A candidate and novel gene search to identify the PFHBII-causative gene

[摘要] ENGLISH ABSTRACT: Heart failure due to cardiomyopathy or cardiac conduction disease is a major cause ofmortality and morbidity in both developed and developing countries. Although defined asseparate clinical entities, inherited forms of cardiomyopathies and cardiac conductiondisorders have been identified that present with overlapping clinical features and/or havecommon molecular aetiologies.The objective of the present study was to identify the molecular cause of progressive familialheart block type II (PFHBII), an inherited cardiac conduction disorder that segregates in aSouth African Caucasian Afrikaner family (Brink and Torrington, 1977). The availability offamily data tracing the segregation of PFHBII meant that linkage analysis could be employedto identify the chromosomal location of the disease-causative gene. Human Genome Project(HGP) databases have provided additional resources to facilitate the identification ofpositional candidate genes.Clinical examinations were performed on individuals of the PFHBII-affected family, and,where available, clinical records of subjects examined in a previous study by Brink andTorrington (1977) were re-assessed. Retrospective data suggested redefining the classificationof PFHBII. Subsequently, linkage analysis was used to test described dilated cardiomyopathy(DCM), hypertrophic cardiomyopathy (HCM) and cardiac conduction-causative loci onchromosomes 1, 2, 3, 6, 7, 9, 11, 14, 15 and 19 for their involvement in the development ofPFHBII. Once a locus was mapped, bioinformatics tools were applied to identify andprioritise positional candidate genes for mutation screening.The retrospective and prospective clinical study redefined PFHBII as a cardiac conductionand DCM-associated disorder and simultaneously allowed more family members to be traced.Fortuitously, candidate loci linkage analysis mapped the PFHBII locus to chromosome 1q32,to a region that overlapped a previously described DCM-associated disorder (CMD1D), bythe generation of a maximum pairwise lod score of 3.13 at D1S3753 (theta [θ]=0.0) and amaximum multipoint lod score of 3.7 between D1S3753 and D1S414. However, genetic finemapping and haplotype analysis placed the PFHBII-causative locus distal to the CMD1Dlocus, within a 3.9 centimorgan (cM) interval on chromosome 1q32.2-q32.3, telomeric ofD1S70 and centromeric of D1S505. Bioinformatics analyses prioritised seven candidate genesfor mutation analysis, namely, a gene encoding a potassium channel (KCNH1), anextracellular matrix protein (LAMB3), a protein phosphatase (PPP2R5A), an adapter proteinthat interacts with a cytoskeletal protein (T3JAM), a putative acyltransferase (KIAA0205) andtwo genes encoding proteins possibly involved in energy homeostasis (RAMP and VWS59).The PFHBII-causative mutation was not identified, although single sequence variations wereidentified in four of the seven candidate genes that were screened.Although the molecular aetiology was not established, the present study defined theunderlying involvement of DCM in the pathogenesis of PFHBII. The new clinicalclassification of PFHBII has been published (Fernandez et al., 2004) and should lead totracing more affected individuals in South Africa or elsewhere. The identification of a noveldisease-causative locus may point toward the future identification of a new DCM-associatedaetiology, which, in turn, might provide insights towards understanding the associatedmolecular pathophysiologies of heart failure.

[发布机构] Stellenbosch University