DTYMK is essential for genome integrity and neuronal survival.

Nucleotide metabolism is a complex pathway regulating crucial cellular processes such as nucleic acid synthesis, DNA repair and proliferation. This study shows that impairment of the biosynthesis of one of the building blocks of DNA, dTTP, causes a severe, early-onset neurodegenerative disease. Here, we describe two unrelated children with bi-allelic variants in DTYMK, encoding dTMPK, which catalyzes the penultimate step in dTTP biosynthesis. The affected children show severe microcephaly and growth retardation with minimal neurodevelopment. Brain imaging revealed severe cerebral atrophy and disappearance of the basal ganglia. In cells of affected individuals, dTMPK enzyme activity was minimal, along with impaired DNA replication. In addition, we generated dtymk mutant zebrafish that replicate this phenotype of microcephaly, neuronal cell death and early lethality. An increase of ribonucleotide incorporation in the genome as well as impaired responses to DNA damage were observed in dtymk mutant zebrafish, providing novel pathophysiological insights. It is highly remarkable that this deficiency is viable as an essential component for DNA cannot be generated, since the metabolic pathway for dTTP synthesis is completely blocked. In summary, by combining genetic and biochemical approaches in multiple models we identified loss-of-function of DTYMK as the cause of a severe postnatal neurodegenerative disease and highlight the essential nature of dTTP synthesis in the maintenance of genome stability and neuronal survival.

The moderating effect of alcohol-specific parental rule-setting on the relation between the dopamine D2 receptor gene (DRD2), the µ-opioid receptor gene (OPRM1) and alcohol use in young adolescents.

AIMS: The main aim of the study was to test the moderating effect of two genetic polymorphisms, one in the dopamine D2 receptor gene (DRD2) and one in the mu-opioid receptor gene (OPRM1), on the link between parental rule-setting and adolescent alcohol use. METHODS: A total of 214 adolescents (M(age )=13.7, 44.9% male) provided saliva samples and completed survey items describing alcohol use and parental rule-setting. RESULTS: Findings indicated that alcohol-specific parental rule-setting was more robustly associated with alcohol use for adolescents with the DRD2 A1 risk allele and for those with the OPRM1 G-allele. CONCLUSION: This study replicates the interaction between parental rule-setting and the DRD2 risk allele on adolescent alcohol use and extends the literature by demonstrating the moderating effects of the OPRM1 risk allele on the link between parental rule-setting and adolescent alcohol use.

Differences in Strength and Timing of the mtDNA Bottleneck between Zebrafish Germline and Non-germline Cells.

We studied the mtDNA bottleneck in zebrafish to elucidate size, timing, and variation in germline and non-germline cells. Mature zebrafish oocytes contain, on average, 19.0 × 10(6) mtDNA molecules with high variation between oocytes. During embryogenesis, the mtDNA copy number decreases to ∼170 mtDNA molecules per primordial germ cell (PGC), a number similar to that in mammals, and to ∼50 per non-PGC. These occur at the same developmental stage, implying considerable variation in mtDNA copy number in (non-)PGCs of the same female, dictated by variation in the mature oocyte. The presence of oocytes with low mtDNA numbers, if similar in humans, could explain how (de novo) mutations can reach high mutation loads within a single generation. High mtDNA copy numbers in mature oocytes are established by mtDNA replication during oocyte development. Bottleneck differences between germline and non-germline cells, due to early differentiation of PGCs, may account for different distribution patterns of familial mutations.

The effect of the OPRM1 and DRD4 polymorphisms on the relation between attentional bias and alcohol use in adolescence and young adulthood.

BACKGROUND: The incentive sensitization theory posits that in the transition from sporadic to problematic alcohol use, the incentive value of alcohol increases (wanting) while its hedonic effects (liking) do not change or decreases. The effect of the OPRM1 c.118A>G polymorphism, associated with liking and wanting, and the DRD4-VNTR polymorphism, related to wanting, on the relation between attentional bias and alcohol use was investigated. METHODS: A total of 195 young adolescents (Study 1) and 86 young adult male heavy drinkers (Study 2) completed a visual probe test. Saliva samples were collected to test both polymorphisms. RESULTS: In Study 1, attentional bias was positively associated with adolescent alcohol use only for OPRM1 G-allele carriers. In Study 2, attentional bias was positively associated with problem drinking for carriers of a DRD4 long allele. DISCUSSION: It is tentatively proposed that an attentional bias for alcohol is related most strongly to liking and wanting in early adolescents, while in young adults, an attentional bias may reflect wanting. In addition, individual differences associated with two both genetic markers should be taken into account when examining the relation between attentional bias and alcohol use.

A functional polymorphism of the mu-opioid receptor gene (OPRM1) influences cue-induced craving for alcohol in male heavy drinkers.

BACKGROUND: The mu-opioid receptor gene (OPRM1) codes for the mu-opioid receptor, which binds beta-endorphin. The A118G polymorphism in this gene affects beta-endorphin binding such that the Asp40 variant (G allele) binds beta-endorphin 3 times more tightly than the more common Asn40 variant (A allele). This study investigated the influence of the A118G polymorphism on cue reactivity after exposure to an alcoholic beverage in male heavy drinkers. METHODS: Participants were either homozygous for the A allele (n=84) or carrying at least 1 copy of the G allele (n=24). All participants took part in a cue-reactivity paradigm where they were exposed to water and beer in 3-minute trials. The dependent variables of main interest were subjective craving for alcohol, subjective arousal, and saliva production. RESULTS: G allele carriers reported significantly more craving for alcohol than the A allele participants (as indicated by the within-subject difference in craving after beer vs after water exposure). No differences were found for subjective arousal and saliva. Both groups did not differ in family history of alcoholism. Participants with the G allele reported a significantly higher lifetime prevalence of drug use than participants homozygous for the A allele. CONCLUSIONS: A stronger urge to drink alcohol after exposure to an alcoholic beverage might contribute to a heightened risk for developing alcohol-related problems in individuals with a copy of the G allele. The G allele might also predispose to drug use in general.