The doctoral thesis is entitled “Genetic Factors Characterising the Clinical Course of Wilson’s Disease”. Wilson’s disease (WD) is an autosomal recessive disorder of copper metabolism caused by approximately 800 allelic variants in gene ATP7B with prevalence 1 per 30 000 individuals in the Europe. WD manifestations are very different, mostly including the hepatic pathology and neurological symptoms. WD can be symptomatic at any age, but predominantly the first symptoms appear at age between five and 35 years. Although the disease is caused by various allelic variants in the ATP7B gene, studies are ongoing to explain the variability of WD clinical presentation. There are several studies on the different effects of the ATP7B gene allelic variants on the protein ATP7B function. The possible effect of other genes on the WD phenotype has been discussed as well, with the main focus on genes encoding proteins involved in copper metabolism, e.g., ATOX1 and COMMD1, as well as genes containing pathogenic variants that can influence inflammation in liver cells, e.g. HFE. WD diagnosis is based on diagnostic guidelines adapted in 2001, where reduced levels of ceruloplasmin in the blood are one of the main diagnostic criteria. Other reasons, such as allelic variants of the CP gene encoding ceruloplasmin, may also cause this change. The aim of this study was to study the genetic factors of WD, describing the spectrum and frequency of disease-causing allelic variants in Latvia, their correlation with clinical manifestations of the disease, and identifying other possible genetic factors affecting WD. Sixty-four unrelated individuals who had clinical and/or molecular confirmation of WD were analyzed in the thesis. The prevalence of WD in newborn cohorts in Latvia was estimated at about 1: 21,800 live births. Using direct sequencing of the ATP7B gene and the PCR-BiPASA method, among the Latvian WD patients 83,59 % disease causing allelic variants of the ATP7B gene were identified, the most common being c.3207C>A (p.His1069Gln). The effect of ATP7B, ATOX1, COMMD1 and HFE gene alleic variants on WD phenotype had not been established. Relation to neurological manifestations of WD by a non-moleculary confirmed genotype in the ATP7B gene was found to CP gene rs66508328 and rs11708215 variants – AA and GG genotypes.
- the Basic Sciences of Medicine
- Medical Genetics
- Summary of the Doctoral Thesis