Analysis of SLC4A11, ZEB1, LOXHD1, COL8A2 and TCF4 gene sequences in a multi-generational family with late-onset Fuchs corneal dystrophy.
The aim of the present study was to determine the genetic basis of a multi-generational family with late-onset (LO) Fuchs corneal dystrophy (FCD). Five FCD causal genes [solute carrier family 4, sodium borate transporter, member 11 (SLC4A11), zinc finger E-box binding homeobox 1 (ZEB1), lipoxygenase homology domains 1 (LOXHD1), collagen, type VIII, alpha 2 (COL8A2) and transcription factor 4 (TCF4)], previously reported to be implicated in the pathogenesis of FCD, were screened. A total of 27 variants [including 22 known single nucleotide polymorphisms (SNPs) from the Single Nucleotide Polymorphism Database (dbSNP) and 5 variants absent from dbSNP] were detected in this FCD pedigree across the SLC4A11, ZEB1, LOXHD1 and COL8A2 genes as follows: i) 22 known SNPs from dbSNP, including 3 coding (p.R161R, p.S213S and p.T833T) and 11 non-coding variants of SLC4A11, 2 intronic SNPs of ZEB1 from dbSNP (rs220057 and rs220060), 1 intronic SNP of LOXHD1 from dbSNP (rs16939650), and 5 SNPs of COL8A2 from dbSNP (p.A35A, p.R155Q, p.L335L, p.G495G and p.T502M); and ii) 5 variants that have not been previously reported in FCD patients and that are absent from dbSNP were identified across the ZEB1 and LOXHD1 genes; these included 3 continuous indels located at the junction of the 5'-UTR and the adjacent exon 1 of ZEB1 [Indel 1 (c.-86_-53delins gggaggggtggaggcggaggggtGGGGGGGAAGG); Indel 2 (c.-52_-46delinsGGGAGGG); and Indel 3 (c.-45_-42delinsAGGG)], and 2 intronic variants of LOXHD1 (c.5332-126C>T and c.1809+155G>A). Apart from one intronic SNP of SLC4A11 from dbSNP (rs372201212), the pathologic consequence of which is uncertain, and 2 intron variants of LOXHD1 (c.5332-126C>T and c.1809+155G>A); the variants likely represent examples of de novo mutations. Neither of the other 24 variants provided strong evidence of pathogenesis in this FCD pedigree. An analysis of 7 SNPs in TCF4 from dbSNP, which have been associated with LO FCD in different populations, revealed that these 7 SNPs were not associated with FCD in this specific pedigree. A genome‑wide linkage scan to search for linkage to one of the previously described FCD loci or to identify a novel locus for FCD will need to be performed in this FCD pedigree. Our observation, nevertheless, expands the knowledge of the genetic status of patients with FCD.
College of Environmental Science and Engineering, Kunming University of Science and Technology, Kunming, Yunnan 650500, P.R. China.
Hui
H
Tang
College of Environmental Science and Engineering, Kunming University of Science and Technology, Kunming, Yunnan 650500, P.R. China.
Wen
W
Zhang
College of Environmental Science and Engineering, Kunming University of Science and Technology, Kunming, Yunnan 650500, P.R. China.
Xin-Min
XM
Yan
College of Environmental Science and Engineering, Kunming University of Science and Technology, Kunming, Yunnan 650500, P.R. China.
Lin-Ping
LP
Wang
College of Environmental Science and Engineering, Kunming University of Science and Technology, Kunming, Yunnan 650500, P.R. China.
Hong
H
Dong
Department of Oncology, The First People's Hospital of Yunnan Province, Kunming, Yunnan 650032, P.R. China.
Tao
T
Shou
Department of Ophthalmology, The First People's Hospital of Yunnan Province, Kunming, Yunnan 650032, P.R. China.
Huo
H
Lei
College of Environmental Science and Engineering, Kunming University of Science and Technology, Kunming, Yunnan 650500, P.R. China.
Qiang
Q
Guo
D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D027321:Anion Transport Proteins / Q000235:genetics*; D017920:Antiporters / Q000235:genetics*; D001483:Base Sequence; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D024102:Collagen Type VIII / Q000235:genetics*; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D005642:Fuchs' Endothelial Dystrophy / Q000235:genetics* / Q000473:pathology; D015870:Gene Expression; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007438:Introns; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000235:genetics*; D000071799:Zinc Finger E-box-Binding Homeobox 1 / Q000235:genetics*
D027321:Anion Transport Proteins; D017920:Antiporters; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C443712:COL8A2 protein, human; D002352:Carrier Proteins; D024102:Collagen Type VIII; C543906:LOXHD1 protein, human; C425809:SLC4A11 protein, human; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1