Relative expression of a dominant mutated ABCC8 allele determines the clinical manifestation of congenital hyperinsulinism.

Congenital hyperinsulinism (CHI) is most commonly caused by mutations in the ß-cell ATP-sensitive K(+) (K(ATP)) channel genes. Severe CHI was diagnosed in a 1-day-old girl; the mother's cousin and sister had a similar phenotype. ABCC8 gene sequencing (leukocyte DNA) revealed a heterozygous, exon 37, six-base pair in-frame insertion mutation in the affected patient and aunt but also in her unaffected mother and grandfather. In expression studies using transfected COSm6 cells, mutant sulfonylurea receptor 1 (SUR1) protein was expressed on the cell surface but failed to respond to MgADP even in the heterozygous state. mRNA expression in lymphocytes determined by sequencing cDNA clones and quantifying 6FAM-labeled PCR products found that although the healthy mother predominantly expressed the normal transcript, her affected daughter, carrying the same mutant allele, primarily transcribed the mutant. The methylation pattern of the imprinting control region of chromosome 11p15.5 and ABCC8 promoter was similar for all family members. In conclusion, differences in transcript expression may determine the clinical phenotype of CHI in this maternally inherited dominant mutation. The use of peripheral lymphocytes as a peripheral window to the ß-cell transcription profile can serve in resolving ß-cell phenotypes. The severe, dominant-negative nature of the 1508insAS mutation suggests that it affects the functional stoichiometry of SUR1-regulated gating of K(ATP) channels.

Associations between polymorphisms in dopamine neurotransmitter pathway genes and pain response in healthy humans.

Although evidence shows that several dopamine neurotransmission pathway genes are associated with specific clinical pain syndromes, such as fibromyalgia, chronic headache, and postoperative pain, the exact role of dopamine in pain processing is not fully understood. The aim of this study was to explore the relationship between functional polymorphisms in dopaminergic candidate genes and sensitivity to pain in healthy subjects. Healthy subjects (n=192; 105 F, 87 M) were exposed to experimental tonic cold pain (1 degrees C) and phasic heat pain (47 degrees C) stimuli. DNA samples were obtained from both participants and their parents. The relationships between pain response (intensity in response to heat and cold; threshold and tolerance in response to cold only) and the functional Variable Number of Tandem Repeat (VNTR) polymorphisms of three dopamine-related genes were investigated using a Transmission Disequilibrium Test (TDT). Specifically, 30-bp repeat in the promoter region of the monoamine oxidase-A gene (MAO-A), 40-bp repeat in the 3'-untranslated region of the dopamine transporter gene (DAT-1), and 48-bp repeat in the exon 3 of the dopamine receptor 4 gene (DRD4) were examined. Significant associations between cold pain tolerance and DAT-1 (p=0.008) and MAO-A (p=0.024) polymorphisms were found. Specifically, tolerance was shorter for carriers of allele 10 and the rarer allele 11, as compared to homozygous for allele 9, and for carriers of allele 4 as compared to homozygous for allele 3, respectively. These results, together with the known function of the investigated candidate gene polymorphisms, suggest that low dopaminergic activity can be associated with high pain sensitivity and vice versa.

Association between sodium- and potassium-activated adenosine triphosphatase alpha isoforms and bipolar disorders.

BACKGROUND: The sodium- and potassium-activated adenosine triphosphatase (Na+, K+-ATPase) is a major plasma membrane transporter for sodium and potassium. We recently suggested that bipolar disorders (BD) may be associated with alterations in brain Na+, K+-ATPase. We further conjectured that the differences in Na+, K+-ATPase in BD patients could result partially from genetic variations in Na+, K+-ATPase alpha isoforms. METHODS: To test our hypothesis, we undertook a comprehensive study of 13 tagged single nucleotide polymorphisms (SNPs) across the three genes of the brain alpha isoforms of Na+, K+- ATPase (ATP1A1, ATP1A2, and ATP1A3, which encode the three alpha isoforms, alpha1, alpha2, and alpha3, respectively) identified using HapMap data and the Haploview algorithm. Altogether, 126 subjects diagnosed with BD from 118 families were genotyped (parents and affected siblings). Both individual SNPs and haplotypes were tested for association using family-based association tests as provided in the UNPHASED and PBAT set of programs. RESULTS: Significant nominal association with BD was observed for six single SNPs (alpha1: rs11805078; alpha2: rs2070704, rs1016732, rs2854248, and rs2295623; alpha3: rs919390) in the three genes of Na+, K+-ATPase alpha isoforms. Haplotype analysis of the alpha2 isoform (ATP1A2 gene) showed a significant association with two loci haplotypes with BD (rs2295623: rs2070704; global p value = .0198, following a permutation test). CONCLUSIONS: This study demonstrates for the first time that genetic variations in Na+, K+-ATPase are associated with BD, suggesting a role of this enzyme in the etiology of this disease.