: 2/24/2006
dkim: 12/16/1998
terry: 6/18/1998
alopez: 7/29/1997
alopez: 7/7/1997
carol: 12/1/1994
carol: 10/14/1993
supermim: 3/16/1992
carol: 3/4/1992
carol: 1/31/1991
carol: 12/17/1990
MIM
146700
*RECORD*
*FIELD* NO
146700
*FIELD* TI
#146700 ICHTHYOSIS VULGARIS
;;ICHTHYOSIS SIMPLEX
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
read moreichthyosis vulgaris can be caused by homozygous or heterozygous mutation
in the filaggrin gene (FLG; 135940) on chromosome 1q21.
CLINICAL FEATURES
Ichthyosis is one of the most frequent single-gene disorders in humans.
The most widely cited incidence figure is 1 in 250 based on a survey of
6,051 healthy English schoolchildren (Wells and Kerr, 1966). The
phenotypic characteristics of ichthyosis vulgaris include palmar
hyperlinearity, keratosis pilaris, and a fine scale that is most
prominent over the lower abdomen, arms, and legs.
Wells and Kerr (1965) suggested that dominant ichthyosis vulgaris is
distinguishable clinically from the X-linked variety (308100). In the
dominant form, the first skin involvement is usually noted after the
first 3 months of life and less of the body surface is affected. Lesions
are rarely observed in the axillae or antecubital and popliteal fossae
but the palms and soles often show increased markings. There are some
histologic differences also. A considerable proportion of patients with
dominant ichthyosis have asthma, eczema, or hay fever. For a useful
classification and discussion of the various forms of ichthyosis, see
Schnyder (1970).
Mevorah et al. (1978) described ichthyosis in a mother and 6 of her
sons. A seventh son and 2 daughters were normal. The disorder in the
mother was clinically and histologically of the dominant type, whereas
the affected sons showed features of both the autosomal dominant and
X-linked recessive forms. The authors concluded that the mother was
heterozygous for both forms.
BIOCHEMICAL FEATURES
Anton-Lamprecht (1978) pointed out that electron microscopy is
particularly revealing in dominant disorders in which structural
abnormality of a protein is likely to be found, whereas biochemistry is
more likely to be revealing in recessive disorders. The examples he used
from dermatology to illustrate electron microscopic abnormalities were
structural defects of tonofibrils in hystrix-like ichthyoses, of the
anchoring fibrils in dominant dystrophic epidermolysis bullosa of
Pasini, and of keratohyalin in autosomal dominant ichthyosis vulgaris.
In skin fibroblasts from patients with autosomal dominant ichthyosis
vulgaris, Meyer et al. (1982) found elevation of arylsulfatase C
activity using 4-methylumbelliferylsulfate. This may correspond to the f
isoform (ARSC2; 301780) (see Chang et al., 1986, 1990). However, Meyer
et al. (1982) found that steroid sulfatase (STS; 300747) activity using
3-dehydroepiandrosteronsulfate was normal. In leukocytes, both
activities were the same in patients and controls.
Ichthyosis vulgaris is characterized histologically by absent or reduced
keratohyalin granules in the epidermis and mild hyperkeratosis.
Keratohyalin contains a histidine-rich protein which is the precursor
form (profilaggrin) of filaggrin (FLG; 135940), a keratin
filament-aggregating protein. Using an antiserum, Sybert et al. (1985)
demonstrated that profilaggrin and filaggrin were reduced or absent in 5
patients from 2 kindreds with ichthyosis vulgaris. The biochemical
abnormality correlated with the morphologic reduction in amount of
keratohyalin.
Nirunsuksiri et al. (1998) presented evidence that profilaggrin mRNA in
keratinocytes cultured from subjects with ichthyosis vulgaris is
intrinsically unstable and has a shorter half-life compared with that in
normal cells. When ichthyosis vulgaris-affected keratinocytes were
treated with the protein synthesis inhibitor cycloheximide, the
steady-state level of profilaggrin mRNA was increased due to
stabilization of the transcript. The number of filaggrin repeats (10 to
12) in individuals with ichthyosis vulgaris did not differ from that of
unaffected subjects. Expression of the gene was biallelic and coequal in
both control and affected individuals. The results of Nirunsuksiri et
al. (1998) suggested a model in which a labile ribonuclease and a
stabilizing factor may modulate the profilaggrin mRNA steady-state level
in normal cells, whereas the stabilizing factor may be absent or
functionally inactive in ichthyosis vulgaris-affected keratinocytes.
MAPPING
By linkage analysis, Zhong et al. (2003) identified a locus for
ichthyosis vulgaris on chromosome 1q22 with a maximum 2-point lod score
of 2.47 at marker D1S1653 with a recombination fraction of 0.00. The
epidermal differentiation complex (EDC; see 152445) comprises 3 gene
families that are functionally related and mapped to 1q21. Zhong et al.
(2003) stated that there was no overlap between the EDC region and the
ichthyosis vulgaris locus on 1q22. However, only 4 Mb of genomic DNA
separated EDC from D1S1653.
In an American family, Compton et al. (2002) showed linkage between
ichthyosis vulgaris associated with a histologically absent granular
layer and markers in the EDC on 1q21. The EDC is a dense cluster of
genes encoding scores of epidermal structural proteins including
filaggrin, loricrin (LOR; 152445), involucrin (IVL; 147360),
trichohyalin (THH; 190370), and others.
MOLECULAR GENETICS
Smith et al. (2006) analyzed the filaggrin gene in 7 unrelated
ichthyosis vulgaris patients and 8 sporadic cases, based on linkage and
histologic evidence presented by Compton et al. (2002) and Zhong et al.
(2003). In 1 family they identified a homozygous mutation, R501X
(135940.0001), near the start of repeat 1 in exon 3 of the FLG gene.
Further studies showed this mutation in the other 14 ichthyosis vulgaris
kindreds studied. The mutation created a new restriction enzyme site
which could be used to confirm the mutation and screen populations. By
this means, they found the mutation to be present in relatively high
allele frequencies in Irish, Scottish, and European American populations
(combined frequency, 0.027).
In 3 families, Smith et al. (2006) found that ichthyosis vulgaris
patients with a very pronounced phenotype were homozygous for R501X. In
other families, they found individuals with the marked ichthyosis
vulgaris phenotype to be heterozygous for R501X. Further sequencing in
these cases showed the existence of a second mutation, 2282del4
(135940.0002), in exon 3 of the FLG gene. The 2282del4 mutation leads to
a premature termination codon 107 bp downstream and, like R501X, stops
protein translation within the first filaggrin repeat. This mutation
also created a restriction enzyme site which could be used to screen
ichthyosis vulgaris families and populations. The 2282del4 mutation
segregated in 10 of the ichthyosis vulgaris families. Of the 8
'sporadic' cases of clinically significant ichthyosis vulgaris in which
family history was not available, 4 were homozygous for R501X and the
remaining 4 were R501X/2282del4 compound heterozygotes. Restudy of the
family reported by Compton et al. (2002) showed that severely affected
individuals were compound heterozygotes for these 2 mutations.
The association of ichthyosis vulgaris with atopic diathesis is well
established; 37 to 50% of people with ichthyosis vulgaris have atopic
diseases, and roughly 8% of patients with atopic dermatitis (603165)
have classic features of ichthyosis vulgaris.
Nomura et al. (2007) sequenced the entire FLG gene in 7 Japanese
patients with ichthyosis vulgaris from 4 unrelated families who were
negative for the R501X and 2282del4 mutations, and identified
heterozygosity for 2 novel mutations, S2554X (135940.0003) and 3321delA
(135940.0004), respectively. The older sister of 1 proband, who had a
more severe presentation of the disease, was found to be homozygous for
the S2554X mutation. Noting that the R501X and 2282del4 mutations were
absent from a total of 253 Japanese individuals, including their
patients with ichthyosis vulgaris and atopic dermatitis, Nomura et al.
(2007) concluded that FLG mutations in Japan are different from those
found in European-origin populations.
INHERITANCE
In one family studied by Smith et al. (2006), the semidominant mode of
inheritance of ichthyosis vulgaris was exemplified by multiple examples
of patients with very mild presentation as well as by R501X homozygotes
and R501X/2282del4 compound heterozygotes with the full ichthyosis
vulgaris phenotype. In their series of families studied by Smith et al.
(2006), there were only 2 individuals who were heterozygous for a null
mutation, namely R501X, and had no obvious phenotype. On the basis of
these small numbers, Smith et al. (2006) calculated the penetrance in
heterozygotes to be about 90%.
ANIMAL MODEL
Presland et al. (2000) demonstrated that 'flaky tail' (ft) mice express
an abnormal profilaggrin (135940) polypeptide that does not form normal
keratohyalin F-granules and is not proteolytically processed to
filaggrin. This autosomal recessive trait maps to the central region of
mouse chromosome 3, in the vicinity of the epidermal differentiation
complex. Affected homozygous ft/ft mice exhibit large, disorganized
scales on tail and paw skin, marked attenuation of the epidermal
granular layer, mild acanthosis, and orthokeratotic hyperkeratosis.
Cultured ft/ft keratinocytes synthesized reduced amounts of profilaggrin
mRNA and protein, demonstrating that the defect in profilaggrin
expression is intrinsic to epidermal cells. Presland et al. (2000)
proposed that the absence of filaggrin, and in particular the
hygroscopic, filaggrin-derived amino acids that are thought to function
in epidermal hydration, underlies the dry, scaly skin characteristic of
ft/ft mice.
*FIELD* SA
Anton-Lamprecht and Hofbauer (1972); Kuokkanen (1969); Traupe et
al. (1981); Williams and Elias (1986)
*FIELD* RF
1. Anton-Lamprecht, I.: Electron microscopy in the early diagnosis
of genetic disorders of the skin. Dermatologica 157: 65-85, 1978.
2. Anton-Lamprecht, I.; Hofbauer, M.: Ultrastructural distinction
of autosomal dominant ichthyosis vulgaris and X-linked recessive ichthyosis. Humangenetik 15:
261-264, 1972.
3. Chang, P. L.; Mueller, O. T.; Lafrenie, R. M.; Varey, P. A.; Rosa,
N. E.; Davidson, R. G.; Henry, W. M.; Shows, T. B.: The human arylsulfatase-C
isoenzymes: two distinct genes that escape from X inactivation. Am.
J. Hum. Genet. 46: 729-737, 1990.
4. Chang, P. L.; Varey, P. A.; Rosa, N. E.; Ameen, M.; Davidson, R.
G.: Association of steroid sulfatase with one of the arylsulfatase
C isozymes in human fibroblasts. J. Biol. Chem. 261: 14443-14447,
1986.
5. Compton, J. G.; DiGiovanna, J. J.; Johnston, K. A.; Fleckman, P.;
Bale, S. J.: Mapping of the associated phenotype of an absent granular
layer in ichthyosis vulgaris to the epidermal differentiation complex
on chromosome 1. Exp. Derm. 11: 518-526, 2002.
6. Kuokkanen, K.: Ichthyosis vulgaris: A clinical and histopathological
study of patients and their close relatives in the autosomal dominant
and sex-linked forms of the disease. Acta Derm. Venerol. 49 (suppl.
62): 1-72, 1969.
7. Mevorah, B.; Frenk, E.; Pescia, G.: Ichthyosis vulgaris showing
features of the autosomal dominant and the X-linked recessive variant
in the same family. Clin. Genet. 13: 462-470, 1978.
8. Meyer, J. C.; Grundmann, H.; Weiss, H.: Elevated levels of arylsulfatase
C activity in cultured skin fibroblasts of patients with autosomal
dominant ichthyosis vulgaris. Hum. Genet. 60: 69-70, 1982.
9. Nirunsuksiri, W.; Zhang, S.-H.; Fleckman, P.: Reduced stability
and bi-allelic, coequal expression of profilaggrin mRNA in keratinocytes
cultured from subjects with ichthyosis vulgaris. J. Invest. Derm. 110:
854-861, 1998.
10. Nomura, T.; Sandilands, A.; Akiyama, M.; Liao, H.; Evans, A. T.;
Sakai, K.; Ota, M.; Sugiura, H.; Yamamoto, K.; Sato, H.; Palmer, C.
N. A.; Smith, F. J. D.; McLean, W. H. I.; Shimizu, H.: Unique mutations
in the filaggrin gene in Japanese patients with ichthyosis vulgaris
and atopic dermatitis. J. Allergy Clin. Immun. 119: 434-440, 2007.
11. Presland, R. B.; Boggess, D.; Lewis, S. P.; Hull, C.; Fleckman,
P.; Sundberg, J. P.: Loss of normal profilaggrin and filaggrin in
flaky tail (ft/ft) mice: an animal model for the filaggrin-deficient
skin disease ichthyosis vulgaris. J. Invest. Derm. 115: 1072-1081,
2000.
12. Schnyder, U. W.: Inherited ichthyoses. Arch. Derm. 102: 240-252,
1970.
13. Smith, F. J. D.; Irvine, A. D.; Terron-Kwiatkowski, A.; Sandilands,
A.; Campbell, L. E.; Zhao, Y.; Liao, H.; Evans, A. T.; Goudie, D.
R.; Lewis-Jones, S.; Arseculeratne, G.; Munro, C. S.; Sergeant, A.;
O'Regan, G.; Bale, S. J.; Compton, J. G.; DiGiovanna, J. J.; Presland,
R. B.; Fleckman, P.; McLean, W. H. I.: Loss-of-function mutations
in the gene encoding filaggrin cause ichthyosis vulgaris. Nature
Genet. 38: 337-342, 2006.
14. Sybert, V. P.; Dale, B. A.; Holbrook, K. A.: Ichthyosis vulgaris:
identification of a defect in synthesis of filaggrin correlated with
an absence of keratohyaline granules. J. Invest. Derm. 84: 191-194,
1985.
15. Traupe, H.; Happle, R.; Ropers, H. H.; Muller, C. R.: X-linked
recessive ichthyosis and autosomal dominant ichthyosis segregating
in the same family. Arch. Derm. Res. 271: 149-156, 1981.
16. Wells, R. S.; Kerr, C. B.: Clinical features of autosomal dominant
and sex-linked ichthyosis in an English population. Brit. Med. J. 1:
947-950, 1966.
17. Wells, R. S.; Kerr, C. B.: Genetic classification of ichthyosis. Arch.
Derm. 92: 1-6, 1965.
18. Williams, M. L.; Elias, P. M.: Ichthyosis: genetic heterogeneity,
genodermatoses, and genetic counseling. Arch. Derm. 122: 529-531,
1986.
19. Zhong, W.; Cui, B.; Zhang, Y.; Jiang, H.; Wei, S.; Bu, L.; Zhao,
G.; Hu, L.; Kong, X.: Linkage analysis suggests a locus of ichthyosis
vulgaris on 1q22. J. Hum. Genet. 48: 390-392, 2003.
*FIELD* CS
Skin:
Ichthyosis vulgaris;
Ichthyosis simplex
Misc:
Onset usually after 3 months age;
Lesions rare in the axillae, antecubital or popliteal fossae;
Palms and soles often show increased markings;
Frequent asthma, eczema or hay fever
Inheritance:
Autosomal dominant
*FIELD* CN
Marla J. F. O'Neill - updated: 4/18/2008
Anne M. Stumpf - updated: 3/2/2006
Victor A. McKusick - updated: 2/24/2006
Victor A. McKusick - updated: 8/27/2003
Gary A. Bellus - updated: 3/28/2001
*FIELD* CD
Victor A. McKusick: 6/2/1986
*FIELD* ED
terry: 03/20/2012
mgross: 2/13/2009
carol: 11/3/2008
ckniffin: 11/3/2008
carol: 11/3/2008
carol: 4/18/2008
alopez: 1/24/2007
alopez: 3/17/2006
alopez: 3/2/2006
terry: 2/24/2006
joanna: 3/19/2004
cwells: 9/2/2003
terry: 8/27/2003
cwells: 4/3/2001
cwells: 3/28/2001
mark: 2/26/1998
mimadm: 11/5/1994
carol: 5/24/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/27/1989
marie: 3/25/1988
*RECORD*
*FIELD* NO
146700
*FIELD* TI
#146700 ICHTHYOSIS VULGARIS
;;ICHTHYOSIS SIMPLEX
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
read moreichthyosis vulgaris can be caused by homozygous or heterozygous mutation
in the filaggrin gene (FLG; 135940) on chromosome 1q21.
CLINICAL FEATURES
Ichthyosis is one of the most frequent single-gene disorders in humans.
The most widely cited incidence figure is 1 in 250 based on a survey of
6,051 healthy English schoolchildren (Wells and Kerr, 1966). The
phenotypic characteristics of ichthyosis vulgaris include palmar
hyperlinearity, keratosis pilaris, and a fine scale that is most
prominent over the lower abdomen, arms, and legs.
Wells and Kerr (1965) suggested that dominant ichthyosis vulgaris is
distinguishable clinically from the X-linked variety (308100). In the
dominant form, the first skin involvement is usually noted after the
first 3 months of life and less of the body surface is affected. Lesions
are rarely observed in the axillae or antecubital and popliteal fossae
but the palms and soles often show increased markings. There are some
histologic differences also. A considerable proportion of patients with
dominant ichthyosis have asthma, eczema, or hay fever. For a useful
classification and discussion of the various forms of ichthyosis, see
Schnyder (1970).
Mevorah et al. (1978) described ichthyosis in a mother and 6 of her
sons. A seventh son and 2 daughters were normal. The disorder in the
mother was clinically and histologically of the dominant type, whereas
the affected sons showed features of both the autosomal dominant and
X-linked recessive forms. The authors concluded that the mother was
heterozygous for both forms.
BIOCHEMICAL FEATURES
Anton-Lamprecht (1978) pointed out that electron microscopy is
particularly revealing in dominant disorders in which structural
abnormality of a protein is likely to be found, whereas biochemistry is
more likely to be revealing in recessive disorders. The examples he used
from dermatology to illustrate electron microscopic abnormalities were
structural defects of tonofibrils in hystrix-like ichthyoses, of the
anchoring fibrils in dominant dystrophic epidermolysis bullosa of
Pasini, and of keratohyalin in autosomal dominant ichthyosis vulgaris.
In skin fibroblasts from patients with autosomal dominant ichthyosis
vulgaris, Meyer et al. (1982) found elevation of arylsulfatase C
activity using 4-methylumbelliferylsulfate. This may correspond to the f
isoform (ARSC2; 301780) (see Chang et al., 1986, 1990). However, Meyer
et al. (1982) found that steroid sulfatase (STS; 300747) activity using
3-dehydroepiandrosteronsulfate was normal. In leukocytes, both
activities were the same in patients and controls.
Ichthyosis vulgaris is characterized histologically by absent or reduced
keratohyalin granules in the epidermis and mild hyperkeratosis.
Keratohyalin contains a histidine-rich protein which is the precursor
form (profilaggrin) of filaggrin (FLG; 135940), a keratin
filament-aggregating protein. Using an antiserum, Sybert et al. (1985)
demonstrated that profilaggrin and filaggrin were reduced or absent in 5
patients from 2 kindreds with ichthyosis vulgaris. The biochemical
abnormality correlated with the morphologic reduction in amount of
keratohyalin.
Nirunsuksiri et al. (1998) presented evidence that profilaggrin mRNA in
keratinocytes cultured from subjects with ichthyosis vulgaris is
intrinsically unstable and has a shorter half-life compared with that in
normal cells. When ichthyosis vulgaris-affected keratinocytes were
treated with the protein synthesis inhibitor cycloheximide, the
steady-state level of profilaggrin mRNA was increased due to
stabilization of the transcript. The number of filaggrin repeats (10 to
12) in individuals with ichthyosis vulgaris did not differ from that of
unaffected subjects. Expression of the gene was biallelic and coequal in
both control and affected individuals. The results of Nirunsuksiri et
al. (1998) suggested a model in which a labile ribonuclease and a
stabilizing factor may modulate the profilaggrin mRNA steady-state level
in normal cells, whereas the stabilizing factor may be absent or
functionally inactive in ichthyosis vulgaris-affected keratinocytes.
MAPPING
By linkage analysis, Zhong et al. (2003) identified a locus for
ichthyosis vulgaris on chromosome 1q22 with a maximum 2-point lod score
of 2.47 at marker D1S1653 with a recombination fraction of 0.00. The
epidermal differentiation complex (EDC; see 152445) comprises 3 gene
families that are functionally related and mapped to 1q21. Zhong et al.
(2003) stated that there was no overlap between the EDC region and the
ichthyosis vulgaris locus on 1q22. However, only 4 Mb of genomic DNA
separated EDC from D1S1653.
In an American family, Compton et al. (2002) showed linkage between
ichthyosis vulgaris associated with a histologically absent granular
layer and markers in the EDC on 1q21. The EDC is a dense cluster of
genes encoding scores of epidermal structural proteins including
filaggrin, loricrin (LOR; 152445), involucrin (IVL; 147360),
trichohyalin (THH; 190370), and others.
MOLECULAR GENETICS
Smith et al. (2006) analyzed the filaggrin gene in 7 unrelated
ichthyosis vulgaris patients and 8 sporadic cases, based on linkage and
histologic evidence presented by Compton et al. (2002) and Zhong et al.
(2003). In 1 family they identified a homozygous mutation, R501X
(135940.0001), near the start of repeat 1 in exon 3 of the FLG gene.
Further studies showed this mutation in the other 14 ichthyosis vulgaris
kindreds studied. The mutation created a new restriction enzyme site
which could be used to confirm the mutation and screen populations. By
this means, they found the mutation to be present in relatively high
allele frequencies in Irish, Scottish, and European American populations
(combined frequency, 0.027).
In 3 families, Smith et al. (2006) found that ichthyosis vulgaris
patients with a very pronounced phenotype were homozygous for R501X. In
other families, they found individuals with the marked ichthyosis
vulgaris phenotype to be heterozygous for R501X. Further sequencing in
these cases showed the existence of a second mutation, 2282del4
(135940.0002), in exon 3 of the FLG gene. The 2282del4 mutation leads to
a premature termination codon 107 bp downstream and, like R501X, stops
protein translation within the first filaggrin repeat. This mutation
also created a restriction enzyme site which could be used to screen
ichthyosis vulgaris families and populations. The 2282del4 mutation
segregated in 10 of the ichthyosis vulgaris families. Of the 8
'sporadic' cases of clinically significant ichthyosis vulgaris in which
family history was not available, 4 were homozygous for R501X and the
remaining 4 were R501X/2282del4 compound heterozygotes. Restudy of the
family reported by Compton et al. (2002) showed that severely affected
individuals were compound heterozygotes for these 2 mutations.
The association of ichthyosis vulgaris with atopic diathesis is well
established; 37 to 50% of people with ichthyosis vulgaris have atopic
diseases, and roughly 8% of patients with atopic dermatitis (603165)
have classic features of ichthyosis vulgaris.
Nomura et al. (2007) sequenced the entire FLG gene in 7 Japanese
patients with ichthyosis vulgaris from 4 unrelated families who were
negative for the R501X and 2282del4 mutations, and identified
heterozygosity for 2 novel mutations, S2554X (135940.0003) and 3321delA
(135940.0004), respectively. The older sister of 1 proband, who had a
more severe presentation of the disease, was found to be homozygous for
the S2554X mutation. Noting that the R501X and 2282del4 mutations were
absent from a total of 253 Japanese individuals, including their
patients with ichthyosis vulgaris and atopic dermatitis, Nomura et al.
(2007) concluded that FLG mutations in Japan are different from those
found in European-origin populations.
INHERITANCE
In one family studied by Smith et al. (2006), the semidominant mode of
inheritance of ichthyosis vulgaris was exemplified by multiple examples
of patients with very mild presentation as well as by R501X homozygotes
and R501X/2282del4 compound heterozygotes with the full ichthyosis
vulgaris phenotype. In their series of families studied by Smith et al.
(2006), there were only 2 individuals who were heterozygous for a null
mutation, namely R501X, and had no obvious phenotype. On the basis of
these small numbers, Smith et al. (2006) calculated the penetrance in
heterozygotes to be about 90%.
ANIMAL MODEL
Presland et al. (2000) demonstrated that 'flaky tail' (ft) mice express
an abnormal profilaggrin (135940) polypeptide that does not form normal
keratohyalin F-granules and is not proteolytically processed to
filaggrin. This autosomal recessive trait maps to the central region of
mouse chromosome 3, in the vicinity of the epidermal differentiation
complex. Affected homozygous ft/ft mice exhibit large, disorganized
scales on tail and paw skin, marked attenuation of the epidermal
granular layer, mild acanthosis, and orthokeratotic hyperkeratosis.
Cultured ft/ft keratinocytes synthesized reduced amounts of profilaggrin
mRNA and protein, demonstrating that the defect in profilaggrin
expression is intrinsic to epidermal cells. Presland et al. (2000)
proposed that the absence of filaggrin, and in particular the
hygroscopic, filaggrin-derived amino acids that are thought to function
in epidermal hydration, underlies the dry, scaly skin characteristic of
ft/ft mice.
*FIELD* SA
Anton-Lamprecht and Hofbauer (1972); Kuokkanen (1969); Traupe et
al. (1981); Williams and Elias (1986)
*FIELD* RF
1. Anton-Lamprecht, I.: Electron microscopy in the early diagnosis
of genetic disorders of the skin. Dermatologica 157: 65-85, 1978.
2. Anton-Lamprecht, I.; Hofbauer, M.: Ultrastructural distinction
of autosomal dominant ichthyosis vulgaris and X-linked recessive ichthyosis. Humangenetik 15:
261-264, 1972.
3. Chang, P. L.; Mueller, O. T.; Lafrenie, R. M.; Varey, P. A.; Rosa,
N. E.; Davidson, R. G.; Henry, W. M.; Shows, T. B.: The human arylsulfatase-C
isoenzymes: two distinct genes that escape from X inactivation. Am.
J. Hum. Genet. 46: 729-737, 1990.
4. Chang, P. L.; Varey, P. A.; Rosa, N. E.; Ameen, M.; Davidson, R.
G.: Association of steroid sulfatase with one of the arylsulfatase
C isozymes in human fibroblasts. J. Biol. Chem. 261: 14443-14447,
1986.
5. Compton, J. G.; DiGiovanna, J. J.; Johnston, K. A.; Fleckman, P.;
Bale, S. J.: Mapping of the associated phenotype of an absent granular
layer in ichthyosis vulgaris to the epidermal differentiation complex
on chromosome 1. Exp. Derm. 11: 518-526, 2002.
6. Kuokkanen, K.: Ichthyosis vulgaris: A clinical and histopathological
study of patients and their close relatives in the autosomal dominant
and sex-linked forms of the disease. Acta Derm. Venerol. 49 (suppl.
62): 1-72, 1969.
7. Mevorah, B.; Frenk, E.; Pescia, G.: Ichthyosis vulgaris showing
features of the autosomal dominant and the X-linked recessive variant
in the same family. Clin. Genet. 13: 462-470, 1978.
8. Meyer, J. C.; Grundmann, H.; Weiss, H.: Elevated levels of arylsulfatase
C activity in cultured skin fibroblasts of patients with autosomal
dominant ichthyosis vulgaris. Hum. Genet. 60: 69-70, 1982.
9. Nirunsuksiri, W.; Zhang, S.-H.; Fleckman, P.: Reduced stability
and bi-allelic, coequal expression of profilaggrin mRNA in keratinocytes
cultured from subjects with ichthyosis vulgaris. J. Invest. Derm. 110:
854-861, 1998.
10. Nomura, T.; Sandilands, A.; Akiyama, M.; Liao, H.; Evans, A. T.;
Sakai, K.; Ota, M.; Sugiura, H.; Yamamoto, K.; Sato, H.; Palmer, C.
N. A.; Smith, F. J. D.; McLean, W. H. I.; Shimizu, H.: Unique mutations
in the filaggrin gene in Japanese patients with ichthyosis vulgaris
and atopic dermatitis. J. Allergy Clin. Immun. 119: 434-440, 2007.
11. Presland, R. B.; Boggess, D.; Lewis, S. P.; Hull, C.; Fleckman,
P.; Sundberg, J. P.: Loss of normal profilaggrin and filaggrin in
flaky tail (ft/ft) mice: an animal model for the filaggrin-deficient
skin disease ichthyosis vulgaris. J. Invest. Derm. 115: 1072-1081,
2000.
12. Schnyder, U. W.: Inherited ichthyoses. Arch. Derm. 102: 240-252,
1970.
13. Smith, F. J. D.; Irvine, A. D.; Terron-Kwiatkowski, A.; Sandilands,
A.; Campbell, L. E.; Zhao, Y.; Liao, H.; Evans, A. T.; Goudie, D.
R.; Lewis-Jones, S.; Arseculeratne, G.; Munro, C. S.; Sergeant, A.;
O'Regan, G.; Bale, S. J.; Compton, J. G.; DiGiovanna, J. J.; Presland,
R. B.; Fleckman, P.; McLean, W. H. I.: Loss-of-function mutations
in the gene encoding filaggrin cause ichthyosis vulgaris. Nature
Genet. 38: 337-342, 2006.
14. Sybert, V. P.; Dale, B. A.; Holbrook, K. A.: Ichthyosis vulgaris:
identification of a defect in synthesis of filaggrin correlated with
an absence of keratohyaline granules. J. Invest. Derm. 84: 191-194,
1985.
15. Traupe, H.; Happle, R.; Ropers, H. H.; Muller, C. R.: X-linked
recessive ichthyosis and autosomal dominant ichthyosis segregating
in the same family. Arch. Derm. Res. 271: 149-156, 1981.
16. Wells, R. S.; Kerr, C. B.: Clinical features of autosomal dominant
and sex-linked ichthyosis in an English population. Brit. Med. J. 1:
947-950, 1966.
17. Wells, R. S.; Kerr, C. B.: Genetic classification of ichthyosis. Arch.
Derm. 92: 1-6, 1965.
18. Williams, M. L.; Elias, P. M.: Ichthyosis: genetic heterogeneity,
genodermatoses, and genetic counseling. Arch. Derm. 122: 529-531,
1986.
19. Zhong, W.; Cui, B.; Zhang, Y.; Jiang, H.; Wei, S.; Bu, L.; Zhao,
G.; Hu, L.; Kong, X.: Linkage analysis suggests a locus of ichthyosis
vulgaris on 1q22. J. Hum. Genet. 48: 390-392, 2003.
*FIELD* CS
Skin:
Ichthyosis vulgaris;
Ichthyosis simplex
Misc:
Onset usually after 3 months age;
Lesions rare in the axillae, antecubital or popliteal fossae;
Palms and soles often show increased markings;
Frequent asthma, eczema or hay fever
Inheritance:
Autosomal dominant
*FIELD* CN
Marla J. F. O'Neill - updated: 4/18/2008
Anne M. Stumpf - updated: 3/2/2006
Victor A. McKusick - updated: 2/24/2006
Victor A. McKusick - updated: 8/27/2003
Gary A. Bellus - updated: 3/28/2001
*FIELD* CD
Victor A. McKusick: 6/2/1986
*FIELD* ED
terry: 03/20/2012
mgross: 2/13/2009
carol: 11/3/2008
ckniffin: 11/3/2008
carol: 11/3/2008
carol: 4/18/2008
alopez: 1/24/2007
alopez: 3/17/2006
alopez: 3/2/2006
terry: 2/24/2006
joanna: 3/19/2004
cwells: 9/2/2003
terry: 8/27/2003
cwells: 4/3/2001
cwells: 3/28/2001
mark: 2/26/1998
mimadm: 11/5/1994
carol: 5/24/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/27/1989
marie: 3/25/1988
MIM
605803
*RECORD*
*FIELD* NO
605803
*FIELD* TI
#605803 DERMATITIS, ATOPIC, 2; ATOD2
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
read moresusceptibility to atopic dermatitis (ATOD2) linked to chromosome 1q21 is
conferred by variation in the FLG gene (135940).
For a clinical description of atopic dermatitis and an overview of
linkage studies, see 603165.
MAPPING
Cookson et al. (2001) identified linkage of atopic dermatitis to
chromosome 1q21 at markers D1S252 and D1S498. The marker D1S498 is
linked to psoriasis (PSORS4; 603935).
MOLECULAR GENETICS
In genotype and haplotype analysis of 2 independent cohorts of 128
psoriasis triads and 120 atopic dermatitis triads, Giardina et al.
(2006) detected a significant association between haplotypes defined by
MIDDLE and ENDAL16 markers and psoriasis (p = 0.0000036) and atopic
dermatitis (p = 0.0276), colocalizing within a 42-kb interval on
chromosome 1q21 containing a single gene, LOR (152445). Analysis of LOR
SNPs from regulatory and coding regions did not show evidence of
association for either of the 2 diseases, but expression profiles of LOR
in skin biopsies showed reduced levels in psoriasis and increased levels
in atopic dermatitis, suggesting a specific misregulation of LOR mRNA
production.
The FLG gene encodes a key protein that facilitates terminal
differentiation of the epidermis and formation of the skin barrier.
Palmer et al. (2006) showed that 2 independent loss-of-function genetic
variants in the FLG gene, R501X (135940.0001) and 2282del4
(135940.0002), are very strong predisposing factors for atopic
dermatitis. These mutations had been shown to be the cause of ichthyosis
vulgaris (146700) in 15 families and isolated cases by Smith et al.
(2006). The R501X and 2282del4 variants, carried by approximately 9% of
people of European origin, also showed highly significant association
with asthma (see 600807) occurring in the context of atopic dermatitis.
Using the transmission-disequilibrium test in 476 German
parent-offspring trios with atopic dermatitis, Weidinger et al. (2006)
found a significant association between the loss-of-function mutations
R501X and 2282del4 in the FLG gene and extrinsic atopic dermatitis,
allergic sensitization, total IgE level, asthma, and palmar
hyperlinearity; there was no significant association with intrinsic
atopic dermatitis.
Marenholz et al. (2006) genotyped 1,092 children with eczema (atopic
dermatitis) from 2 large European populations for the R501X and 2282del4
mutations in the FLG gene and confirmed a highly significant association
between the null mutations and eczema and concomitant asthma. Moreover,
the authors found that these mutations predisposed to asthma, allergic
rhinitis, and allergic sensitization only in the presence of eczema, and
that the mutations predisposed equally to atopic (intrinsic) and
nonatopic (extrinsic) forms of eczema. They demonstrated that the
presence of 2 null alleles was an independent risk factor for asthma in
children with eczema (OR, 11.76, p = 0.0085). Together, the 2 mutations
accounted for an estimated 11% of eczema cases in the German population.
Noting that previous expression of eczema was a prerequisite for the
manifestation of allergic airways disease and specific sensitization,
Marenholz et al. (2006) emphasized the importance of the epidermal
barrier in the pathogenesis of these disorders (the so-called 'atopic
march').
Nomura et al. (2007) studied 143 Japanese patients with atopic
dermatitis from 140 unrelated families who were negative for known
mutations in the FLG gene, screening them for 2 novel FLG mutations that
the authors had identified in Japanese ichthyosis vulgaris patients,
S2554X (135940.0003) and 3321delA (135940.0004). The S2554X mutation was
identified in 6 patients and 3321delA in 2 patients; neither was found
in 156 unrelated Japanese nonatopic and nonichthyotic controls, yielding
a chi-square p value of 0.0015. Noting that the R501X and 2282del4
mutations were absent from a total of 253 Japanese individuals,
including their patients with ichthyosis vulgaris and atopic dermatitis,
Nomura et al. (2007) concluded that FLG mutations in Japan are different
from those found in European-origin populations.
*FIELD* RF
1. Cookson, W. O. C. M.; Ubhi, B.; Lawrence, R.; Abecasis, G. R.;
Walley, A. J.; Cox, H. E.; Coleman, R.; Leaves, N. I.; Trembath, R.
C.; Moffatt, M. F.; Harper, J. I.: Genetic linkage of childhood atopic
dermatitis to psoriasis susceptibility loci. Nature Genet. 27: 372-373,
2001.
2. Giardina, E.; Sinibaldi, C.; Chini, L.; Moschese, V.; Marulli,
G.; Provini, A.; Rossi, P.; Paradisi, M.; Chimenti, S.; Galli, E.;
Brunetti, E.; Girolomoni, G.; Novelli, G.: Co-localization of susceptibility
loci for psoriasis (PSORS4) and atopic dermatitis (ATOD2) on human
chromosome 1q21. Hum. Hered. 61: 229-236, 2006.
3. Marenholz, I.; Nickel, R.; Ruschendorf, F.; Schulz, F.; Esparza-Gordillo,
J.; Kerscher, T.; Gruber, C.; Lau, S.; Worm, M.; Keil, T.; Kurek,
M.; Zaluga, E.; Wahn, U.; Lee, Y.-A.: Filaggrin loss-of-function
mutations predispose to phenotypes involved in the atopic march. J.
Allergy Clin. Immun. 118: 866-871, 2006.
4. Nomura, T.; Sandilands, A.; Akiyama, M.; Liao, H.; Evans, A. T.;
Sakai, K.; Ota, M.; Sugiura, H.; Yamamoto, K.; Sato, H.; Palmer, C.
N. A.; Smith, F. J. D.; McLean, W. H. I.; Shimizu, H.: Unique mutations
in the filaggrin gene in Japanese patients with ichthyosis vulgaris
and atopic dermatitis. J. Allergy Clin. Immun. 119: 434-440, 2007.
5. Palmer, C. N. A.; Irvine, A. D.; Terron-Kwiatkowski, A.; Zhao,
Y.; Liao, H.; Lee, S. P.; Goudie, D. R.; Sandilands, A.; Campbell,
L. E.; Smith, F. J. D.; O'Regan, G. M.; Watson, R. M.; and 15 others
: Common loss-of-function variants of the epidermal barrier protein
filaggrin are a major predisposing factor for atopic dermatitis. Nature
Genet. 38: 441-446, 2006.
6. Smith, F. J. D.; Irvine, A. D.; Terron-Kwiatkowski, A.; Sandilands,
A.; Campbell, L. E.; Zhao, Y.; Liao, H.; Evans, A. T.; Goudie, D.
R.; Lewis-Jones, S.; Arseculeratne, G.; Munro, C. S.; Sergeant, A.;
O'Regan, G.; Bale, S. J.; Compton, J. G.; DiGiovanna, J. J.; Presland,
R. B.; Fleckman, P.; McLean, W. H. I.: Loss-of-function mutations
in the gene encoding filaggrin cause ichthyosis vulgaris. Nature
Genet. 38: 337-342, 2006.
7. Weidinger, S.; Illig, T.; Baurecht, H.; Irvine, A. D.; Rodriquez,
E.; Diaz-Lacava, A.; Klopp, N.; Wagenpfeil, S.; Zhao, Y.; Liao, H.;
Lee, S. P.; Palmer, C. N. A.; Jenneck, C.; Maintz, L.; Hagemann, T.;
Behrendt, H.; Ring, J.; Nothen, M. M.; McLean, W. H. I.; Novak, N.
: Loss-of-function variations within the filaggrin gene predispose
for atopic dermatitis with allergic sensitizations. J. Allergy Clin.
Immun. 118: 214-219, 2006. Note: Erratum: J. Allergy Clin. Immun.
118: 922 only, 2006. Erratum: J. Allergy Clin. Immun. 118: 724 only,
2006.
*FIELD* CN
Marla J. F. O'Neill - updated: 4/18/2008
Marla J. F. O'Neill - updated: 9/27/2006
*FIELD* CD
Ada Hamosh: 3/29/2001
*FIELD* ED
terry: 03/28/2013
carol: 4/30/2012
terry: 3/26/2012
alopez: 10/8/2009
terry: 7/25/2008
carol: 4/18/2008
carol: 4/14/2008
wwang: 9/28/2006
terry: 9/27/2006
alopez: 3/19/2004
alopez: 4/2/2001
alopez: 3/29/2001
*RECORD*
*FIELD* NO
605803
*FIELD* TI
#605803 DERMATITIS, ATOPIC, 2; ATOD2
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
read moresusceptibility to atopic dermatitis (ATOD2) linked to chromosome 1q21 is
conferred by variation in the FLG gene (135940).
For a clinical description of atopic dermatitis and an overview of
linkage studies, see 603165.
MAPPING
Cookson et al. (2001) identified linkage of atopic dermatitis to
chromosome 1q21 at markers D1S252 and D1S498. The marker D1S498 is
linked to psoriasis (PSORS4; 603935).
MOLECULAR GENETICS
In genotype and haplotype analysis of 2 independent cohorts of 128
psoriasis triads and 120 atopic dermatitis triads, Giardina et al.
(2006) detected a significant association between haplotypes defined by
MIDDLE and ENDAL16 markers and psoriasis (p = 0.0000036) and atopic
dermatitis (p = 0.0276), colocalizing within a 42-kb interval on
chromosome 1q21 containing a single gene, LOR (152445). Analysis of LOR
SNPs from regulatory and coding regions did not show evidence of
association for either of the 2 diseases, but expression profiles of LOR
in skin biopsies showed reduced levels in psoriasis and increased levels
in atopic dermatitis, suggesting a specific misregulation of LOR mRNA
production.
The FLG gene encodes a key protein that facilitates terminal
differentiation of the epidermis and formation of the skin barrier.
Palmer et al. (2006) showed that 2 independent loss-of-function genetic
variants in the FLG gene, R501X (135940.0001) and 2282del4
(135940.0002), are very strong predisposing factors for atopic
dermatitis. These mutations had been shown to be the cause of ichthyosis
vulgaris (146700) in 15 families and isolated cases by Smith et al.
(2006). The R501X and 2282del4 variants, carried by approximately 9% of
people of European origin, also showed highly significant association
with asthma (see 600807) occurring in the context of atopic dermatitis.
Using the transmission-disequilibrium test in 476 German
parent-offspring trios with atopic dermatitis, Weidinger et al. (2006)
found a significant association between the loss-of-function mutations
R501X and 2282del4 in the FLG gene and extrinsic atopic dermatitis,
allergic sensitization, total IgE level, asthma, and palmar
hyperlinearity; there was no significant association with intrinsic
atopic dermatitis.
Marenholz et al. (2006) genotyped 1,092 children with eczema (atopic
dermatitis) from 2 large European populations for the R501X and 2282del4
mutations in the FLG gene and confirmed a highly significant association
between the null mutations and eczema and concomitant asthma. Moreover,
the authors found that these mutations predisposed to asthma, allergic
rhinitis, and allergic sensitization only in the presence of eczema, and
that the mutations predisposed equally to atopic (intrinsic) and
nonatopic (extrinsic) forms of eczema. They demonstrated that the
presence of 2 null alleles was an independent risk factor for asthma in
children with eczema (OR, 11.76, p = 0.0085). Together, the 2 mutations
accounted for an estimated 11% of eczema cases in the German population.
Noting that previous expression of eczema was a prerequisite for the
manifestation of allergic airways disease and specific sensitization,
Marenholz et al. (2006) emphasized the importance of the epidermal
barrier in the pathogenesis of these disorders (the so-called 'atopic
march').
Nomura et al. (2007) studied 143 Japanese patients with atopic
dermatitis from 140 unrelated families who were negative for known
mutations in the FLG gene, screening them for 2 novel FLG mutations that
the authors had identified in Japanese ichthyosis vulgaris patients,
S2554X (135940.0003) and 3321delA (135940.0004). The S2554X mutation was
identified in 6 patients and 3321delA in 2 patients; neither was found
in 156 unrelated Japanese nonatopic and nonichthyotic controls, yielding
a chi-square p value of 0.0015. Noting that the R501X and 2282del4
mutations were absent from a total of 253 Japanese individuals,
including their patients with ichthyosis vulgaris and atopic dermatitis,
Nomura et al. (2007) concluded that FLG mutations in Japan are different
from those found in European-origin populations.
*FIELD* RF
1. Cookson, W. O. C. M.; Ubhi, B.; Lawrence, R.; Abecasis, G. R.;
Walley, A. J.; Cox, H. E.; Coleman, R.; Leaves, N. I.; Trembath, R.
C.; Moffatt, M. F.; Harper, J. I.: Genetic linkage of childhood atopic
dermatitis to psoriasis susceptibility loci. Nature Genet. 27: 372-373,
2001.
2. Giardina, E.; Sinibaldi, C.; Chini, L.; Moschese, V.; Marulli,
G.; Provini, A.; Rossi, P.; Paradisi, M.; Chimenti, S.; Galli, E.;
Brunetti, E.; Girolomoni, G.; Novelli, G.: Co-localization of susceptibility
loci for psoriasis (PSORS4) and atopic dermatitis (ATOD2) on human
chromosome 1q21. Hum. Hered. 61: 229-236, 2006.
3. Marenholz, I.; Nickel, R.; Ruschendorf, F.; Schulz, F.; Esparza-Gordillo,
J.; Kerscher, T.; Gruber, C.; Lau, S.; Worm, M.; Keil, T.; Kurek,
M.; Zaluga, E.; Wahn, U.; Lee, Y.-A.: Filaggrin loss-of-function
mutations predispose to phenotypes involved in the atopic march. J.
Allergy Clin. Immun. 118: 866-871, 2006.
4. Nomura, T.; Sandilands, A.; Akiyama, M.; Liao, H.; Evans, A. T.;
Sakai, K.; Ota, M.; Sugiura, H.; Yamamoto, K.; Sato, H.; Palmer, C.
N. A.; Smith, F. J. D.; McLean, W. H. I.; Shimizu, H.: Unique mutations
in the filaggrin gene in Japanese patients with ichthyosis vulgaris
and atopic dermatitis. J. Allergy Clin. Immun. 119: 434-440, 2007.
5. Palmer, C. N. A.; Irvine, A. D.; Terron-Kwiatkowski, A.; Zhao,
Y.; Liao, H.; Lee, S. P.; Goudie, D. R.; Sandilands, A.; Campbell,
L. E.; Smith, F. J. D.; O'Regan, G. M.; Watson, R. M.; and 15 others
: Common loss-of-function variants of the epidermal barrier protein
filaggrin are a major predisposing factor for atopic dermatitis. Nature
Genet. 38: 441-446, 2006.
6. Smith, F. J. D.; Irvine, A. D.; Terron-Kwiatkowski, A.; Sandilands,
A.; Campbell, L. E.; Zhao, Y.; Liao, H.; Evans, A. T.; Goudie, D.
R.; Lewis-Jones, S.; Arseculeratne, G.; Munro, C. S.; Sergeant, A.;
O'Regan, G.; Bale, S. J.; Compton, J. G.; DiGiovanna, J. J.; Presland,
R. B.; Fleckman, P.; McLean, W. H. I.: Loss-of-function mutations
in the gene encoding filaggrin cause ichthyosis vulgaris. Nature
Genet. 38: 337-342, 2006.
7. Weidinger, S.; Illig, T.; Baurecht, H.; Irvine, A. D.; Rodriquez,
E.; Diaz-Lacava, A.; Klopp, N.; Wagenpfeil, S.; Zhao, Y.; Liao, H.;
Lee, S. P.; Palmer, C. N. A.; Jenneck, C.; Maintz, L.; Hagemann, T.;
Behrendt, H.; Ring, J.; Nothen, M. M.; McLean, W. H. I.; Novak, N.
: Loss-of-function variations within the filaggrin gene predispose
for atopic dermatitis with allergic sensitizations. J. Allergy Clin.
Immun. 118: 214-219, 2006. Note: Erratum: J. Allergy Clin. Immun.
118: 922 only, 2006. Erratum: J. Allergy Clin. Immun. 118: 724 only,
2006.
*FIELD* CN
Marla J. F. O'Neill - updated: 4/18/2008
Marla J. F. O'Neill - updated: 9/27/2006
*FIELD* CD
Ada Hamosh: 3/29/2001
*FIELD* ED
terry: 03/28/2013
carol: 4/30/2012
terry: 3/26/2012
alopez: 10/8/2009
terry: 7/25/2008
carol: 4/18/2008
carol: 4/14/2008
wwang: 9/28/2006
terry: 9/27/2006
alopez: 3/19/2004
alopez: 4/2/2001
alopez: 3/29/2001