Two cases of 5-fluorouracil toxicity linked with gene variants in the DPYD gene.

Objectives: Dihydropyrimidine dehydrogenase (DPD) is the initial rate-limiting enzyme in endogenous pyrimidine catabolism and is responsible for the reduction of the pyrimidine analog 5-fluorouracil (5-FU). DPD deficiency is known to cause potentially lethal toxicity in patients receiving 5-FU. We here report a frequency analysis of one of the major splice-site mutations in the DPDY gene, and further two new DPYD gene variants.

A population-based study of genotypic and phenotypic variability in children with spinal muscular atrophy.

Aims: To describe the occurrence of spinal muscular atrophy (SMA) in childhood; to evaluate if any of the genes in the SMA region on chromosome 5q13 correlates with disease severity; to make genotype-phenotype correlations; to evaluate the variability of different disease alleles in carriers and the sensitivity of multiplex ligation-dependent probe amplification (MLPA) for detecting carriers.

Methods: In a population-based study from Western Sweden MLPA was used to determine the copy-numbers of several genes in the SMA region (SMN1, SMN2, BIRC1, GTF2H2 and SERF1A) in SMA-patients and their parents.

Results: We estimated the incidence of SMN1-related SMA in childhood at 1 in 11 800 live births and confirmed the relationship between the number of SMN2 copies and the severity of disease.

Multiplex ligation-dependent probe amplification improves diagnostics in spinal muscular atrophy.

Spinal muscular atrophy (SMA) is an autosomal recessive disease caused by decreased levels of survival motor neuron protein (SMN). In the majority of cases, this decrease is due to absence of the SMN1 gene. Multiplex ligation-dependent probe amplification (MLPA) is a modern quantitative molecular method.

A high frequency of germline BRCA1/2 mutations in western Sweden detected with complementary screening techniques.

Dominant inheritance is presumed in 6-10% of breast and ovarian cancers. Mutations in BRCA1 and BRCA2 genes are the most commonly identified causative genes in such families. The frequency of mutation carriers with breast/ovarian cancer depends on the population studied, and display considerable variation that coincides with ethnic and geographical diversity.

A Caenorhabditis elegans mutant lacking functional nicotinamide nucleotide transhydrogenase displays increased sensitivity to oxidative stress.

Proton-translocating mitochondrial nicotinamide nucleotide transhydrogenase (NNT) was investigated regarding its physiological role in Caenorhabditis elegans. NNT catalyzes the reduction of NADP(+) by NADH driven by the electrochemical proton gradient, Deltap, and is thus a potentially important source of mitochondrial NADPH. Mitochondrial detoxification of reactive oxygen species (ROS) by glutathione-dependent peroxidases depends on NADPH for regeneration of reduced glutathione.

Expression of proton-pumping nicotinamide nucleotide transhydrogenase in mouse, human brain and C elegans.

Proton-translocating nicotinamide nucleotide transhydrogenase is located in the mitochondrial inner membrane and catalyzes the reduction of NADP(+) by NADH to NADPH and NAD(+). The present investigation describes the expression of the transhydrogenase gene in various mouse organs, subsections of the human brain and Caenorhabditis elegans. In the mouse, the expression was highest in heart tissue (100%) followed by kidney (64%), testis (52%), adrenal gland (41%), liver (35%), pancreas (34%), bladder (26%), lung (25%), ovary (21%) and brain (14%).