Bioinformatics-based strategies to identify PFHBII-causing and HCM main locus and/or HCM modifying mutations

[摘要] ENGLISH ABSTRACT: Progressive familial heart block type II (PFHBII) is an inherited cardiac conduction disorder ofunknown aetiology, which has been described in a South African family. The disorder wasmapped to a 2.9 centimorgan (cM) locus on chromosome 1q32.2-32.3. Clinically, PFHBIImanifests cardiac conduction aberrations, that progress to a disease of the heart muscle, dilatedcardiomyopathy (DCM). DCM is also reported as an end phase in hypertrophic cardiomyopathy(HCM), another heart muscle disorder. These cardiomyopathies are genetically heterogeneouswith some of the genes reported as causes of both disorders. Therefore, genes identified as causesof HCM and DCM were considered plausible candidates for PFHBII mutation analysis.Additionally, this study provided an opportunity to assess potential modifiers of HCM. HCMexhibits marked phenotypic variability, observed within and between families harbouring thesame causative mutation.Genes within the PFHBII locus were selected for PCR-SSCP analysis based on homology togenes previously reported as causing conduction system disorders associated with arrhythmias,DCM and/or HCM. Results were confirmed by direct sequencing and association between thedetected variants and HCM parameters was assessed using a quantitative transmissiondisequilibrium test (QTDT).Eleven plausible candidate genes were selected within the PFHBII locus and two of the genes,PFKFB2 and ATF3, that encode for 6-phosphofructo-2,6-bisphosphatase (PFK-2/FBPase-2) andactivating transcription factor 3 (ATF3), respectively, were analysed for PFHBII-causing andHCM main locus and/or HCM modifying mutations. Mutation analysis of PFKFB2 and ATF3 inthe PFHBII family revealed no PFHBII causal mutation. PFKFB2 and ATF3 were later localised outside the PFHBII locus, and, therefore, were excluded as PFHBII plausible candidates. Furtheranalysis of the two genes for HCM main locus and/or HCM modifying mutations in the HCMpanel identified several sequence variants. QTDT analysis of these variants showed no significantassociation.Completion of the Human Genome Project (HGP) and annotation of new genes within thePFHBII locus allowed the identification of more PFHBII plausible candidate genes. Identificationof causal mutations in plausible PFHBII candidate genes will allow molecular diagnosis ofPFHBII pathophysiology. Furthermore, identification of both HCM-modifying and HCM-causinggenes will give insight into the phenotypic variability noted among South African HCM-affectedindividuals and into the molecular cause of the disease among individuals with HCM-like clinicalfeatures.

[发布机构] Stellenbosch University