ERCC6
Chimeric ERCC6-PGBD3 protein (Chimeric CSB-PGBD3 protein)
Publications[править]
Cockayne Syndrome (CS) is a rare autosomal recessive disorder, which leads to neurodegeneration, growth failure and premature aging. Most of the cases are due to mutations in the [[ERCC6]] gene, which encodes the protein CSB. CSB is involved in several functions including DNA repair and transcription. Here we describe two Danish brothers with CS. Both patients carried a novel splice site mutation (c.2382 2T>G), and a previously described nonsense mutation (c.3259C>T, p.Arg1087X) in a biallelic state. Both patients presented the cardinal features of the disease including microcephaly, congenital cataract and postnatal growth failure. In addition, their fibroblasts were hypersensitive to UV irradiation and exhibited increased superoxide levels in comparison to fibroblasts from healthy age and gender matched individuals. Metabolomic analysis revealed a distinctive metabolic profile in cells from the CS patients compared to control cells. Among others, α-ketoglutarate, hydroxyglutarate and certain amino acids (ornithine, proline and glycine) were reduced in the CS patient fibroblasts, whereas glycolytic intermediates (glucose-6-phosphate and pyruvic acid) and fatty acids (palmitic, stearic and myristic acid) were increased. Our data not only provide additional information to the database of CS mutations, but also point towards targets for potential treatment of this devastating disease.
MeSH Terms
- Child, Preschool
- Cockayne Syndrome
- DNA Helicases
- DNA Mutational Analysis
- DNA Repair Enzymes
- Energy Metabolism
- Genetic Predisposition to Disease
- Humans
- Infant
- Magnetic Resonance Imaging
- Male
- Metabolomics
- Mutation
- Phenotype
- Poly-ADP-Ribose Binding Proteins
- RNA Splice Sites
- Tomography, X-Ray Computed
Keywords
- CSB
- Cockayne Syndrome
- ERCC6
- Metabolomics
- Premature aging
- Splice site mutation
Age-related cataract (ARC) is one of the most common causes of severe visual impairment among the elderly worldwide with four subtypes, such as cortical, nuclear, subcapsular, and mixed types. DNA damage and malfunction of DNA repair are believed to contribute to the pathogenesis of ARC. This study examined the associations of 18 single nucleotide polymorphisms (SNPs) in four DNA repair genes (BLM, WRN, [[ERCC6]], and OGG1) with ARC in Han Chinese from the Jiangsu Eye Study, a population-based epidemiologic study. We also determined the possible functional consequence of the SNPs to DNA damage. Eighteen SNPs in four DNA repair genes were genotyped in 789 ARC patients and 531 normal controls from the Jiangsu Eye Study. The Comet assay was to assess the extent of DNA damage in peripheral lymphocytes of selected subjects. The results show that WRN-rs11574311 was initially associated with ARC in general, cortical, and mixed cataracts (P = 0.003, odds ratio [OR] = 1.49; P = 0.001, OR = 1.68; and P < 0.0001, OR = 2.08), BLM-rs1063147 with nuclear cataract (P = 0.03, OR = 1.31), WRN-rs2725383 with cortical cataract (P = 0.01, OR = 1.49), and WRN-rs4733220 and WRN-rs2725338 with mixed cataract (P = 0.04, OR = 0.74; P = 0.003, OR = 0.60). However, the significances of some of the above-cited associations disappeared after multiple testing corrections. WRN-rs11574311 remains associated with cortical and mixed cataract and WRN-rs2725338 with mixed cataract after multiple testing correction. We did not find any correlation between DNA damage of peripheral lymphocytes and SNP types. We concluded that WRN genes might be involved in ARC pathogenesis in the Han Chinese population. The associations were ARC subtype specific. These findings stress the importance of detailed phenotyping in ARC subtypes, which may be associated with different risk factors and disease mechanisms.
MeSH Terms
- Adult
- Aged
- Aging
- Asian Continental Ancestry Group
- Cataract
- China
- Comet Assay
- DNA Damage
- DNA Glycosylases
- DNA Helicases
- DNA Repair
- DNA Repair Enzymes
- Exodeoxyribonucleases
- Female
- Genetic Predisposition to Disease
- Haplotypes
- Humans
- Lymphocytes
- Male
- Middle Aged
- Poly-ADP-Ribose Binding Proteins
- Polymorphism, Single Nucleotide
- RecQ Helicases
- Risk Factors
- Werner Syndrome Helicase
This study investigates age-related macular degeneration (AMD) genetic risk factors through identification of a functional single-nucleotide polymorphism (SNP) and its disease association. We chose [[ERCC6]] because of its roles in the aging process, DNA repair, and ocular degeneration from the gene disruption. Bioinformatics indicated a putative binding-element alteration on the sequence containing C-6530>G SNP in the 5' flanking region of [[ERCC6]] from Sp1 on the C allele to SP1, GATA-1, and OCT-1 on the G allele. Electrophoretic mobility shift assays displayed distinctive C and G allele-binding patterns to nuclear proteins. Luciferase expression was higher in the vector construct containing the G allele than that containing the C allele. A cohort of 460 advanced AMD cases and 269 age-matched controls was examined along with pathologically diagnosed 57 AMD and 18 age-matched non-AMD archived cases. [[ERCC6]] C-6530>G was associated with AMD susceptibility, both independently and through interaction with an SNP (rs380390) in the complement factor H (CFH) intron reported to be highly associated with AMD. A disease odds ratio of 23 was conferred by homozygozity for risk alleles at both [[ERCC6]] and CFH compared with homozygozity for nonrisk alleles. Enhanced [[ERCC6]] expression was observed in lymphocytes from healthy donors bearing [[ERCC6]] C-6530>G alleles. Intense immunostaining of [[ERCC6]] was also found in AMD eyes from [[ERCC6]] C-6530>G carriers. The strong AMD predisposition conferred by the [[ERCC6]] and CFH SNPs may result from biological epistasis, because [[ERCC6]] functions in universal transcription as a component of RNA pol I transcription complex.
MeSH Terms
- 5' Flanking Region
- Aging
- Animals
- Case-Control Studies
- Complement Factor H
- DNA Helicases
- DNA Repair Enzymes
- Genes, Reporter
- Genetic Predisposition to Disease
- Humans
- Lymphocytes
- Macular Degeneration
- Pigment Epithelium of Eye
- Poly-ADP-Ribose Binding Proteins
- Polymorphism, Single Nucleotide
- Retina