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Mapping 136 pathogenic mutations into functional modules in human DNA polymerase ? establishes predictive genotype-phenotype correlations for the complete spectrum of POLG syndromes.

ABSTRACT: We establish the genotype-phenotype correlations for the complete spectrum of POLG syndromes by refining our previously described protocol for mapping pathogenic mutations in the human POLG gene to functional clusters in the catalytic core of the mitochondrial replicase, Pol ? (1). We assigned 136 mutations to five clusters and identify segments of primary sequence that can be used to delimit the boundaries of each cluster. We report that compound heterozygotes with two mutations from different clusters manifested more severe, earlier-onset POLG syndromes, whereas two mutations from the same cluster are less common and generally are associated with less severe, later onset POLG syndromes. We also show that specific cluster combinations are more severe than others and have a higher likelihood to manifest at an earlier age. Our clustering method provides a powerful tool to predict the pathogenic potential and predicted disease phenotype of novel variants and mutations in POLG, the most common nuclear gene underlying mitochondrial disorders. We propose that such a prediction tool would be useful for routine diagnostics for mitochondrial disorders. This article is part of a Special Issue entitled: 18th European Bioenergetic Conference.

SUBMITTER: Farnum GA

PROVIDER: S-EPMC4687743 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Mapping 136 pathogenic mutations into functional modules in human DNA polymerase γ establishes predictive genotype-phenotype correlations for the complete spectrum of POLG syndromes.

Farnum Gregory A GA Nurminen Anssi A Kaguni Laurie S LS

Biochimica et biophysica acta 20140207 7

We establish the genotype-phenotype correlations for the complete spectrum of POLG syndromes by refining our previously described protocol for mapping pathogenic mutations in the human POLG gene to functional clusters in the catalytic core of the mitochondrial replicase, Pol γ (1). We assigned 136 mutations to five clusters and identify segments of primary sequence that can be used to delimit the boundaries of each cluster. We report that compound heterozygotes with two mutations from different ...[more]

PMID: 24508722

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Project description:AimTo investigate genotype-phenotype correlations in patients with perianal Crohn's disease (PCD) in order to determine which factors predispose to development of perianal disease in Crohn's patients.MethodsSeven-hundred and ninety-five Caucasian individuals (317 CD patients and 478 controls without inflammatory bowel disease, IBD) were prospectively enrolled into a clinical/genetic database. Demographic and clinical data, as well as peripheral blood leukocyte DNA were obtained from all patients. The following were evaluated: three NOD2/CARD15 polymorphisms: R702W, G908R, and 1007insC; five IL-23r risk alleles: rs1004819, rs10489629, rs2201841, rs11465804, and rs11209026; a well-characterized single-nucleotide polymorphism (SNP) on the IBD5 risk haplotype (OCTN1) and two peripheral tag SNPs (IGR2060 and IGR3096).ResultsPCD occurred in 147 (46%) of CD patients. There was no significant difference in the age at disease diagnosis between non-PCD and PCD patients (33 vs. 29 years, respectively). PCD patients were more likely to have disease located in the colon and ileocolic regions (79 PCD vs. 57% non-PCD; n = 116 vs. n = 96; p < 0.001), whereas patients with non-PCD were more likely to have Crohn's within the terminal ileum and upper gastrointestinal tract (43% non-PCD vs. 21% PCD; n = 73 vs. n = 31; p < 0.05). Thirty-four percent of patients with PCD required a permanent ileostomy (n = 50) compared to only 4% of non-PCD patients (n = 6; p < 0.05). Mutations in CARD15/NOD2 and IL-23r were risk factors for CD overall; however, in contrast to prior reports, in this patient population, OCTN1 and IGR variations within the IBD5 haplotype were not significant predictors of PCD.ConclusionColon/ileocolic CD location appears to be a significant predictor of perianal manifestations of CD. Patients with PCD are more likely to require permanent fecal diversion. We did not identify any genetic variations or combination of clinical findings and genetic variations within the CARD15/NOD2, IL-23r, and OCTN1 genes or IGR that were predictive of PCD.

Dataset Information

Mapping 136 pathogenic mutations into functional modules in human DNA polymerase ? establishes predictive genotype-phenotype correlations for the complete spectrum of POLG syndromes.

Publications

Mapping 136 pathogenic mutations into functional modules in human DNA polymerase γ establishes predictive genotype-phenotype correlations for the complete spectrum of POLG syndromes.

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