The Effects of Polymorphisms in One-carbon Metabolism Genes on Manifestation of Ichthyosis Vulgaris

BACKGROUND: Ichthyosis vulgaris is the most common type of Mendelian disorders of cornification, caused by loss-of-function mutations in the gene encoding epidermal protein filaggrin (FLG), namely R501X and 2282del4. FLG 2282del4 mutation in heterozygotes is incompletely penetrant. Polymorphisms in one-carbon metabolism genes could be associated with clinical manifestation of ichthyosis vulgaris. AIM: The purpose of the present study was to analyze the effects of MTHFR, MTR and MTRR polymorphisms in patients with ichthyosis vulgaris. METHODS: 31 patients with ichthyosis vulgaris, 7 their FLG heterozygous relatives without symptoms of disorder, and 150 healthy controls were enrolled in study. FLG null mutations —R501X (rs61816761) and 2282del4 (rs558269137) — and one-carbon metabolism gene polymorphisms — MTHFR C677T (rs1801133), MTHFR A1298C (rs1801131), MTR A2756G (rs1805087) and MTRR A66G (rs1801394) — were analyzed by a polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assay. RESULTS: Among patients with ichthyosis, heterozygous for FLG 2282del4 mutation, the distributions of genotypes for folate metabolism genes were: MTHFR C677T CC:CT:TT —29.4%:70.6%:0.0%; MTHFR A1298C AA:AC:CC — 52.9%:47.1%:0.0%; MTR A2756G AA:AG:GG — 70.3%:23.5%:5.9%; MTRR A66G AA:AG:GG — 23.4%:52.9%:23.5%. The frequencies of MTR 2756AA and MTRR 66GG genotypes were 1.4–1.6 times higher in affected individuals heterozygous for 2282del4 than in patients with other FLG genotypes. In affected 2282del4 heterozygotes, the frequency of MTR 2756AA genotype was 1.6 times greater than in healthy controls (p<0.01). The strongest association was found between MTHFR 677CT/MTHFR 1298AA/MTR 2756AA/MTRR 66AG genotype and ichthyosis — OR=11.23 (95% CI 2.51−50.21, p=0.002). CONCLUSIONS: Various genotypes of one-carbon metabolism genes increase the risk of ichthyosis in heterozygotes for the FLG 2282del4 mutation (OR 2.799‑11.231). The most probable predisposing genotype is 677CT/1298AA/2756AA+AG/66AG.

Epidermal Proliferation and Differentiation in Ichthyosis Vulgaris

A B S T R A C TEpidermal proliferation and differentiation is a physiological process which playscrucial role in protecting human body from external environment. Ichthyosisvulgaris is a disease caused by disruption of epidermal differentiation process.Disrupted of profilaggrin conversion to filaggrin caused by mutations from thefilaggrin gene (FLG) located on chromosome 1q21. Recently, caused of ichthyosisvulgaris is mutation of the CASP14 gene on chromosome 19p13.12 which producescaspase-14, is involved in the proteolytic degradation of filaggrin. Clinicalmanifestations of ichthyosis vulgaris are hyperlinear palmar and plantar, keratosispilaris, xerosis, and localized or generalized scaling of the skin. Application ofemollients, humectants and keratolytic agents are the main treatment of ichthyosisvulgaris. Further research on caspase-14 as a therapeutic target is needed in thetreatment of ichthyosis vulgaris.

A loss of function mutation in the filaggrin gene associated with ichthyosis vulgaris and rheumatoid arthritis

Introduction Mutations in the filaggrin ( FLG) gene are known to cause ichthyosis vulgaris. Methods We used whole-genome sequencing (WGS) technology to investigate the genetic causes of rare and complex inherited diseases including rheumatoid arthritis, ichthyosis, and congenital fibrosis of the extraocular muscles type 1 (CFEOM1) in a Chinese family. WGS was performed in four topics, and the identified candidate mutations were further verified through Sanger sequencing. Results We identified a mutation in FLG gene (g.152280098 C>A, p.E2422∗) that may be associated with ichthyosis and arthritis. Moreover, a mutation in KIF21A (g.39726207 G>A, p.R954 W) was also determined in affected members as the cause of CFEOM1. The gene interaction network demonstrated an interesting correlation between FLG and genes associated with arthritis and ichthyosis. Functional enrichment analysis of these interacting genes revealed several possible pathways that might be linked to arthritis and ichthyosis. Conclusion In general, we confirmed a loss of function mutation in the FLG gene associated with ichthyosis vulgaris and rheumatoid arthritis in this family.

Mutation variability in the filaggrin gene in patients with ichthyosis vulgaris

Обследован 21 пациент с клиническими проявлениями вульгарного ихтиоза. Наиболее часто у них выявлялась мутация 2282del4 в гене FLG как в гомозиготном (у 6 больных), так и в гетерозиготном состояниях. We examined 21 patients with clinical manifestations of ichthyosis vulgaris. Most often, they had the 2282del4 mutation in the FLG gene both in homozygous (in 6 patients) and heterozygous states.