Thesis (Ph. D.)--University of Queensland, 2001. / Includes bibliographical references.

Hereditär hemokromatos (HH) är en vanlig multigenetisk defekt som leder till ett onormalt förhöjt järnupptag i tarmen och ses framförallt hos kaukasisk befolkning. Sjukdomen har på senare år visats orsakats av mutationen c.845G>A men även mer ovanliga varianter som c.187C>G och c.193A>T, vilka alla finns belägna i genen HFE. HFE som finns lokaliserad intill Human Leukocyte Antigen (HLA)-genen på kromosom sex korta arm kodar för ett HFE-protein som har till uppgift att reglera kroppens järnmetabolism i interaktion med hormonet hepcidin. Vid HH avtar proteinets järnregulatoriska funktion och järnackumulation uppstår. Idag diagnostiseras HH främst via genotypning där ovanstående genvarianter påvisas. Beroende på genvariant löper individer olika hög risk för sjukdomsutveckling. I studien var syftet att verifiera det kommersiella kitet LightMix® in-vitro diagnostics kit HFE H63D S65C C282Y diagnostics kit för kvalitativ diagnostik av HFE-genotyper via Realtids-Polymerase Chain Reaction (PCR) via smältkurveanalys för eventuell införsel i rutindiagnostik. I studien kunde samtliga patientprover (n=49) ifrån Halmstad med misstänkt hemokromatos genotypas för genvarianterna i HFE-genen. Utifrån godkända resultat i prov-till-prov variation tillsammans med icke-frekventa skillnader i imprecisionstest samt 100 % samstämmighet gentemot referensmetoder på externa laboratorier, kunde slutsatsen dras att metoden är relevant för rutinverksamheten på Länssjukhuset Ryhov, Region Jönköpings Län. / Hereditary hemochromatosis (HH) is a common multi-genetic defect that results in abnormally elevated iron uptake mainly in Caucasian populations. The disease has recently been found to be caused by mutation c.845G>A, in addition to the unusual variants c.187C>G and c.193A>T, all of which are detected in the gene HFE. HFE is located adjacent to the Human Leukocyte Antigen (HLA)-gene on chromosome six’s short arm and encodes for a HFE-protein, responsible for the body's iron metabolism regulation in interaction with the hormone hepcidin. As HH decreases the protein's iron-regulatory function, the iron accumulation increases. Today HH is diagnosed primarily through genotyping where variants in the HFE-gene are detected. Depending on the variant, individuals are put at varying high risk of disease development. The aim of this study was to verify the commercial LightMix® in-vitro diagnostics kit HFE H63D S65C C282Y for qualitative diagnosis of HFE-genotypes through Real-time Polymerase Chain Reaction (PCR) and melting-curve analysis for possible introduction in routine diagnostics. In the study, all samples (n=49) from patients with suspicious hemochromatosis were genotyped for the gene variants in HFE-gene. Based on all accepted results with non-frequent differences in imprecision test and 100 % consistency against the reference methods at external laboratories conclusions could be drawn that the method is applicable for routine diagnostics at the County Hospital Ryhov in Region Jönköping.

Haemochromatosis is the most common single gene disorder to afflict North- West European populations. It is probably the most common genetic disorder of iron metabolism worldwide. As many as 1 in 250 people in the UK are affected and although the phenotype causes only a mild increase in gastrointestinal iron absorption a proportion of affected individuals will accumulate sufficient iron over their life-time to cause cirrhosis and hepatocellular carcinoma. Venesection treatment instituted before cirrhosis has established ensures a normal life expectancy, but clinical presentation is often late in life after irreversible organ injury has occurred. Identification of people at risk in the early, asymptomatic stage by measurements of iron status is unreliable. The genetic defect responsible for haemochromatosis has been sought in the hope that its identification might facilitate early diagnosis and that studies on the gene product would lead to a greater understanding of the mechanisms of mammalian iron absorption. Genetic linkage to HLA-A3 placed the gene responsible for haemchromatosis in, or close to, the major histocompatibilty complex (MHC) on the short arm of chromosome 6 and a positional cloning strategy has been adopted. This thesis describes work directed to the identification of the haemochromatosis gene by positional cloning. The region telomeric to the MHC was mapped using yeast artificial chromosomes, from which new microsatellites were isolated. These markers were used in linkage disequilibrium analyses and the mapping of a recombination breakpoint that defined a haemochromatosis gene region. This region was physically mapped in fine detail and positional candidates sought by EST database analysis. Before a systematic search for genes in the region began a strong positional candidate was reported (Feder et al 1996). Analysis of this mutation in patients from the UK confirmed this to be the ancestral haemochromatosis mutation.

Although a central etiology for Alzheimer disease (AD) has not yet been determined, support has amassed for the notion that oxidative stress may be involved in the pathogenesis of AD. The disruption of iron homeostasis and iron's excessive deposition in AD brain tissues has received increased attention due to the metal's capacity to promote the production of harmful free radicals. Several studies have recently examined whether DNA mutations involved in the iron overload disorder, hemochromatosis, pose an increased risk of acquiring AD. However, the small sample size and low generalizability of previous studies have warranted further investigation. We genotyped 213 AD patients, 106 Mild Cognitively Impaired (MCI) individuals, and 63 Normal Elderly Control (NEC) subjects for the H63D and C282Y HFE mutations to examine whether a relationship exists between HFE gene status and AD presentation in our patient population. DNA analysis was conducted by polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP). We did not find any statistically significant associations between HFE gene status and the clinical, demographic, or neuropsychological aspects of AD in our patient population. Interesting trends that fell short of statistical significance included: (a) a deleterious effect of HFE mutations on motor performance, (b) an influence of H63D homozygosity on an earlier onset of cognitive decline, and (c) an influence of H63D homozygosity on an accelerated progression from MCI to AD.

Thesis (M.Sc.)--University of Western Australia, 2004.

Thesis (Ph. D.)--Duke University, 2007.

Thesis (MSc)--University of Stellenbosch, 2007. / Bibliography. Also available via the Internet.

Thesis (Ph.D.) - University of Queensland, 2003. / Includes bibliography.

Thesis (M.P.H.)--University of Queensland, 2002. / Includes bibliography.

No description available.