No description available.

Abstract This work engaged Finnish females affected with osteoarthritis (OA) of the hand to define the role of common sequence variations within the genes of the important structural protein of cartilage, aggrecan (AGC1), and the genes of inflammatory mediators, the interleukin 1 gene cluster and interleukin 6 (IL6), as possible risk factors for the disease. Also, a genome-wide linkage analysis was performed in a sample consisting of Finnish families with multiple individuals affected with hip and knee OA in order to reveal new chromosomal areas that are likely to contain disease associated variations. OA is a chronic disease that leads to the degeneration of articular cartilage in synovial joints. The etiology of the disease is for the most part unknown. Joints of the hand, hip and knee are most commonly affected, and obesity, trauma and excess mechanical stress are known risk factors for the disease. OA also has a significant genetic component. AGC1 carries a variable number of tandem repeats (VNTR) polymorphism, which may be significant for the biomechanical properties of cartilage. It was shown that the most common allele with 27 tandem repeats is protective against hand OA (HOA) (odds ratio 0.46, 95% confidence interval 0.27–0.78). Also, carrying two copies of any of the shorter or longer alleles increased the risk of the disease. Inflammation seems to play a role in the etiology of OA and certain polymorphisms within the interleukin 1 gene cluster and IL6 have been previously shown to increase the transcription of these molecules and to associate with OA. In this study it was shown that the G alleles in three common IL6 promoter single nucleotide polymorphism (SNP) sites are associated with the risk of more severe forms of HOA (p =  0.001 for GGG haplotype). A SNP in IL1B associated with the bilateral form of the disease (p =  0.006) and two IL1B-IL1RN extended haplotype alleles were associated with the same phenotype. Genome-wide and fine mapping linkage analyses recognized chromosomal locus 2q21 with a multipoint LOD score of 3.96. Despite the association analyses of several candidate genes within the locus, no disease-associating sequence variants were identified.

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No description available.

The Dalmatian is affected by deafness more than any other breed of domestic dog, with 30% of the United States population suffering from unilateral or bilateral deafness. The genetic origin of deafness in the Dalmatian is unknown. The objective of this work was to identify, using linkage analysis, any chromosomal region(s) in which the gene(s) responsible for deafness in the Dalmatian may be located. To achieve this objective it was necessary to 1) develop multiplexed microsatellite markers for an efficient whole genome scan, 2) assemble a multigenerational Dalmatian kindred segregating deafness, 3) estimate the heritability of deafness and perform complex segregation analysis, and 4) perform linkage analysis of deafness, and other phenotypic traits, in the Dalmatian kindred. A set of 172 microsatellite markers, termed Minimal Screening Set 1 (MSS1), was characterized, prior to this work, for whole genome scans of the domestic dog. 155 of the MSS1 markers were multiplexed into 48 multiplex sets. Amplification of the multiplex sets was achieved using a single thermal cycling program. The markers were labeled with fluorescent dyes and optimized for resolution on an ABI 310 Genetic Analyzer or ABI 377 Sequencer. A kindred of 266 Dalmatians was assembled, of which 199 had been diagnosed using the brainstem auditory evoked response to determine auditory status. Of these, 74.4% (N = 148) had normal hearing, 18.1% (N = 36) were unilaterally deaf, and 7.5% (N = 15) were bilaterally deaf. A heritability of 0.73 was estimated considering deafness a dichotomous trait and 0.75 as a trichotomous trait. Although deafness in the Dalmatian is clearly heritable, the evidence for the presence of a major gene affecting the disorder was not persuasive. Dalmatians (N = 117) from the assembled kindred were genotyped for the MSS1 markers (149 were polymorphic). Linkage analysis was performed for deafness, eye color, and spot color. The maximum LOD scores for deafness were found with markers Cos15 on CFA17 (LOD = 1.69) and FH2585 on CFA28 (LOD = 1.34). No significant linkage was found with eye color. Significant linkage for spot color was found with marker FH2319 (LOD = 9.7) on CFA11.

The Dalmatian is affected by deafness more than any other breed of domestic dog, with 30% of the United States population suffering from unilateral or bilateral deafness. The genetic origin of deafness in the Dalmatian is unknown. The objective of this work was to identify, using linkage analysis, any chromosomal region(s) in which the gene(s) responsible for deafness in the Dalmatian may be located. To achieve this objective it was necessary to 1) develop multiplexed microsatellite markers for an efficient whole genome scan, 2) assemble a multigenerational Dalmatian kindred segregating deafness, 3) estimate the heritability of deafness and perform complex segregation analysis, and 4) perform linkage analysis of deafness, and other phenotypic traits, in the Dalmatian kindred. A set of 172 microsatellite markers, termed Minimal Screening Set 1 (MSS1), was characterized, prior to this work, for whole genome scans of the domestic dog. 155 of the MSS1 markers were multiplexed into 48 multiplex sets. Amplification of the multiplex sets was achieved using a single thermal cycling program. The markers were labeled with fluorescent dyes and optimized for resolution on an ABI 310 Genetic Analyzer or ABI 377 Sequencer. A kindred of 266 Dalmatians was assembled, of which 199 had been diagnosed using the brainstem auditory evoked response to determine auditory status. Of these, 74.4% (N = 148) had normal hearing, 18.1% (N = 36) were unilaterally deaf, and 7.5% (N = 15) were bilaterally deaf. A heritability of 0.73 was estimated considering deafness a dichotomous trait and 0.75 as a trichotomous trait. Although deafness in the Dalmatian is clearly heritable, the evidence for the presence of a major gene affecting the disorder was not persuasive. Dalmatians (N = 117) from the assembled kindred were genotyped for the MSS1 markers (149 were polymorphic). Linkage analysis was performed for deafness, eye color, and spot color. The maximum LOD scores for deafness were found with markers Cos15 on CFA17 (LOD = 1.69) and FH2585 on CFA28 (LOD = 1.34). No significant linkage was found with eye color. Significant linkage for spot color was found with marker FH2319 (LOD = 9.7) on CFA11.

Abstract Genetic factors have been shown to have an important role in intervertebral disc disease. The associations of known genetic risk factors and whole-body vibration, a proposed environmental risk factor, for intervertebral disc disease (IDD) were evaluated. Eleven variations in eight genes (COL9A2, COL9A3, COL11A2, IL1A, IL1B, IL6, MMP-3 and VDR) were genotyped in 150 male train engineers with an average of 21-year exposure to whole-body vibration and 61 male paper mill workers with no occupational exposure to vibration. The number of individuals belonging to the IDD group was significantly higher among train engineers (42% of train engineers vs. 17.5% of sedentary workers; p = 0.005). In addition, the IL1A-889T allele represented a risk factor for the IDD-phenotype. In order to clarify the role of genetic variations in the genes coding for several proinflammatory mediators, hundred fifty-five Finnish individuals with IDD were analyzed for mutations in the genes coding for inflammatory mediators IL-1α, IL-1β, IL-6 and TNF-α. In addition, sixteen single nucleotide polymorphisms (SNPs) in inflammatory mediator genes were genotyped. An association was identified between IDD and IL6 polymorphism +15T>A in exon 5 (p = 0.007). In addition, IL6 haplotype GGGA of -597G>A, -572G>C, -174G>C and +15T>A in exon 5 associated with IDD (p = 0.0033). A functional SNP in the CILP gene has been suggested to cause IDD in the Japanese population. This functional variation was analyzed in 243 Finnish IDD patients and 259 controls, and in 348 Chinese individuals with degenerative MRI findings and 343 Chinese individuals with normal MRI. No association was found in the Finnish and Chinese study populations. In order to reveal chromosomal susceptibility loci and new candidate gene(s) for IDD a genome-wide scan was performed on 14 Finnish families with 186 individuals. Genome-wide and fine mapping analysis provided maximum two-point LOD scores of 2.71, 2.36 and 2.04 for chromosomes 21, 4, and 6, respectively. Second fine mapping confirmed the susceptibility of chromosome 21. Two candidate genes, ADAMTS-1 and ADAMTS-5, were analyzed in the region suggesting linkage, leading to the identification of thirteen sequence variations. However, none of the variations were disease causing.

Objectives: We sought to identify a novel gene for dilated cardiomyopathy (DCM). Background: DCM is a heritable, genetically heterogeneous disorder that remains idiopathic in the majority of patients. Familial cases provide an opportunity to discover unsuspected molecular bases of DCM, enabling pre-clinical risk detection. Methods: Two large families with autosomal-dominant DCM were studied. Genome-wide linkage analysis was used to identify a disease locus, followed by fine mapping and positional candidate gene sequencing. Mutation scanning was then performed in 278 unrelated subjects with idiopathic DCM, prospectively identified at the Mayo Clinic. Results: Overlapping loci for DCM were independently mapped to chromosome 10q25-q26. Deoxyribonucleic acid sequencing of affected individuals in each family revealed distinct heterozygous missense mutations in exon 9 of RBM20, encoding ribonucleic acid (RNA) binding motif protein 20. Comprehensive coding sequence analyses identified missense mutations clustered within this same exon in 6 additional DCM families. Mutations segregated with DCM (peak composite logarithm of the odds score >11.49), were absent in 480 control samples, and altered residues within a highly conserved arginine/serine (RS)-rich region. Expression of RBM20 messenger RNA was confirmed in human heart tissue. Conclusions: Our findings establish RBM20 as a DCM gene and reveal a mutation hotspot in the RS domain. RBM20 is preferentially expressed in the heart and encodes motifs prototypical of spliceosome proteins that regulate alternative pre-messenger RNA splicing, thus implicating a functionally distinct gene in human cardiomyopathy. RBM20 mutations are associated with young age at diagnosis, end-stage heart failure, and high mortality.

No description available.

No description available.