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Exome sequencing identifies ZNF644 mutations in high myopia.

Shi Y, Li Y, Zhang D, Zhang H, Li Y, Lu F, Liu X, He F, Gong B, Cai L, Li R, Liao S, Ma S, Lin H, Cheng J, Zheng H, Shan Y, Chen B, Hu J, Jin X, Zhao P, Chen Y, Zhang Y, Lin Y, Li X, Fan Y, Yang H, Wang J, Yang Z - PLoS Genet. (2011)

Bottom Line: Recently, the exome sequencing approach has been successfully used for the disease gene identification of Mendelian disorders.A mutation A672G in zinc finger protein 644 isoform 1 (ZNF644) was identified as being related to the phenotype of this family.The ZNF644 gene was expressed in human retinal and retinal pigment epithelium (RPE).

View Article: PubMed Central - PubMed

Affiliation: The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, Sichuan, China.

ABSTRACT
Myopia is the most common ocular disorder worldwide, and high myopia in particular is one of the leading causes of blindness. Genetic factors play a critical role in the development of myopia, especially high myopia. Recently, the exome sequencing approach has been successfully used for the disease gene identification of Mendelian disorders. Here we show a successful application of exome sequencing to identify a gene for an autosomal dominant disorder, and we have identified a gene potentially responsible for high myopia in a monogenic form. We captured exomes of two affected individuals from a Han Chinese family with high myopia and performed sequencing analysis by a second-generation sequencer with a mean coverage of 30× and sufficient depth to call variants at ∼97% of each targeted exome. The shared genetic variants of these two affected individuals in the family being studied were filtered against the 1000 Genomes Project and the dbSNP131 database. A mutation A672G in zinc finger protein 644 isoform 1 (ZNF644) was identified as being related to the phenotype of this family. After we performed sequencing analysis of the exons in the ZNF644 gene in 300 sporadic cases of high myopia, we identified an additional five mutations (I587V, R680G, C699Y, 3'UTR+12 C>G, and 3'UTR+592 G>A) in 11 different patients. All these mutations were absent in 600 normal controls. The ZNF644 gene was expressed in human retinal and retinal pigment epithelium (RPE). Given that ZNF644 is predicted to be a transcription factor that may regulate genes involved in eye development, mutation may cause the axial elongation of eyeball found in high myopia patients. Our results suggest that ZNF644 might be a causal gene for high myopia in a monogenic form.

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Genomic structure of the exons encoding the open reading frame of ZNF644 and identified mutations.Five out of six exons are translated (green), and exon 1 and portions of exon 2 and exon 6 are untranslated (red) in the ZNF644 gene (upper panel). Six different mutations in the ZNF644 gene and their sequencing traces are shown at the bottom of the figure (lower panel).
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pgen-1002084-g003: Genomic structure of the exons encoding the open reading frame of ZNF644 and identified mutations.Five out of six exons are translated (green), and exon 1 and portions of exon 2 and exon 6 are untranslated (red) in the ZNF644 gene (upper panel). Six different mutations in the ZNF644 gene and their sequencing traces are shown at the bottom of the figure (lower panel).

Mentions: We then performed segregation analysis by Sanger sequencing on the 66 validated SNPs and 254 indels, using the available 19 members of family 951 (Figure 1). Only one variant co-segregated with the disease phenotype in this family: an A to G change in exon 3 (2156A>G), resulting in an S672G amino acid change, in the zinc finger protein 644 gene isoform 1 (ZNF644, located at 1p22.2) (Table 1, Figure 1, Figure 3). We obtained a LOD score of 3.19 at theta = 0 given an autosomal dominant mode of inheritance with full penetrance and 0.0001 for the disease allele frequency. The power to obtain a LOD score greater than 3 was 88% when tested by SLINK, providing further support for this mutation being the disease-causing change for family 951. We then assessed the presence of the co-segregating mutation in the 600 matched normal controls using direct PCR sequencing of the ZNF644 exon 3, and did not find it in the 600 controls.


Exome sequencing identifies ZNF644 mutations in high myopia.

Shi Y, Li Y, Zhang D, Zhang H, Li Y, Lu F, Liu X, He F, Gong B, Cai L, Li R, Liao S, Ma S, Lin H, Cheng J, Zheng H, Shan Y, Chen B, Hu J, Jin X, Zhao P, Chen Y, Zhang Y, Lin Y, Li X, Fan Y, Yang H, Wang J, Yang Z - PLoS Genet. (2011)

Genomic structure of the exons encoding the open reading frame of ZNF644 and identified mutations.Five out of six exons are translated (green), and exon 1 and portions of exon 2 and exon 6 are untranslated (red) in the ZNF644 gene (upper panel). Six different mutations in the ZNF644 gene and their sequencing traces are shown at the bottom of the figure (lower panel).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3111487&req=5

pgen-1002084-g003: Genomic structure of the exons encoding the open reading frame of ZNF644 and identified mutations.Five out of six exons are translated (green), and exon 1 and portions of exon 2 and exon 6 are untranslated (red) in the ZNF644 gene (upper panel). Six different mutations in the ZNF644 gene and their sequencing traces are shown at the bottom of the figure (lower panel).
Mentions: We then performed segregation analysis by Sanger sequencing on the 66 validated SNPs and 254 indels, using the available 19 members of family 951 (Figure 1). Only one variant co-segregated with the disease phenotype in this family: an A to G change in exon 3 (2156A>G), resulting in an S672G amino acid change, in the zinc finger protein 644 gene isoform 1 (ZNF644, located at 1p22.2) (Table 1, Figure 1, Figure 3). We obtained a LOD score of 3.19 at theta = 0 given an autosomal dominant mode of inheritance with full penetrance and 0.0001 for the disease allele frequency. The power to obtain a LOD score greater than 3 was 88% when tested by SLINK, providing further support for this mutation being the disease-causing change for family 951. We then assessed the presence of the co-segregating mutation in the 600 matched normal controls using direct PCR sequencing of the ZNF644 exon 3, and did not find it in the 600 controls.

Bottom Line: Recently, the exome sequencing approach has been successfully used for the disease gene identification of Mendelian disorders.A mutation A672G in zinc finger protein 644 isoform 1 (ZNF644) was identified as being related to the phenotype of this family.The ZNF644 gene was expressed in human retinal and retinal pigment epithelium (RPE).

View Article: PubMed Central - PubMed

Affiliation: The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, Sichuan, China.

ABSTRACT
Myopia is the most common ocular disorder worldwide, and high myopia in particular is one of the leading causes of blindness. Genetic factors play a critical role in the development of myopia, especially high myopia. Recently, the exome sequencing approach has been successfully used for the disease gene identification of Mendelian disorders. Here we show a successful application of exome sequencing to identify a gene for an autosomal dominant disorder, and we have identified a gene potentially responsible for high myopia in a monogenic form. We captured exomes of two affected individuals from a Han Chinese family with high myopia and performed sequencing analysis by a second-generation sequencer with a mean coverage of 30× and sufficient depth to call variants at ∼97% of each targeted exome. The shared genetic variants of these two affected individuals in the family being studied were filtered against the 1000 Genomes Project and the dbSNP131 database. A mutation A672G in zinc finger protein 644 isoform 1 (ZNF644) was identified as being related to the phenotype of this family. After we performed sequencing analysis of the exons in the ZNF644 gene in 300 sporadic cases of high myopia, we identified an additional five mutations (I587V, R680G, C699Y, 3'UTR+12 C>G, and 3'UTR+592 G>A) in 11 different patients. All these mutations were absent in 600 normal controls. The ZNF644 gene was expressed in human retinal and retinal pigment epithelium (RPE). Given that ZNF644 is predicted to be a transcription factor that may regulate genes involved in eye development, mutation may cause the axial elongation of eyeball found in high myopia patients. Our results suggest that ZNF644 might be a causal gene for high myopia in a monogenic form.

Show MeSH
Related in: MedlinePlus