Thesis (PhD)--Stellenbosch University, 2004. / Bibliography / ENGLISH ABSTRACT: Heart failure due to cardiomyopathy or cardiac conduction disease is a major cause of
mortality and morbidity in both developed and developing countries. Although defined as
separate clinical entities, inherited forms of cardiomyopathies and cardiac conduction
disorders have been identified that present with overlapping clinical features and/or have
common molecular aetiologies.
The objective of the present study was to identify the molecular cause of progressive familial
heart block type II (PFHBII), an inherited cardiac conduction disorder that segregates in a
South African Caucasian Afrikaner family (Brink and Torrington, 1977). The availability of
family data tracing the segregation of PFHBII meant that linkage analysis could be employed
to identify the chromosomal location of the disease-causative gene. Human Genome Project
(HGP) databases have provided additional resources to facilitate the identification of
positional 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 and
Torrington (1977) were re-assessed. Retrospective data suggested redefining the classification
of PFHBII. Subsequently, linkage analysis was used to test described dilated cardiomyopathy
(DCM), hypertrophic cardiomyopathy (HCM) and cardiac conduction-causative loci on
chromosomes 1, 2, 3, 6, 7, 9, 11, 14, 15 and 19 for their involvement in the development of
PFHBII. Once a locus was mapped, bioinformatics tools were applied to identify and
prioritise positional candidate genes for mutation screening.
The retrospective and prospective clinical study redefined PFHBII as a cardiac conduction
and 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), by
the generation of a maximum pairwise lod score of 3.13 at D1S3753 (theta [θ]=0.0) and a
maximum multipoint lod score of 3.7 between D1S3753 and D1S414. However, genetic fine
mapping and haplotype analysis placed the PFHBII-causative locus distal to the CMD1D
locus, within a 3.9 centimorgan (cM) interval on chromosome 1q32.2-q32.3, telomeric of
D1S70 and centromeric of D1S505. Bioinformatics analyses prioritised seven candidate genes
for mutation analysis, namely, a gene encoding a potassium channel (KCNH1), an
extracellular matrix protein (LAMB3), a protein phosphatase (PPP2R5A), an adapter protein
that interacts with a cytoskeletal protein (T3JAM), a putative acyltransferase (KIAA0205) and
two genes encoding proteins possibly involved in energy homeostasis (RAMP and VWS59).
The PFHBII-causative mutation was not identified, although single sequence variations were
identified in four of the seven candidate genes that were screened. Although the molecular aetiology was not established, the present study defined the
underlying involvement of DCM in the pathogenesis of PFHBII. The new clinical
classification of PFHBII has been published (Fernandez et al., 2004) and should lead to
tracing more affected individuals in South Africa or elsewhere. The identification of a novel
disease-causative locus may point toward the future identification of a new DCM-associated
aetiology, which, in turn, might provide insights towards understanding the associated
molecular pathophysiologies of heart failure. / AFRIKAANSE OPSOMMING: Hartversaking as gevolg van kardiomiopatie of kardiale geleidingsiekte is ‘n hoof-oorsaak
van mortaliteit and morbiditeit in beide ontwikkelde en ontwikkelende lande. Alhoewel
gedefinieer as verskillende kliniese entiteite is oorerflike vorms van kardiomiopatie en
kardiale geleidingsstoornisse geïdentifiseer met oorvleuelende kliniese eienskappe en/of
molukulêre oorsake.
Die doelwit van hierdie studie was om die molukulêre oorsaak van progressiewe familiële
hartblok tipe II (PFHBII), ‘n oorerflike kardiale geleidingsstoornis, wat in ‘n Suid-Afrikaanse
Kaukasiër familie segregeer (Brink en Torrington, 1977), te identifiseer. Die beskikbaarheid
van familie data, beteken dat koppelingsanalise gebruik kan word om die chromosomale
posisie van die siekte-veroorsakende geen te identifiseer. Menslike Genoom Projek (MGP)
databanke het addisionele hulpbronne beskikbaar gestel om die identifikasie van posisionele
kandidaat gene te vergemaklik.
Kliniese ondersoeke is uitgevoer op PFHBII-geaffekteerde familielede, en waar beskikbaar is
kliniese rekords van persone, wat in ‘n vorige studie deur Brink en Torrington (1977)
geassesseer was, herontleed. Retrospektiewe data-analise het die kliniese herdefinisie van
PFHBII voorgestel. Daarna is koppelingsanalise gebruik om dilateerde kardiomiopatie
(DKM), hipertrofiese kardiomiopatie (HKM) en kardiale geleidingssiekte-veroorsakende loki
op chromosoom 1, 2, 3, 6, 7, 9, 11, 14, 15 en 19 te ondersoek vir hul moontlike bydrae tot die
ontwikkeling van PFHBII. Toe die lokus gekarteer was, is bioinformatiese ondersoeke
gebruik om posisionele kandidaat gene te identifiseer en prioritiseer vir mutasie analise.
Die retrospektiewe en prospektiewe kliniese ondersoek het PFHBII herdefinieer as ‘n
geleidingsstoornis en DKM-verbonde siekte, en terselfde tyd het dit gelei tot die opsporing van nog familielede. Toevallig het kandidaat loki-analise die PFHBII lokus op chromosoom
1q32 gekarteer, na ‘n gebied wat met ‘n voorheen-beskyfde DKM-verbonde stoornis
(CMD1D) oorvleuel, met die opwekking van ‘n makisimum paargewyse lod-getal van 3.13
by D1S3753 (theta [θ] = 0.0) en ‘n maksimum multipunt lod-getal van 3.7 tussen D1S3753 en
D1S414. Genetiese fynkartering en haplotipe-analise het die PFHBII-veroorsakende lokus
afwaards van die CMD1D lokus geplaas, in ‘n 3.9 centimorgan (cM) gebied op chromosoom
1q32.2-q32.3, telomeries van D1S70 en sentromeries van D1S505. Bioinformatiese analise
het daarnatoe gelei dat sewe kandidaat gene vir mutasie analise geprioritiseerd is, naamlik,
gene wat onderskeidelik ‘n kalium kanaal (KCNH1), ‘n ekstrasellulêre matriksproteïen
(LAMB3), ‘n proteïen fosfatase (PPP2R5A), ‘n aansluiter proteïen wat met ‘n sitoskilet
proteïen bind (T3JAM), ‘n asieltansferase (KIAA0205) en twee gene moontlik betrokke in
energie homeostase (RAMP en VWS59) enkodeer. Die PFHBII-veroorsakende geen is nie
geïdentifiseer nie, alhoewel enkele volgorde-wisselings geïdentifiseer is in vier van die sewe
geanaliseerde kandidaat gene. Alhowel die molekulêre oorsaak van die siekte nie vasgestel is nie, het die huidige studie die
onderliggende betrokkenheid van DKM in die pathogenese van PFHBII gedefinieer. Die
nuwe kliniese klassifikasie van PFHBII is gepubiliseer (Fernandez et al., 2004) en sal lei tot
die identifisering van nog geaffekteerde persone in Suid Afrika of in ander lande. Die
identifikasie van ‘n nuwe siekte-verbonde lokus mag lei tot die toekomstige identifikasie van
‘n nuwe DKM-verbonde genetiese oorsaak wat, opsig self, dalk insig kan gee in die
molekulêre patofisiologie van hartversaking.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:sun/oai:scholar.sun.ac.za:10019.1/36913 |
| Date | 12 1900 |
| Creators | Fernandez, Pedro |
| Contributors | Corfield, Valerie A., Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Biomedical Sciences. |
| Publisher | Stellenbosch : Stellenbosch University |
| Source Sets | South African National ETD Portal |
| Language | en_ZA |
| Detected Language | English |
| Type | Thesis |
| Format | xix, 132 p. : col. ill. |
| Rights | Stellenbosch University |
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