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Identification of the Responsible Gene for a Dilated Cardiomyopathy Pedigree and Susceptibility Locus for Schizophrenia

Author: HuZhengMao
Tutor: XiaJiaHui;XiaKun;PanQian
School: Central South University
Course: Genetics
Keywords: dilated cardiomyopathy mutation screen Real-Time PCR 5’-RACE schizophrenia linkage analysis chromosome 12p12-q13
CLC: R542.2
Type: PhD thesis
Year: 2007
Downloads: 197
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Abstract


Dilated cardiomyopathy (DCM, MIM 115200) is the most commonform of primary cardiac muscle disease, characterized by cardiac dilationand reduced systolic function. It is a leading cause of heart failure and themost frequent indication for heart transplantation in young patients. Theexactly pathological mechanism of this disease is still unknown and thereis no ideal therapeutic methods existed.Approximately 35% DCM patients have family history. Nowadays,at least 26 loci for DCM were mapped, and mutations of 22 genes werefound to be responsible for the disease. Our previous study reported oneChinese family with autosomal dominant familial dilated cardiomyopathywith conduction defect, and the disease associated locus was localized toa 5.0 cM region between markers D3S1763 and D3S1282 onchromosome 3q26.1-3q26.2 by genome-wide scanning and linkageanalysis. The locus was firstly reported.To find out the novel predisposing gene and understand the geneticmechanisms underlying this Chinese DCM family, using candidateapproach, we screen 28 genes including APRM1, DNAJC19, KCNMB2and TNIK, related to cytoskeleton, for the mutation by PCR-direct sequencing. A heterozygous varation of c. 153A>G in TNIK was detected.Further analysis showed a perfect segregation of this varation with thedisease haplotype in the family. No mutation of TNIK was detected inunaffected members of the family, and 300 ethnically appropriate normalcontrols.Expression of the wild type TNIK and the mutation in lymphocytewas analyzed to elucidate the underlying molecular mechanism that howthis variation led to the DCM disease in this family, 1) RT-PCR wasperformed to detect the isoforms of mRNA, the results showed thisc.153A>G variation did not alter the RNA splicing of TNIK gene inperipheral blood lymphocyte. 2) Real-Time PCR was also carried out todetect the expression level of TNIK gene in peripheral blood lymphocyte,however no significant change in RNA profiles compare to controls wasfound. The 5’-RACE was further carried to detect the RNA transcript inthe human heart cDNA library, the results suggested that the transcript inheart was different from that in peripheral blood lymphocyte.Further investigation is needed in order to explain how the TNIKc.153A>G variation cause DCM disease. Schizophrenia (MIM 181500) is the most common psychosis,characterized by a constellation of symptoms including hallucinations anddelusions, and symptoms such as severely inappropriate emotionalresponses, disordered thinking and concentration, erratic behavior. Itappears to have a significant genetic component and recently study ofschizophrenia using linkage analysis have revealed a number ofchromosomal regions which may contain the gene for this disease,including 1q21-22, 1q42, 5q21-q33, 6p22-24, 6q21-25, 8p21-22,10p15-p11, 13q32-34, 22q11-12, etc.To investigate the susceptive locus for schizophrenia in Chinesepopulation, genome-wide scan and linkage analysis were performed inthis study. A large Chinese schizophrenia pedigree was collected andgenotyped with 400 markers throughout the genome. Assumingautosomal dominant inheritance, the maximum two-point LOD score 2.51(θ=0) was obtained at microsatellite marker D12S1643, and LOD score2.33 was found at d12s1621 with LINKAGE; the two-point LOD scorewas 2.58 and 2.43 at D12S1643 and d12s1621 with GENEHUNTER. Themultipoint LOD score was 2.69 at D12S1687 and 2.61 at D12S1668. Of the 7 affected cases in this family, 6 share a large haplotype spanning~19cM from D12S1617 to D12S85.In a follow-up study, 15 other schizophrenia families whichcontained 44 schizophrenic cases were genotyped for this region. Theresults for D12S1631 gave a suggestive linkage evdience: HLOD=2.94(α=1), under multipoint and dominant model. The two-point LOD scorewas 1.91 (θ=0.08)at D12S1643.Combining all 16 families, the maximum single-point LOD score of4.15 (θ=0.05) was obtained at D12S1643 with the LINKAGE and themaximum single-point HLOD was 3.76 (α=0.77) at D12S1643 withGENEHUNTER. The maximum multipoint HLOD score 3.90 (α=1.0)was obtained at D12S1631. The nonparametric linkage analysis gavesuggestive linkage results.The linkage and haplotype sharing results provide evidence for a12p12-q13 locus predisposing to schizophrenia in a subset of families inChinese population.

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CLC: > Medicine, health > Internal Medicine > Heart, blood vessels ( circulatory ) disease > Heart disease > Myocardial diseases
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