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A novel COL4A5 mutation identified in a Chinese Han family using exome sequencing.

Xiu X, Yuan J, Deng X, Xiao J, Xu H, Zeng Z, Guan L, Xu F, Deng S - Biomed Res Int (2014)

Bottom Line: This mutation, absent in 1,000 genomes project, HapMap, dbSNP132, YH1 databases, and 100 normal controls, cosegregated with patients in the family.The phenotypes of patients in this AS family were characterized by early onset-age and rapidly developing into end-stage renal disease (ESRD).Our discovery broadens the mutation spectrum in the COL4A5 gene associated with AS, which may also shed new light on genetic counseling for AS.

View Article: PubMed Central - PubMed

Affiliation: Center for Experimental Medicine and Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China ; Department of Pharmacy, Xiangya Hospital, Central South University, Xiangya Road 87, Kaifu District, Changsha, Hunan 410008, China.

ABSTRACT
Alport syndrome (AS) is a monogenic disease of the basement membrane (BM), resulting in progressive renal failure due to glomerulonephropathy, variable sensorineural hearing loss, and ocular anomalies. It is caused by mutations in the collagen type IV alpha-3 gene (COL4A3), the collagen type IV alpha-4 gene (COL4A4), and the collagen type IV alpha-5 gene (COL4A5), which encodes type IV collagen α3, α4, and α5 chains, respectively. To explore the disease-related gene in a four-generation Chinese Han pedigree of AS, exome sequencing was conducted on the proband, and a novel deletion mutation c.499delC (p.Pro167Glnfs*36) in the COL4A5 gene was identified. This mutation, absent in 1,000 genomes project, HapMap, dbSNP132, YH1 databases, and 100 normal controls, cosegregated with patients in the family. Neither sensorineural hearing loss nor typical COL4A5-related ocular abnormalities (dot-and-fleck retinopathy, anterior lenticonus, and the rare posterior polymorphous corneal dystrophy) were present in patients of this family. The phenotypes of patients in this AS family were characterized by early onset-age and rapidly developing into end-stage renal disease (ESRD). Our discovery broadens the mutation spectrum in the COL4A5 gene associated with AS, which may also shed new light on genetic counseling for AS.

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Conservation analysis of COL4A5 p.Pro167 amino acid residue.
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fig3: Conservation analysis of COL4A5 p.Pro167 amino acid residue.

Mentions: A novel deletion mutation, c.499delC (p.Pro167Glnfs*36), was identified in exon 9 of the COL4A5 gene in the proband. This mutation results in premature stop codon and a truncated protein. The same mutation was subsequently verified in all four affected family members (II: 1, III: 1, III: 3, and IV: 1; Figure 1), while being absent in unaffected members and 100 ethnically matched normal controls by Sanger sequencing (Figure 2). It is also absent in 1,000 genomes project, HapMap, YanHuang1 (YH1) project, and dbSNP. The mutation is located in the Gly-X-Y repeats. The p.Pro167 is a highly conserved amino acid residue among different species from chicken to human, suggesting its structural and functional importance (Figure 3). This mutation was predicted to affect the protein features and be disease causing (predicted by http://www.mutationtaster.org/). SIFT prediction also showed a damaging effect with a confidence score of 0.858 (http://sift.bii.a-star.edu.sg/www/SIFT_indels2.html).


A novel COL4A5 mutation identified in a Chinese Han family using exome sequencing.

Xiu X, Yuan J, Deng X, Xiao J, Xu H, Zeng Z, Guan L, Xu F, Deng S - Biomed Res Int (2014)

Conservation analysis of COL4A5 p.Pro167 amino acid residue.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4109303&req=5

fig3: Conservation analysis of COL4A5 p.Pro167 amino acid residue.
Mentions: A novel deletion mutation, c.499delC (p.Pro167Glnfs*36), was identified in exon 9 of the COL4A5 gene in the proband. This mutation results in premature stop codon and a truncated protein. The same mutation was subsequently verified in all four affected family members (II: 1, III: 1, III: 3, and IV: 1; Figure 1), while being absent in unaffected members and 100 ethnically matched normal controls by Sanger sequencing (Figure 2). It is also absent in 1,000 genomes project, HapMap, YanHuang1 (YH1) project, and dbSNP. The mutation is located in the Gly-X-Y repeats. The p.Pro167 is a highly conserved amino acid residue among different species from chicken to human, suggesting its structural and functional importance (Figure 3). This mutation was predicted to affect the protein features and be disease causing (predicted by http://www.mutationtaster.org/). SIFT prediction also showed a damaging effect with a confidence score of 0.858 (http://sift.bii.a-star.edu.sg/www/SIFT_indels2.html).

Bottom Line: This mutation, absent in 1,000 genomes project, HapMap, dbSNP132, YH1 databases, and 100 normal controls, cosegregated with patients in the family.The phenotypes of patients in this AS family were characterized by early onset-age and rapidly developing into end-stage renal disease (ESRD).Our discovery broadens the mutation spectrum in the COL4A5 gene associated with AS, which may also shed new light on genetic counseling for AS.

View Article: PubMed Central - PubMed

Affiliation: Center for Experimental Medicine and Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China ; Department of Pharmacy, Xiangya Hospital, Central South University, Xiangya Road 87, Kaifu District, Changsha, Hunan 410008, China.

ABSTRACT
Alport syndrome (AS) is a monogenic disease of the basement membrane (BM), resulting in progressive renal failure due to glomerulonephropathy, variable sensorineural hearing loss, and ocular anomalies. It is caused by mutations in the collagen type IV alpha-3 gene (COL4A3), the collagen type IV alpha-4 gene (COL4A4), and the collagen type IV alpha-5 gene (COL4A5), which encodes type IV collagen α3, α4, and α5 chains, respectively. To explore the disease-related gene in a four-generation Chinese Han pedigree of AS, exome sequencing was conducted on the proband, and a novel deletion mutation c.499delC (p.Pro167Glnfs*36) in the COL4A5 gene was identified. This mutation, absent in 1,000 genomes project, HapMap, dbSNP132, YH1 databases, and 100 normal controls, cosegregated with patients in the family. Neither sensorineural hearing loss nor typical COL4A5-related ocular abnormalities (dot-and-fleck retinopathy, anterior lenticonus, and the rare posterior polymorphous corneal dystrophy) were present in patients of this family. The phenotypes of patients in this AS family were characterized by early onset-age and rapidly developing into end-stage renal disease (ESRD). Our discovery broadens the mutation spectrum in the COL4A5 gene associated with AS, which may also shed new light on genetic counseling for AS.

Show MeSH
Related in: MedlinePlus