Ichthyosis is a heterogeneous group of scaling disorders that are classified on the basis of clinical presentation, histopathologic change, and pattern of inheritance. Accounting to more than 95% of ichthyosis cases, the most common form of disease is autosomal dominant ichthyosis vulgaris (IV; OMIM #146700). It affects approximately one in 2557 people in Ukraine. Loss-of-function mutations in a gene coding for filaggrin protein (FLG) are strongly associated with IV and disrupt the skin barrier. More than 40 FLG gene mutations have been discovered, all leading to loss of filaggrin expression. Two most common mutations in European populations (R501X and 2282del4) have been reported to cause the skin abnormalities in IV. As it was previously described/discovered these mutations are inherited in semidominant pattern where heterozygotes manifest a moderate phenotype with 80100% penetrance while homozygotes and compound heterozygotes manifest a severe phenotype. These findings prompted us to investigate mutations in FLG gene and corresponding patient’s genotypes in Ukrainian population. Nineteen patients with a marked generalized scaling phenotype from Kharkiv region (East Ukraine) were tested in this study. Each patient was genotyped for the two most prevalent FLG null mutations (R501X and 2282del4) by PCR-RFLP. The presence of FLG mutations in all IV patients was revealed. In five patients R501X mutation in heterozygous condition was found. All of them were members of families from Western districts of Kharkiv region. Genotyping of these patients for 2282del4 mutation revealed it in four individuals in homozygous condition and in 15 patients in heterozygous one. Three individuals were compound heterozygous for both mutations in FLG gene. Thus the two mutations (R501X and 2282del4), the most common for European populations, have been also detected in Kharkiv region of Ukraine. We estimated 2282del4:R501X mutation ratio in the East Ukrainian population as 4:1. The penetrance of FLG null mutations was 100% in homozygotes for 2282del4 and compounds, 100% in heterozygous individuals with R501X mutation and 84.2% in heterozygous individuals with 2282del4 mutation. Homozygotes for 2282del4 mutation and compound heterozygotes manifest a severe phenotype then afflicted heterozygous individuals with significantly different phenotypes.

Keywords: ichthyosis, filaggrin, FLG mutations

Full text: PDF (Rus) 108K

1. Amelina SS, Vetrova IV, Degtereva EV, i dr. Raznoobrazie nasledstvennyih zabolevaniy kozhi u naseleniya Rostovskoy oblasti. Valeologiya. 2014; 4: 12-7.
2. Mavrov II, Bolotnaya LA, Serbina IM. Osnovyi diagnostiki i lecheniya v dermatologii i venerologii. H: Fakt; 2007. 792 s.
3. Maksimov VN, Kulikov IV, Semaev SE, i dr. Deletsiya 2282del4 v gene filaggrina v populyatsii zhiteley Novosibirska i u bolnyih vulgarnyim ihtiozom. Med genetika. 2007; 8: 21-3.
4. MKB-10. Mizhnarodna statistichna klasifikatsiya hvorob ta sporidnenih problem ohoroni zdorov'ya. Desyatiy pereglyad. K: Zdorov'ya; 2001. 3: 817 s.
5. Mordovtsev VN, Alieva PM, Sergeev AS. Zabolevaniya kozhi s nasledstvennyim predraspolozheniem. M: DNTs RAN; 2002. 260 s.
6. Mutevelich-Arslanagich N. Genodermatozyi na territorii Respubliki Bosnii i Gertsegovinyi. Vestn dermatologii i venerologii. 1992; 4: 40–2.
7. Tsvetkova GM, Mordovtseva VV, Vavilov AM, Mordovtsev VN. Patomorfologiya bolezney kozhi: Rukovodstvo dlya vrachey. M: Meditsina; 2003. 496 s.
8. Suvorova KN, Antonev AA. Nasledstvennyie dermatozyi. M: Meditsina; 1977. 230 s.
9. Fedota OM. Genodermatozi v doslidzhenni problem genetichnoyi bezpeki lyudini: Abstr. Dr. Sci. (Biol.). K; 2012. 40 s.
10. Ballardini N, Kull I, Söderhäll C, Lilja G, Wickman M, Wahlgren CF. Eczema severity in preadolescent children and its relation to sex, filaggrin mutations, asthma, rhinitis, aggravating factors and topical treatment: a report from the BAMSE birth cohort. Br J Dermatol. 2013; 168 (3): 588–94. https://doi.org/10.1111/bjd.12196
11. Brown SJ, Relton CL, H, Liao Y Zhao, A Sandilands, WHI McLean, HJ Cordell, NJ Reynolds. Filaggrin haploinsufficiency is highly penetrant and is associated with increased severity of eczema: further delineation of the skin phenotype in a prospective epidemiological study of 792 school children. Br J Dermatol. 2009; 161 (4): 884–9. https://doi.org/10.1111/j.1365-2133.2009.09339.x
12. Brown SJ, Relton CL, H, Liao Sandilands A, Wilson IJ, Burn J, Reynolds NJ, McLean WH, Cordell HJ. Filaggrin null mutations and childhood atopic eczema: a population-based case-control study. J Allergy Clin Immunol. 2008; 121 (4): 940–6. https://doi.org/10.1016/j.jaci.2008.01.013
13. Brown SJ, Sandilands A, Zhao Y, Irwin McLean. Prevalent and low-frequency null mutations in the filaggrin gene are associated with early-onset and persistent atopic eczema. J Invest Dermatol. 2008; 128 (6): 1591–4. https://doi.org/10.1038/sj.jid.5701206
14. Cascella R, Cuzzola VF, Lepre T, et al. Full sequencing of the FLG gene in Italian patients with atopic eczema: evidence of new mutations, but lack of an association. J Invest Dermatol. 2011; 131 (4): 982–4. https://doi.org/10.1038/jid.2010.398
15. Ezzedine K, Droitcourt C, Ged C, A Diallo, T Hubiche, H de Verneuil, F Boralevi, A Taïeb. Usefulness of a global clinical ichthyosis vulgaris scoring system for predicting common FLG null mutations in an adult caucasian population. Br J Dermatol. 2012; 167 (5): 1165–9. https://doi.org/10.1111/j.1365-2133.2012.11062.x
16. Filaggrin: Basic science, epidemiology, clinical aspects and management. Eds JP Thyssen, HI. Maibach. Heidelberg: Springer; 2014. 373 p.
17. Fleckman P, Brumbaugh S. Absence of the granular layer and keratohyalin define a morphologically distinct subset of individuals with ichthyosis vulgaris. Exp Dermatol. 2002; 11 (4): 327–36.https://doi.org/10.1034/j.1600-0625.2002.110406.x
18. Frost P, van Scott EJ. Ichthyosiform dermatoses: classification based on anatomic and biometric observations. Arch Dermatol. 1966; 94 (2): 113–26. https://www.ncbi.nlm.nih.gov/pubmed/5911500
19. Gruber R, Janecke AR, Fauth C, Utermann G, Fritsch PO, Schmuth M. Filaggrin mutations p.R501X and c.2282del4 in ichthyosis vulgaris. Eur J Hum Genet. 2007; 15 (2): 179–84. https://doi.org/10.1038/sj.ejhg.5201742
20. Kezic S, Kemperman PMJH, Koster ES, de Jongh CM, Thio HB, Campbell LE, Irvine AD, McLean WH, Puppels GJ, Caspers PJ. Loss-of-function mutations in the filaggrin gene lead to reduced level of natural moisturizing factor in the stratum corneum. J Invest Dermatol. 2008; 128 (8): 2117–9. https://doi.org/10.1038/jid.2008.29
21. Oji V, Traupe H. Ichthyosis: clinical manifestations and practical treatment options. Am J Clin Dermatol. 2009; 10 (6): 351–64. https://doi.org/10.2165/11311070-000000000-00000
22. OMIM®. Online Mendelian Inheritance in Man®: an online catalog of human genes and genetic disorders. 1996–2015. Available from: omim.org (30.11.2015).
23. Palmer CN, Irvine AD, Terron-Kwiatkowski A, Zhao Y, Liao H, Lee SP, Goudie DR, Sandilands A, Campbell LE, Smith FJ, O'Regan GM, Watson RM, Cecil JE, Bale SJ, Compton JG, DiGiovanna JJ, et al. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet. 2006; 38 (4): 441–6. PMID: 16550169. https://doi.org/10.1038/ng1767
24. Perusquía-Ortiz AM, Oji V, Sauerland MC, et al. Complete filaggrin deficiency in ichthyosis vulgaris is associated with only moderate changes in epidermal permeability barrier function profile. J Eur Acad Dermatol Venereol. 2013; 27 (12): 1552–8. https://doi.org/10.1111/jdv.12079
25. Rawlings AV, Matts PJ. Stratum corneum moisturization at the molecular level: an update in relation to dry skin cycle. J Invest Dermatol. 2005; 124 (6): 1099–10. https://doi.org/10.1111/j.1523-1747.2005.23726.x
26. Sandilands A, Terron-Kwiatkowski A, Hull PR, O'Regan GM, Clayton TH, Watson RM, Carrick T, Evans AT, Liao H, Zhao Y, Campbell LE, Schmuth M, Gruber R, et al. Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema. Nat Genet. 2007; 39 (5): 650–4. https://www.ncbi.nlm.nih.gov/pubmed/17417636. https://doi.org/10.1038/ng2020
27. Schmuth M, Martinz V, Janecke AR, Fauth C, Schossig A, Zschocke J, Gruber R. Inherited ichthyoses/gereralized Mendelian disorders of cornification. Eur J Hum Gen. 2013; 21 (2): 123–33. https://doi.org/10.1038/ejhg.2012.121
28. Smith FJD, Irvine AD, Terron-Kwiatkowski A, Sandilands A, Campbell LE, Zhao Y, Liao H, Evans AT, Goudie DR, Lewis-Jones S, Arseculeratne G, Munro CS, et al. Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nat Genet. 2006; 38 (3): 337–42. https://doi.org/10.1038/ng1743
29. Thyssen JP, Godoy-Gijon E, Elias PM. Ichthyosis vulgaris: the filaggrin mutation disease. Br J Dermatol. 2013; 168 (5): 1155–66. https://doi.org/10.1111/bjd.12219
30. Visser MJ, Landeck L, Campbell LE, Kezic S. Impact of loss-of-function mutations in the filaggrin gene and atopic dermatitis on the development of occupational irritant contact dermatitis. Br J Dermatol. 2013; 168 (2): 326–32. https://doi.org/10.1111/bjd.12083
31. Weidinger S, O'Sullivan M, Illig T, et al. Filaggrin mutations, atopic eczema, hay fever, and asthma in children. J Allergy Clin Immunol. 2008; 121 (5): 1203–9. https://doi.org/10.1016/j.jaci.2008.02.014
32. Wells RS, Kerr CB. Clinical features of autosomal dominant and sex-linked ichthyosis in an English population. Brit Med J. 1966; 1 (5493): 947–50. https://doi.org/10.1136/bmj.1.5493.947
33. Winge MC, Suneson J, Lysell J, Nikamo P, Liedén A, Nordenskjöld M, Wahlgren CF, Bradley M, Ståhle M. Lack of association between filaggrin gene mutations and onset of psoriasis in childhood. J Eur Acad Dermatol Venereol. 2011; 27 (1): e124–e127. https://www.ncbi.nlm.nih.gov/pubmed/22182180. https://doi.org/10.1111/j.1468-3083.2011.04403.x
34. Zinchenko RA, El'chinova GI, Baryshnikova NV, et al. Prevalences of hereditary diseases in different populations of Russia. Russian Journal of Genetics. 2007; 43 (9): 1038–45. https://doi.org/10.1134/S1022795407090104