Barbara Vetter

Increased efficiency of mRNA 3' end formation: a new genetic mechanism contributing to hereditary thrombophilia.

The G→A mutation at position 20210 of the prothrombin or coagulation factor II gene (F2) represents a common genetic risk factor for the occurrence of thromboembolic events. This mutation affects the 3′-terminal nucleotide of the 3′ untranslated region (UTR) of the mRNA and causes elevated prothrombin plasma concentrations by an unknown mechanism. Here, we show that the mutation does not affect the amount of pre-mRNA, the site of 3′ end cleavage or the length of the poly(A) tail of the mature mRNA. Rather, we demonstrate that the physiological F2 3′ end cleavage signal is inefficient and that F2 20210 G→A represents a gain-of-function mutation, causing increased cleavage site recognition, increased 3′ end processing and increased mRNA accumulation and protein synthesis. Enhanced mRNA 3′ end formation efficiency emerges as a novel principle causing a genetic disorder and explains the role of the F2 20210 G→A mutation in the pathogenesis of thrombophilia. This work also illustrates the pathophysiologic importance of quantitatively minor aberrations of RNA metabolism.

Beta‐thalassaemia in the immigrant and non‐immigrant German populations

In Germany homozygous β‐thalassaemia mainly occurs in the immigrant population from endemic regions. In non‐immigrants β‐thalassaemia is rare. Heterozygous β‐thalassaemia minor, however, is more common and must be considered in the differential diagnosis of hypochromic anaemia. The clinical and molecular data of 221 homozygous patients and 256 non‐immigrant German heterozygous individuals are presented. Clinically, 87% (n =192) of the homozygotes are classified as thalassaemia major (TM) and the other 13% as thalassaemia intermedia (TI). There is a wide spectrum of 39 thalassaemia mutations which occur with relatively low frequencies in individual cases. In 17/29 TI patients ‘mild’ mutations have been found and in 16/29 there are mutations that are associated with increased γ‐globin gene activity. α‐Thalassaemia is rare and found only in 3/29.

Homozygous and double heterozygous Factor V Leiden and Factor II G20210A genotypes predispose infants to thromboembolism but are not associated with an increase of foetal loss

Prospective and controlled data about the individual risk profile in asymptomatic children with homozygous or double heterozygous risk genotypes for Factor V Leiden (FVL) and factor II (FII) G20210A are currently unavailable. The systematic and prospective observational study presented here was designed to determine the impact of the homozygous and double heterozygous FVL and FII G20210A genotypes on the prenatal and postnatal risk profiles of affected children. Risk infants and heterozygous controls were identified by screening of 85,304 neonates. Follow-up included the comparison of prenatal and postnatal development, ultrasonography of brain and kidneys, and a panel of independent determinants of thrombophilia. The numbers of identified or expected FVL homozygotes and double heterozygotes did not differ significantly (FVL: 116 versus 91, p=0.08; FVL/FII: 94 versus 76, p=0.17), indicating the absence of a prenatal disadvantage. A prenatal advantage was suggested in FII homozygotes, whose identified number far exceeded the expected (19 versus 4, p=0.002). Clinical and/or imaging abnormalities indicated spontaneous thromboembolic events in 4 of 129 risk infants (3%) but in none of the 178 controls (p=0.02). Physical and neurological development was normal in both groups during the first 2 years of life. The risk genotypes appear to confer a significant predisposition for spontaneous thromboembolic events in infancy without impeding development within the first two years of life. Foetal risk genotypes do not cause an increased foetal loss rate. Moreover, homozygous FII G20210A appears to be associated with a prenatal advantage.

Phenylketonuria and hyperphenylalaninemia in eastern Germany: a characteristic molecular profile and 15 novel mutations.

Phenylketonuria (PKU) is an important error of amino acid metabolism which results in most patients from phenylalanine hydroxylase (PAH) deficiency. PKU displays a marked genotypic heterogeneity both within and between different populations. The aim of this study was to establish the genotypic spectrum of PKU in eastern Germany, and to compare this to the distribution of mutations in western Germany. The study population included 302 patients in 290 families who were followed at treatment centers in Berlin, Leipzig and Jena. The study showed marked genotypic variability with a total of 75 mutations, including 15 that have so far not been described (eleven missense mutations, one splicing mutation, and three small deletions). One of these novel mutations, E183Q, occurred in cis to a R408W mutation. In the non‐immigrant eastern German population, the frequency of R408W accounted for 40.1% of the PKU alleles. In the immigrant Turkish population of the former West Berlin, the most prevalent mutation was IVS10‐11G>A (57%). There was a marked difference of the genotypic spectrum between the population studied here and the data reported from the western part of the country. Hum Mutat 15:254–260, 2000.

Chronic Haemolytic Anaemia and Glucose-6-Phosphate Dehydrogenase Deficiency

Deficiency in glucose-6-phosphate dehydrogenase (G6PD) is the most common enzymopathy, and more than 125 different mutations causing G6PD deficiency have been identified. Chronic haemolytic anaemia (CHA) associated with G6PD deficiency is rare, but there is a cluster of mutations causing CHA between amino acids 361–428 which are encoded by exon 10 of the G6PD gene. This region is involved in the dimer formation of the active G6PD enzyme and therefore plays an important role for enzyme stability and activity. Here, we report a 17-year-old patient with CHA, who carries a rare G → A mutation at nucleotide 1160 which causes an R387H amino acid substitution. We review the reports of the seven previously described patients with this mutation, concluding that G6PD deficiency should be considered as a rare differential diagnosis of chronic haemolytic, non-spherocytic anaemia.

Multi‐track dispositions

It is a familiar point that many ordinary dispositions are multi-track, that is, not fully and adequately characterisable by a single conditional. In this paper, I argue that both the extent and the implications of this point have been severely underestimated. First, I provide new arguments to show that every disposition whose stimulus condition is a determinable quantity must be infinitely multi-track. Secondly, I argue that this result should incline us to move away from the standard assumption that dispositions are in some way importantly linked to conditionals, as presupposed by the debate about various versions of the ‘conditional analysis’ of dispositions. I introduce an alternative conception of dispositionality, which is motivated by linguistic observations about dispositional adjectives and links dispositions to possibility instead of conditionals. I argue that, because of the multi-track nature of dispositions, the possibility-based conception of dispositions is to be preferred.

An Unexpectedly High Frequency of Hypergalactosemia in an Immigrant Bosnian Population Revealed by Newborn Screening

In galactokinase (GALK) deficiency, galactose cannot be phosphorylated into galactose-1-phosphate, which leads to cataract formation. Neonatal screening for hypergalactosemia in Berlin has been performed by thin-layer chromatography since 1978, which detects classical galactosemia and GALK deficiency. Until 1991, GALK deficiency has not been identified in a total of ≈260,000 samples. In contrast, from 1992 to 1999, nine patients were detected in a total of ≈240,000 screened newborns. One Turkish patient was homozygous for two novel S142I/G148C GALK mutations in close proximity to the putative ATP-binding site of the enzyme. The other eight children were born to five families belonging to the Bosnian refugee population consisting of approximately 30,000 individuals who have arrived in Berlin since 1991. In two of these families, GALK deficiency was subsequently diagnosed in siblings who had cataract surgery at 4 and 5 y of age, respectively. In all these 10 Bosnian patients, a homozygous P28T mutation located near the active center of the enzyme was identified. We propose that neonatal screening of populations with a significant proportion of Bosnians and possibly other southeastern Europeans, e.g. Romani, should be particularly directed toward GALK deficiency, an inborn error of metabolism that is readily amenable to effective treatment.

Williamsonian modal epistemology, possibility-based

Williamsonian modal epistemology (WME) is characterized by two commitments: realism about modality, and anti-exceptionalism about our modal knowledge. Williamson’s own counterfactual-based modal epistemology is the best known implementation of WME, but not the only option that is available. I sketch and defend an alternative implementation which takes our knowledge of metaphysical modality to arise, not from knowledge of counterfactuals, but from our knowledge of ordinary possibility statements of the form ‘x can F’. I defend this view against a criticism indicated in Williamson’s own work, and argue that it is better connected to the semantics of modal language.

Are abilities dispositions

Abilities are in many ways central to what being an agent means, and they are appealed to in philosophical accounts of a great many different phenomena. It is often assumed that abilities are some kind of dispositional property, but it is rarely made explicit exactly which dispositional properties are our abilities. Two recent debates provide two different answers to that question: the new dispositionalism in the debate about free will, and virtue reliabilism in epistemology. This paper argues that both answers fail as general accounts of abilities, and discusses the ramifications of this result.

A plenitude of powers

Dispositionalism about modality is the view that metaphysical modality is a matter of the dispositions possessed by actual objects. In a recent paper, David Yates has raised an important worry about the formal adequacy of dispositionalism. This paper responds to Yates’s worry by developing a reply that Yates discusses briefly but dismisses as ad hoc: an appeal to a ’plenitude of powers’ including such powers as the necessarily always manifested power (or disposition) for