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Cyclic nucleotides directly enhance the opening of the tetrameric CNG and HCN channels, although the mechanism remains unclear. We examined why HCN and certain CNG subunits form functional homomeric channels, whereas other CNG subunits only function in heteromeric channels. The “defect” in the CNGA4 subunit that prevents its homomeric expression was localized to its C-linker, which connects the transmembrane domain to the binding domain and contains a tripeptide that decreases the efficacy of ligand gating. Remarkably, replacement of the homologous HCN tripeptide with the CNGA4 sequence transformed cAMP into an inverse agonist that inhibits HCN channel opening. Using analytical ultracentrifugation, we identified the structural basis for this gating switch: whereas cAMP normally enhances the assembly of HCN C-terminal domains into a tetrameric gating ring, inclusion of the CNGA4 tripeptide reversed this action so that cAMP now causes gating ring disassembly. Thus, ligand gating depends on the dynamic oligomerization of C-terminal binding domains. [Copyright &y& Elsevier]

Presents an obituary to Lodewijk A. Sandkuiji, a statistical geneticist who died on December 4, 2002. Contributions of Sandkuiji in setting database for registration of DNA samples in Netherlands; Details of Sandkuiji's early career; Role of Sandkuiji in successfully mapping a minimum of 30 Mendelian disorders; Assignments undertaken in Dutch medical schools.

Elucidating the molecular mechanisms underlying quantitative neurocognitive phenotypes will further our understanding of the brain''s structural and functional architecture and advance the diagnosis and treatment of the psychiatric disorders that these traits underlie. Although many neurocognitive traits are highly heritable, little progress has been made in identifying genetic variants unequivocally associated with these phenotypes. A major obstacle to such progress is the difficulty in identifying heritable neurocognitive measures that are precisely defined and systematically assessed and represent unambiguous mental constructs, yet are also amenable to the high-throughput phenotyping necessary to obtain adequate power for genetic association studies. In this perspective we compare the current status of genetic investigations of neurocognitive phenotypes to that of other categories of biomedically relevant traits and suggest strategies for genetically dissecting traits that may underlie disorders of brain and behavior. [Copyright &y& Elsevier]

The current development of densely spaced collections of single nucleotide polymorphisms (SNPs) will lead to genomewide association studies for a wide range of diseases in many different populations. Determinations of the appropriate number of SNPs to genotype involve a balancing of power and cost. Several variables are important in these determinations. We show that there are different combinations of sample size and marker density that can be expected to achieve the same power. Within certain bounds, investigators can choose between designs with more subjects and fewer markers or those with more markers and fewer subjects. Which designs are more cost-effective depends on the cost of phenotyping versus the cost of genotyping. We show that, under the assumption of a set cost for genotyping, one can calculate a "threshold cost" for phenotyping; when phenotyping costs per subject are less than this threshold, designs with more subjects will be more cost-effective than designs with more markers. This framework for determining a cost-effective study will aid in the planning of studies, especially if there are choices to be made with respect to phenotyping methods or study populations. [ABSTRACT FROM AUTHOR]

Genomewide association studies may offer the best promise for genetic mapping of complex traits. Such studies in outbred populations require very densely spaced single-nucleotide polymorphisms. In recently founded population isolates, however, extensive linkage disequilibrium (LD) may make these studies feasible with currently available sets of short tandem repeat markers, spaced at intervals as large as a few centimorgans. We report the results of a genomewide association study of severe bipolar disorder (BP-I), using patients from the isolated population of the central valley of Costa Rica. We observed LD with BP-I on several chromosomes; the most striking results were in proximal 8p, a region that has previously shown linkage to schizophrenia. This region could be important for severe psychiatric disorders, rather than for a specific phenotype. [ABSTRACT FROM AUTHOR]

Presents a study which performed a genomewide search for linkage in a family with hereditary vascular retinopathy associated with migraine and Raynaud phenomenon in Denmark. Characteristics of patients with vascular retinopathy; Results of the genome search; Occurrence of vascular retinopathy.

Presents a linkage analysis of a complex pedigree with severe bipolar disorder, using a Markov chain Monte Carlo method. Details on the increase in power associated with the large-pedigree study design; Availability of several software packages for linkage analyses.

Analyzes the mapping of the locus for Cholestasis-Lymphedema Syndrome (CLS) to a 6.6-cM interval on chromosome 15q in Norway. Development of chronic severe lymphedema; Performance of genome screen using DNA from patients with CLS; Manifestation of extensive allele and haplotype sharing.

Examines the identification of pitch of tones in the absence of a reference pitch. Use of absolute pitch-1 proband in genetic mapping; Estimation on the number of multiple loci involved in the development of behavioral trait; Distinction of pitch with other complex human behavior.