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Exome sequencing identifies DLG1 as a novel gene for potential susceptibility to Crohn's disease in a Chinese family study.

Xu S, Zhou F, Tao J, Song L, Ng SC, Wang X, Chen L, Yi F, Ran Z, Zhou R, Xia B - PLoS ONE (2014)

Bottom Line: More than 100 susceptibility loci were identified in Western IBD studies, but susceptibility gene has not been found in Chinese IBD patients till now.After genotyping among case and controls, a PLINK analysis showed the variant was of significance (P<0.05). 4 CD patients of the other Chinese family bore another non-synonymous variant c.833G>A (p.R278Q) in exon 9 of DLG1.We have discovered novel genetic variants in the coding regions of DLG1 gene, the results support that DLG1 is a novel potential susceptibility gene for CD in Chinese patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology, Zhongnan Hospital of Wuhan University School of Medicine, Wuhan, People's Republic of China.

ABSTRACT

Background: Genetic variants make some contributions to inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC). More than 100 susceptibility loci were identified in Western IBD studies, but susceptibility gene has not been found in Chinese IBD patients till now. Sequencing of individuals with an IBD family history is a powerful approach toward our understanding of the genetics and pathogenesis of IBD. The aim of this study, which focuses on a Han Chinese CD family, is to identify high-risk variants and potentially novel loci using whole exome sequencing technique.

Methods: Exome sequence data from 4 individuals belonging to a same family were analyzed using bioinformatics methods to narrow down the variants associated with CD. The potential risk genes were further analyzed by genotyping and Sanger sequencing in family members, additional 401 healthy controls (HC), 278 sporadic CD patients, 123 UC cases, a pair of monozygotic CD twins and another Chinese CD family.

Results: From the CD family in which the father and daughter were affected, we identified a novel single nucleotide variant (SNV) c.374T>C (p.I125T) in exon 4 of discs large homolog 1 (DLG1), a gene has been reported to play multiple roles in cell proliferation, T cell polarity and T cell receptor signaling. After genotyping among case and controls, a PLINK analysis showed the variant was of significance (P<0.05). 4 CD patients of the other Chinese family bore another non-synonymous variant c.833G>A (p.R278Q) in exon 9 of DLG1.

Conclusions: We have discovered novel genetic variants in the coding regions of DLG1 gene, the results support that DLG1 is a novel potential susceptibility gene for CD in Chinese patients.

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Related in: MedlinePlus

Chromatogram of DLG1 gene mutations.The Sanger sequence traces from normal human controls are shown in panel A and B; the mutations were heterozygous at the corresponding locus (orange arrows indicating) in panel C and D.
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pone-0099807-g002: Chromatogram of DLG1 gene mutations.The Sanger sequence traces from normal human controls are shown in panel A and B; the mutations were heterozygous at the corresponding locus (orange arrows indicating) in panel C and D.

Mentions: By examining all of the exons of PDCL and DLG1 in 25 young and intractable CD patients, we found two cases (Table 2, Patient ID are 3 and 4) who carried another variant in DLG1 (Figure 2, exon 9, c.833G>A, p.R278Q). We traced Patient 3, 4 and their families, and found that two cousin sisters (Cases CJ2 and CJ3) and one brother (Case CJ4) of Patient 4 who were unexpectedly found to have ulcers in the terminal ileum by endoscopy, and a biopsy showed non-specific chronic inflammation. After being treated with 5-ASA and azathioprine, four affected cases in this family have almost achieved their colonic mucosal healing. Cases CJ2, CJ3 and CJ4 were all found to be carriers of mutation R278Q (c.833G>A) by Sanger sequencing, and the family was called family B. We found 4 unaffected carriers (CJ5, CJ6, CJ7 and CJ8) of this variant after sequencing the other 15 members of family B, and these individuals will be followed up. CJ5 received a diagnosis of rheumatic heart disease with arthritis. The variants and carriers of DLG1 are listed in Table 9. Neither of the monozygotic CD twins carried any mutation in all 3 exons of PDCL or in all 25 exons of DLG1.


Exome sequencing identifies DLG1 as a novel gene for potential susceptibility to Crohn's disease in a Chinese family study.

Xu S, Zhou F, Tao J, Song L, Ng SC, Wang X, Chen L, Yi F, Ran Z, Zhou R, Xia B - PLoS ONE (2014)

Chromatogram of DLG1 gene mutations.The Sanger sequence traces from normal human controls are shown in panel A and B; the mutations were heterozygous at the corresponding locus (orange arrows indicating) in panel C and D.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4061034&req=5

pone-0099807-g002: Chromatogram of DLG1 gene mutations.The Sanger sequence traces from normal human controls are shown in panel A and B; the mutations were heterozygous at the corresponding locus (orange arrows indicating) in panel C and D.
Mentions: By examining all of the exons of PDCL and DLG1 in 25 young and intractable CD patients, we found two cases (Table 2, Patient ID are 3 and 4) who carried another variant in DLG1 (Figure 2, exon 9, c.833G>A, p.R278Q). We traced Patient 3, 4 and their families, and found that two cousin sisters (Cases CJ2 and CJ3) and one brother (Case CJ4) of Patient 4 who were unexpectedly found to have ulcers in the terminal ileum by endoscopy, and a biopsy showed non-specific chronic inflammation. After being treated with 5-ASA and azathioprine, four affected cases in this family have almost achieved their colonic mucosal healing. Cases CJ2, CJ3 and CJ4 were all found to be carriers of mutation R278Q (c.833G>A) by Sanger sequencing, and the family was called family B. We found 4 unaffected carriers (CJ5, CJ6, CJ7 and CJ8) of this variant after sequencing the other 15 members of family B, and these individuals will be followed up. CJ5 received a diagnosis of rheumatic heart disease with arthritis. The variants and carriers of DLG1 are listed in Table 9. Neither of the monozygotic CD twins carried any mutation in all 3 exons of PDCL or in all 25 exons of DLG1.

Bottom Line: More than 100 susceptibility loci were identified in Western IBD studies, but susceptibility gene has not been found in Chinese IBD patients till now.After genotyping among case and controls, a PLINK analysis showed the variant was of significance (P<0.05). 4 CD patients of the other Chinese family bore another non-synonymous variant c.833G>A (p.R278Q) in exon 9 of DLG1.We have discovered novel genetic variants in the coding regions of DLG1 gene, the results support that DLG1 is a novel potential susceptibility gene for CD in Chinese patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology, Zhongnan Hospital of Wuhan University School of Medicine, Wuhan, People's Republic of China.

ABSTRACT

Background: Genetic variants make some contributions to inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC). More than 100 susceptibility loci were identified in Western IBD studies, but susceptibility gene has not been found in Chinese IBD patients till now. Sequencing of individuals with an IBD family history is a powerful approach toward our understanding of the genetics and pathogenesis of IBD. The aim of this study, which focuses on a Han Chinese CD family, is to identify high-risk variants and potentially novel loci using whole exome sequencing technique.

Methods: Exome sequence data from 4 individuals belonging to a same family were analyzed using bioinformatics methods to narrow down the variants associated with CD. The potential risk genes were further analyzed by genotyping and Sanger sequencing in family members, additional 401 healthy controls (HC), 278 sporadic CD patients, 123 UC cases, a pair of monozygotic CD twins and another Chinese CD family.

Results: From the CD family in which the father and daughter were affected, we identified a novel single nucleotide variant (SNV) c.374T>C (p.I125T) in exon 4 of discs large homolog 1 (DLG1), a gene has been reported to play multiple roles in cell proliferation, T cell polarity and T cell receptor signaling. After genotyping among case and controls, a PLINK analysis showed the variant was of significance (P<0.05). 4 CD patients of the other Chinese family bore another non-synonymous variant c.833G>A (p.R278Q) in exon 9 of DLG1.

Conclusions: We have discovered novel genetic variants in the coding regions of DLG1 gene, the results support that DLG1 is a novel potential susceptibility gene for CD in Chinese patients.

Show MeSH
Related in: MedlinePlus