Frederik H Aidt

Long QT syndrome (LQTS) is a cardiac ion channelopathy which presents clinically with palpitations, syncope or sudden death. More than 700 LQTS-causing mutations have been identified in 13 genes, all of which encode proteins involved in the execution of the cardiac action potential. The most frequently affected genes, covering > 90% of cases, are KCNQ1, KCNH2 and SCN5A. We describe 64 different mutations in 70 unrelated Danish families using a routine five-gene screen, comprising KCNQ1, KCNH2 and SCN5A as well as KCNE1 and KCNE2. Twenty-two mutations were found in KCNQ1, 28 in KCNH2, 9 in SCN5A, 3 in KCNE1 and 2 in KCNE2. Twenty-six of these have only been described in the Danish population and 18 are novel. One double heterozygote (1.4% of families) was found. A founder mutation, p.F29L in KCNH2, was identified in 5 “unrelated” families. Disease association, in 31.2% of cases, was based on the type of mutation identified (nonsense, insertion/deletion, frameshift or splice-site). Functional data was available for 22.7% of the missense mutations. None of the mutations were found in 364 Danish alleles and only three, all functionally characterised, were recorded in the Exome Variation Server, albeit at a frequency of < 1:1000. The genetic etiology of LQTS in Denmark is similar to that found in other populations. A large founder family with p.F29L in KCNH2 was identified. In 48.4% of the mutations disease causation was based on mutation type or functional analysis.

Aims: To investigate in prion diseases the in‐situ localization of prion protein oligomers sharing a common epitope with amyloid oligomers involved in a range of neurodegenerative diseases.Methods and results: We performed immunohistochemistry on sporadic Creutzfeldt–Jakob disease (sCJD) (n = 9) and hereditary Gerstmann–Sträussler–Scheinker disease (GSS) (n = 1) specimens with the anti‐oligomer antibody A11 to determine the localization of reactive species. We found that A11 reactivity in the sCJD specimens was localized to the cerebral and cerebellar cortices both in spongiform and adjacent, non‐spongiform areas, reminiscent of multicentric or diffuse plaques. In the GSS specimens, we found that staining was closely associated with kuru‐like plaques, and that A11‐reactive species colocalized with protease‐resistant prion protein (Prp^Sc). We also observed sporadic neuronal cytosolic staining in both types of specimen.Conclusions: We confirm that intracellular and extracellular A11‐reactive species are present in situ in sCJD cases and GSS, and that immunoreactivity for A11 and Prp^Sc overlaps. We argue that the A11‐reactive species are indeed composed of oligomeric Prp^Sc, and suggest that the toxic effects of Prp^Sc oligomers could be related to the generic oligomeric conformation recognized by A11.

Background: The gene family KCNE1-5, which encode modulating β-subunits of several repolarising K⁺-ion channels, has been associated with genetic cardiac diseases such as long QT syndrome, atrial fibrillation and Brugada syndrome. The minK peptide, encoded by KCNE1, is attached to the Z-disc of the sarcomere as well as the T-tubules of the sarcolemma. It has been suggested that minK forms part of an "electro-mechanical feed-back" which links cardiomyocyte stretching to changes in ion channel function. We examined whether mutations in KCNE genes were associated with hypertrophic cardiomyopathy (HCM), a genetic disease associated with an improper hypertrophic response. Results: The coding regions of KCNE1, KCNE2, KCNE3, KCNE4, and KCNE5 were examined, by direct DNA sequencing, in a cohort of 93 unrelated HCM probands and 188 blood donor controls. Fifteen genetic variants, four previously unknown, were identified in the HCM probands. Eight variants were non-synonymous and one was located in the 3'UTR-region of KCNE4. No disease-causing mutations were found and no significant difference in the frequency of genetic variants was found between HCM probands and controls. Two variants of likely functional significance were found in controls only. Conclusions: Mutations in KCNE genes are not a common cause of HCM and polymorphisms in these genes do not seem to be associated with a propensity to develop arrhythmia