Genetic mapping using haplotype and model‐free linkage analysis supports previous evidence for a locus predisposing to severe bipolar disorder at 5q31‐33

Hong, Kyung Sue; McInnes, L. Alison; Song, Terry; Lucas, Jennifer; Silva, Sandra; Fournier, Eduardo; León, Pedro; Molina, Julio; Reus, Victor I.; Sandkuijl, Lodewijk A.

doi:10.1002/ajmg.b.20091

Cited by 27 publications

(18 citation statements)

References 14 publications

(20 reference statements)

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“…This locus is associated with BD (Lewis et al, 2003;Hong et al, 2004;Herzberg et al, 2006;Kerner et al, 2007). A recent study demonstrated a significant increase in homozygosity of the minor allele, which contains a single-nucleotide polymorphism in a putative enhancer for the Pcdha gene, in patients with BD (Pedrosa et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Protocadherin-α Family Is Required for Serotonergic Projections to Appropriately Innervate Target Brain Areas

Katori¹,

Hamada²,

Noguchi³

et al. 2009

J. Neurosci.

151

160

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Serotonergic axons from the raphe nuclei in the brainstem project to every region of the brain, where they make connections through their extensive terminal arborizations. This serotonergic innervation contributes to various normal behaviors and psychiatric disorders. The protocadherin-␣ (Pcdha) family of clustered protocadherins consists of 14 cadherin-related molecules generated from a single gene cluster. We found that the Pcdhas were strongly expressed in the serotonergic neurons. To elucidate their roles, we examined serotonergic fibers in a mouse mutant (Pcdha ⌬CR/⌬CR ) lacking the Pcdha cytoplasmic region-encoding exons, which are common to the gene cluster. In the first week after birth, the distribution pattern of serotonergic fibers in Pcdha ⌬CR/⌬CR mice was similar to wild-type, but by 3 weeks of age, when the serotonergic axonal termini complete their arborizations, the distribution of the projections was abnormal. In some target regions, notably the globus pallidus and substantia nigra, the normally even distribution of serotonin axonal terminals was, in the mutants, dense at the periphery of each region, but sparse in the center. In the stratum lacunosum-moleculare of the hippocampus, the mutants showed denser serotonergic innervation than in wild-type, and in the dentate gyrus of the hippocampus and the caudateputamen, the innervation was sparser. Together, the abnormalities suggested that Pcdha proteins are important in the late-stage maturation of serotonergic projections. Further examination of alternatively spliced exons encoding the cytoplasmic tail showed that the A-type (but not the B-type) cytoplasmic tail was essential for the normal development of serotonergic projections.

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Section: Discussionmentioning

confidence: 99%

Protocadherin-α Family Is Required for Serotonergic Projections to Appropriately Innervate Target Brain Areas

Katori¹,

Hamada²,

Noguchi³

et al. 2009

J. Neurosci.

151

160

View full text Add to dashboard Cite

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“…Previous findings on chromosome 5q have been reported, but these are more distal to our region: Coon et al [1993] reported a LOD score of 1.4 with the marker D5S62 at 5q35. More recently, Hong et al [2004] reported significant identity-by-descent allele sharing among affected relatives in an extended Costa Rican pedigree in the region 5q31-33. Such regions are, however, 18-56 cM from our finding.…”

Section: Linkage Analyses and Genetic Parametersmentioning

confidence: 98%

A genome‐wide linkage search for bipolar disorder susceptibility loci in a large and complex pedigree from the eastern part of Cuba

Marcheco-Teruel

Flint²,

Wikman³

et al. 2006

American J of Med Genetics Pt B

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We present results from a genome-wide scan of a six generation pedigree with 28 affected members with apparently dominant bipolar I disorder from eastern Cuba. Genotypes were obtained using the early access version of the Genechip Mapping 10K Xba array from AFFYMETRIX. Parametric and non-parametric linkage analyses under dominant and recessive models were performed using GENEHUNTER v2.1r5. Two phenotypic models were included in the analyses: bipolar I disorder and recurrent depressive disorder, or bipolar I disorder only. LOD scores were calculated for the entire family combined, and for four subdivisions of the family. For the entire family a suggestive parametric LOD score was obtained under the dominant model and the broader phenotype at 14q11.2-12 (LOD = 2.05). In the same region, a non-parametric LOD score close to genome-wide significance was also obtained, based on the entire family (NPL = 7.31, P-value = 0.07). For two individual branches of the pedigree, genome-wide significance (P < 0.005) was obtained with NPL scores of 8.71 and 12.99, respectively, also in the same region on chromosome 14. Chromosome 5q21.3-22.3 also showed close to genome-wide significant linkage for the complete pedigree (NPL = 7.26, P = 0.07), also supported by significant linkage in one individual branch (NPL = 9.86, P < 0.005). In addition, genome-wide significant nonparametric results (P-values <0.005) were obtained for individual branches at 5p13.1-q12.3, 6p22.3, 8q13.3-21.13, and 10q22.3-23.32. Finally, 2p25.1-25.3, 2p13.3-14, 3p14.2, 6p22.3-24.1, 7p14.1-14.2, 8q12.2-12.3, 10q21.1-21.2, 14q13.1-21.1, 15q15.1-21.2, and 22q12.3-13.32 showed suggestive linkage in the complete family. Most of these potential susceptibility loci overlap with, or are close, to previous linkage findings. The locus on 5q may, however, represent a novel susceptibility locus.

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“…Consequently, mortalin overexpression is linked to cancer research and has been studied in this respect for many years. Human mortalin (HSPA9) is encoded on a single gene, which has been assigned to chromosome 5-band q31.1 (Xie et al 2000), a gene locus previously implicated with various neurological disorders (Crowe and Vieland 1999;Hong et al 2004;Lewis et al 2003;Sklar et al 2004). Similar reports have now implicated mortalin as a key protein in Parkinson's disease, specifically demonstrating that mortalin is significantly reduced in the early onset of the disease and worsens during the progression of the disease (Shi et al 2008).…”

Section: Discussionmentioning

confidence: 99%

Cloning, characterization, and functional studies of a human 40-kDa catecholamine-regulated protein: implications in central nervous system disorders

Gabriele

Pontoriero

Thomas

et al. 2009

Cell Stress and Chaperones

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Catecholamine-regulated proteins (CRPs) have been shown to bind dopamine and other structurally related catecholamines; in particular, the 40-kDa CRP (CRP40) protein has been previously cloned and functionally characterized. To determine putative human homologs, BLAST analysis using the bovine CRP40 sequence identified a human established sequence tag (EST) with significant homology (accession #BQ224193). Using this EST, we cloned a recombinant human brain CRP40-like protein, which possessed chaperone activity. Radiolabeled dopamine binding studies with recombinant human CRP40 protein demonstrated the ability of this protein to bind dopamine with low affinity and high capacity. The full-length human CRP40 nucleotide sequence was elucidated (accession #DQ480334) with RNA ligase-mediated rapid amplification of complementary DNA ends polymerase chain reaction, while Northern blot hybridization suggested that human CRP40 is an alternative splice variant of the 70-kDa mitochondrial heat shock protein, mortalin. Human SH-SY5Y neuroblastoma cells treated with the antipsychotic drug, haloperidol, exhibited a significant increase in CRP40 messenger RNA expression compared to untreated control cells, while other dopamine agonists/antagonists also altered CRP40 expression and immunolocalization. In conclusion, these results show that we have cloned a splice variant of mortalin with a novel catecholamine binding function and that this chaperone-like protein may be neuroprotective in dopamine-related central nervous system disorders.

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Genetic mapping using haplotype and model‐free linkage analysis supports previous evidence for a locus predisposing to severe bipolar disorder at 5q31‐33

Cited by 27 publications

References 14 publications

Protocadherin-α Family Is Required for Serotonergic Projections to Appropriately Innervate Target Brain Areas

Protocadherin-α Family Is Required for Serotonergic Projections to Appropriately Innervate Target Brain Areas

A genome‐wide linkage search for bipolar disorder susceptibility loci in a large and complex pedigree from the eastern part of Cuba

Cloning, characterization, and functional studies of a human 40-kDa catecholamine-regulated protein: implications in central nervous system disorders

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