Background-In the congenital long-QT syndrome (LQTS), there can be a marked phenotypic heterogeneity. Founder effects, by which many individuals share a mutation identical by descent, represent a powerful tool to further understand the underlying mechanisms and to predict the natural history of mutation-associated effects. We are investigating one such founder effect, originating in South Africa in approximately AD 1700 and segregating the same KCNQ1 mutation (A341V). Methods and Results-The study population involved 320 subjects, 166 mutation carriers (MCs) and 154 noncarriers.When not taking -blocker therapy, MCs had a wide range of QTc values (406 to 676 ms), and 12% of individuals had a normal QTc (Յ440 ms). A QTc Ͼ500 ms was associated with increased risk for cardiac events (ORϭ4.22; 95% CI, 1.12 to 15.80; Pϭ0.033). We also found that MCs with a heart rate Ͻ73 bpm were at significantly lower risk (ORϭ0.23; 95% CI, 0.06 to 0.86; Pϭ0.035). This study also unexpectedly determined that KCNQ1-A341V is associated with greater risk than that reported for large databases of LQT1 patients: A341V MCs are more symptomatic by age 40 years (79% versus 30%) and become symptomatic earlier (7Ϯ4 versus 13Ϯ9 years, both PϽ0.001). Accordingly, functional studies of KCNQ1-A341V in CHO cells stably expressing IK s were conducted and identified a dominant negative effect of the mutation on wild-type channels. Conclusions-KCNQ1-A341V is a mutation associated with an unusually severe phenotype, most likely caused by the dominant negative effect of the mutation. The availability of an extended kindred with a common mutation allowed us to identify heart rate, an autonomic marker, as a novel risk factor. (Circulation. 2005;112:2602-2610.)
Afrikaners in South Africa (SA) are a recognisable group with a relatively small gene pool and excellent family records over a period of >350 years. The foundations of this group were laid mainly from 1652 until 1807. Afrikaners are derived from settlers from The Netherlands (roughly one-third), Germany (slightly less than onethird) and France (roughly one-quarter), with smaller contributions from other countries, imported slaves and indigenous peoples, [1] the exact proportions differing for each present-day Afrikaner. To illustrate this, a 'deconstruction' of one specific Afrikaner individual who has an incomplete ancestral chart of 926 individuals shows contributions of 37.5% from The Netherlands, 27.4% from Germany and 26.4% from France in his make-up, with 2.2% from people 'van die Kaap' ('from the Cape' , an expression which usually refers to female slaves born in the Cape), 1.9% from Britain and the rest from other countries.[2] There could be a perception that in isolated areas such as the Gamkaskloof more frequent intermarriages might have had an influence on the occurrence of hereditary diseases. However, there is no clear evidence that the people in these areas differed significantly from those in less isolated rural Afrikaner communities. [3] Several disorders among Afrikaners occur at relatively high frequencies due to founder effects. [3,4] A founder effect results when a small subset of a large population establishes a new population. The new population may differ significantly from the original population, both in terms of its genotypes and phenotypes. In the case of Afrikaners, the disorders that occur at an unusually high frequency may indicate that the original Dutch, French and German colonists who settled in the Cape carried those disease-causing genes at high frequency. In some cases the diseases can be traced back to specific founder couples, e.g. for familial colonic polyposis, [4,5] porphyria variegata, [6] progressive familial heart block, [7] Huntington's disease (HD), [8] osteogenesis imperfecta, [9] pseudoxanthoma elasticum (PXE), [10] schizophrenia, [11] long QT syndrome [12,13] and Fanconi's anaemia. [14] Given the evidence of founder effects for other disorders in the Afrikaner population, we sought to determine whether a founder effect for Parkinson's disease (PD) also occurs in this population. PD is a debilitating neurodegenerative condition arising as a result of the progressive loss of dopaminergic neurons in the brainstem associated with proteinaceous inclusions termed Lewy bodies. Cardinal clinical features include resting tremor, rigidity, bradykinesia, postural instability and responsiveness to levodopa. A genetic aetiology has been found in ~10 -15% of PD cases and a number of genes (and corresponding proteins) have been implicated, including parkin, PINK1 (PTEN-induced putative kinase 1), DJ-1 (DJ-1), SNCA (α-synuclein), LRRK2 (leucine-rich repeat kinase 2), VPS35 (vacuolar protein sorting 35) and EIF4G1 (eukaryotic translation initiation factor 4 γ1).For the genetic fo...
SOUTH AFRICA T.N. Dupuy has developed various operations research models in an attempt to quantify lessons that can be learned from military history. We discuss two of his models, the Quantified Judgment Model (QJM), and the "new square law". The QJM was developed by Dupuy for the analysis of military operations. We point out mathematical discrepancies in a part of the model and make suggestions to remove these discrepancies. Dupuy's new square law is an attempt to modify the well-known Lanchester equations for aimed fire, taking into account some results that were obtained in the OJM. We show that the new square law cannot be accepted as a valid mathematical model of combat attrition.
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