Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although there is considerable evidence for a strong genetic component to idiopathic autism, several genome-wide screens for susceptibility genes have been carried out with limited concordance of linked loci, reflecting numerous genes of weak effect and/or sample heterogeneity. In the current study, linkage analysis was carried out in a sample of 62 autism-affected relative pairs with more severe obsessive-compulsive behaviors, selected from a larger (n=115) set of autism-affected relative pairs as a means of reducing sample heterogeneity. Obsessive-compulsive behaviors were assessed using the Autism Diagnostic Interview-Revised (ADI-R). In the sample with more severe obsessive-compulsive behaviors, multipoint NPL scores above 2 were observed on chromosomes 1, 4, 5, 6, 10, 11 and 19, with the strongest evidence for linkage on chromosome 1 at the marker D1S1656, where the multipoint NPL score was 3.06, and the two-point NPL score was 3.21. In follow-up analyses, analyzing the subset of families (n=35) where the patients had the most severe obsessive-compulsive behaviors generated a multipoint NPL score of 2.76, and a two-point NPL score of 2.79, indicating that the bulk of evidence for linkage was derived from the families most severely affected with obsessive-compulsive behaviors. The data suggest that there is an autism susceptibility gene on chromosome 1 and provide further support for the presence of autism susceptibility genes on chromosomes 6 and 19.
Mol Psychiatry 2004 Feb
PMID:Linkage analysis for autism in a subset families with obsessive-compulsive behaviors: evidence for an autism susceptibility gene on chromosome 1 and further support for susceptibility genes on chromosome 6 and 19. 1469 29

Our group first reported a linkage finding for bipolar (BP) disorder on chromosome 8q24 in a study of 50 multiplex pedigrees, with an HLOD score reaching 2.39. Recently, Cichon et al reported an LOD score of 3.62 in the same region using two-point parametric analysis. Subsequently, we published the results of a genome scan for linkage to BP disorder using a sample extended to 65 pedigrees in which chromosome 8q24 provided the best finding, an NPL score of 3.13, approaching the accepted score for suggestive linkage. We have now fine mapped this region of chromosome 8 in our 65 pedigrees by the addition of 19 microsatellite markers reaching a marker density of 0.8 cM and an information content of 0.84. After the addition of the new data, the original NPL score slightly increased to 3.25. Two-point parametric analysis using the model employed by Cichon et al obtained an LOD score of 3.32 for marker D8S256 at theta=0.14 exceeding the proposed threshold for genomewide significance. After adjusting the parameters in accordance with the 'common disease-common variant' hypothesis, multipoint parametric analysis resulted in an HLOD of 2.49 (alpha=0.78) between D8S529 and D8S256, and defined a 1-LOD interval corresponding to a 2.3 Mb region. No allelic association with the disease was observed for our set of microsatellite markers. Biologically, plausible candidate genes in this region include thyroglobulin, KCNQ3 coding for a voltage-gated potassium channel and the gene for brain adenyl-cyclase (ADCY8).
Mol Psychiatry 2004 Feb
PMID:Linkage of bipolar affective disorder on chromosome 8q24: follow-up and parametric analysis. 1496 77

Phenotypic expression of the deafness-associated homoplasmic A1555G mutation in the mitochondrial 12S rRNA gene varies from profound congenital hearing loss to normal hearing. It has been shown that this variability in clinical expression in most patients is due to the complex inheritance of multiple nuclear-encoded modifier genes. Human mitochondrial transcription factor B1 (TFB1M) has been proposed as a candidate for being such a modifier, since it methylates adenine residues in the adjacent loop of the A1555G mutation in the 12S rRNA gene. Polymorphic markers within and adjacent to the TFB1M gene were genotyped in 214 individuals from 41 multiplex families with the A1555G mutation of Spanish, Italian, and Arab-Israeli origin. Multipoint non-parametric linkage analysis of all families combined revealed an NPL score of 1.7 (P = 0.05), and a Lod score of 1.4 (P = 0.04). Linkage disequilibrium by the Transmission Disequilibrium Test at D6S1577, a microsatellite adjacent to TFB1M, showed preferential non-transmission of an allele to affected individuals with chi2 = 8.76; P = 0.003. Sequence analysis of the coding region of the gene and testing of all intragenic SNPs did not reveal a putative causative mutation. These data provide suggestive evidence that TFB1M is a nuclear-encoded modifier gene for phenotypic expression of the A1555G mutation, and that the effect may occur through a regulatory or splicing mutation.
Mol Genet Metab 2004 May
PMID:Human mitochondrial transcription factor B1 as a modifier gene for hearing loss associated with the mitochondrial A1555G mutation. 1511 Mar 15

Familial Alzheimer's disease (AD [MIM 104300]) has been a focus of intense investigation, primarily in Caucasian families from Europe and North America families. Although the late-onset form of familial AD, beginning after age 65 years, has been linked to regions on chromosomes 10q and 12p, the specific genetic variants have not yet been consistently identified. Using a unique cohort of families of Caribbean Hispanics ancestry, we screened the genome using 340 markers on 490 family members from 96 families with predominantly late-onset AD. We observed the strongest support for linkage on 18q (LOD=3.14). However, 17 additional markers (chromosomes 1-6, 8, 10, 12, and 14) exceeded a two-point LOD score of 1.0 under the affecteds-only autosomal dominant model or affected sibpair model. As we previously reported the fine-mapping effort on 12p showing modest evidence of linkage, we focused our fine-mapping efforts on two other candidate regions in the current report, namely 10q and 18q. We added 31 family members and eight additional Caribbean Hispanic families to fine map 10q and 18q. With additional microsatellite markers, the evidence for linkage for 18q strengthened near 112 cM, where the two-point LOD score for D18S541 was 3.37 and the highest NPL score in that region was 3.65 (P=0.000177). This narrow region contains a small number of genes expressed in the brain. However, at 10q (134-138 cM), the NPL score decreased from 3.15 (P=0.000486) to 2.1 (P=0.0218), but two broad peaks remained overlapping with previously reported peaks. Our results provide modest support for linkage on 10q and 12p in this cohort of Caribbean Hispanic families with familial Alzheimer's disease, and strong evidence for a new locus on 18q.
Mol Psychiatry 2004 Nov
PMID:Fine mapping of 10q and 18q for familial Alzheimer's disease in Caribbean Hispanics. 1524 31

Photoparoxysmal response (PPR) is an abnormal visual sensitivity of the brain in reaction to intermittent photic stimulation. It is an epilepsy-related electroencephalographic trait with high prevalence in idiopathic epilepsies, especially in common idiopathic generalized epilepsies (IGEs), such as childhood absence epilepsy and juvenile myoclonic epilepsy. This degree of co-morbidity suggests that PPR may be involved in the predisposition to IGE. The identification of genes for PPR would, therefore, aid the dissection of the genetic basis of IGE. Sixteen PPR-multiplex families were collected to conduct a genome-wide linkage scan using broad (all PPR types) and narrow (exclusion of PPR types I and II and the occipital epilepsy cases) models of affectedness for PPR. We found an empirical genome-wide significance for parametric (HLOD) and non-parametric (NPL) linkage (Pgw(HLOD)=0.004 and Pgw(NPL)=0.01) for two respective chromosomal regions, 7q32 at D7S1804 (HLOD=3.47 with alpha=1, P(NPL)=3.39x10(-5)) and 16p13 at D16S3395 (HLOD=2.44 with alpha=1, P(NPL)=7.91x10(-5)). These two genomic regions contain genes that are important for the neuromodulation of cortical dynamics and may represent good targets for candidate-gene studies. Our study identified two susceptibility loci for PPR, which may be related to the underlying myoclonic epilepsy phenotype present in the families studied.
Hum Mol Genet 2005 Jan 01
PMID:Genome-wide linkage scan of epilepsy-related photoparoxysmal electroencephalographic response: evidence for linkage on chromosomes 7q32 and 16p13. 1554 44

Autism is a pervasive developmental disorder with a strong genetic component. While candidate regions of the genome have been identified, location of genes conferring susceptibility to autism has been hindered by the heterogeneity within this clinically defined disorder, and the likely contribution of many genes of weak effect. Subsetting samples on the basis of distinct, nondiagnostic clinical features has been recommended to decrease sample heterogeneity. In this study, linkage analysis was performed on a subset of families in the database of the Autism Genetic Resource Exchange (AGRE). This set of autism-affected relative pairs (n=34) was also concordant for a history of developmental regression as measured by the Autism Diagnostic Interview-Revised (ADI-R). In this sample, a maximum multipoint LOD score of 3.4 under the dominant mode of inheritance and an NPL score of 3.0 (P=1.3 x 10(-3)) were observed on chromosome 21 near D21S1437. On chromosome 7 near D7S483 a LOD score of 2.0 under the dominant mode of inheritance and an NPL score of 3.7 (P=7.9 x 10(-5)) were observed. Genetic elements in these regions of 21q and 7q are likely to confer susceptibility to autism or modify the disease presentation in a subgroup of children characterized by a history of developmental regression.
Mol Psychiatry 2005 Aug
PMID:Evidence for linkage on 21q and 7q in a subset of autism characterized by developmental regression. 1680 76

In a previous study [Maziade et al. (2005); Mol Psychiatry 10:486-499], we provided evidence for linkage (parametric lod score of 4.05) on chromosome 16p for bipolar affective disorder (BP) in 21 kindreds from Eastern Quebec, a population characterized by a founder effect. Using a stringent design, we performed a replication study in a second sample of 27 kindreds (sample 2) collected from the same population and assessed with the same methodologies as in our original sample (sample 1), that is with the same diagnostic procedure and using a common set of 23 markers studied with model-based (parametric) and model-free (nonparametric) linkage analyses. We replicated our initial finding with P values <0.001. Indeed, maximum NPL(all) scores of 3.7 and 3.52 were found at marker D16S3060 in sample 2 for the narrow and broad BP phenotype definition, respectively. For the latter definition, the nonparametric score reached 3.87 in the combined sample, a value that exceeded the maximum NPL score obtained in each individual sample (NPL(all) = 2.32 in sample 1; NPL(all) = 3.52 in sample 2). Moreover, a refined phenotype restricted to BP associated with psychosis yielded significant evidence for linkage in each individual sample (NPL(all) = 2.38 in sample 1; NPL(all) = 2.72) while yielding the best result (NPL(all) score = 3.90) in the combined sample (samples 1 and 2), despite an important reduction in the number of affected individuals. It is also noteworthy that the use of the refined phenotype provided a location of the maximum linkage peak shared by both samples, that is, at marker D16S668 in 16p13.12, suggesting consistency across samples. Our study provided one of the strongest pieces of evidence for linkage with BP in 16p and illustrated the heuristic potential of a replication study in a second sample ascertained from the same population and using homogeneous methodologies.
 ...
PMID:Replication of linkage with bipolar disorder on chromosome 16p in the Eastern Quebec population. 1816 73

A new lipase gene designated as SlLipA was isolated from Serratia liquefaciens S33 DB-1 by the genomic-walking method. The cloned gene contained an open reading frame (ORF) of 1,845 bp encoding 615 amino acids with a conserved GXSXG motif. Genome sequence analysis showed that an aldo/keto reductase gene closed to the SlLipA gene. The lipase gene was cloned into the expression vector pPICZalphaA and successfully integrated into the heterologous host, methylotrophic yeast Pichia pastoris GS115. Five transformants could be expressed as secreted recombinant proteins with the high activity on Triglyceride-Agarose plate and as candidates to produce the recombinant enzyme. A C-terminal His tag was used for its purification. The lipase activity of different transformants against substrate para-nitrophenyl laurate (p-NPL) varied from 14 to 16 U ml(-1). For the substrates para-nitrophenyl caprate (p-NPC), p-NPL, para-nitrophenyl myristate (p-NPM), para-nitrophenyl palmitate (p-NPP), and para-nitrophenyl stearate (p-NPS), the specific activity was shown to be preferred to long acyl chain length of p-NPS.
Mol Biotechnol 2008 Feb
PMID:Isolation of a novel lipase gene from Serratia liquefaciens S33 DB-1, functional expression in Pichia pastoris and its properties. 1821 90

Bipolar affective disorder is a heritable, relatively common, severe mood disorder with lifetime prevalence up to 4%. We report the results of a genome-wide linkage analysis conducted on a cohort of 35 Australian bipolar disorder families which identified evidence of significant linkage on chromosome 15q25-26 and suggestive evidence of linkage on chromosomes 4q, 6q and 13q. Subsequent fine-mapping of the chromosome 15q markers, using allele frequencies calculated from our cohort, gave significant results with a maximum two-point LOD score of 3.38 and multipoint LOD score of 4.58 for marker D15S130. Haplotype analysis based on pedigree-specific, identical-by-descent allele sharing, supported the location of a bipolar susceptibility gene within the Z(max-1) linkage confidence interval of 17 cM, or 6.2 Mb, between markers D15S979 and D15S816. Non-parametric and affecteds-only linkage analysis further verified the linkage signal in this region. A maximum NPL score of 3.38 (P=0.0008) obtained at 107.16 cM (near D15S130), and a maximum two-point LOD score of 2.97 obtained at marker D15S1004 (affecteds only), support the original genome-wide findings on chromosome 15q. These results are consistent with four independent positive linkage studies of mood and psychotic disorders, and raise the possibility that a common gene for susceptibility to bipolar disorder, and other psychiatric disorders may lie in this chromosome 15q25-26 region.
Mol Psychiatry 2009 May
PMID:A genome screen of 35 bipolar affective disorder pedigrees provides significant evidence for a susceptibility locus on chromosome 15q25-26. 1822 37

With homology modeling techniques, molecular mechanics and molecular dynamics methods, a 3D structure model of N-acetylneuraminate lyase from human (hNAL, EC 4.1.3.3) was created and refined. This model was further assessed by Profile-3D and PROCHECK, which confirms that the refined model is reliable. Furthermore, the docking results of the substrates (sialic acid and KDO) into the active site of hNAL indicate that hNAL can cleave the sialic acid and KDO. Thr51 and Tyr143 may be the key amino acids residues as they have strong hydrogen bonding interactions with the substrates, which is in good agreement with the experimental results by Izard et al. (Structure 2:361-369. doi:10.1016/S0969-2126(00)00038-1 (1994)). From the docking studies, we also suggest that Asp176 and Ser218 only form hydrogen bonds with sialic acid, therefore, they may help sialic acid interact with hNAL steadly.
J Mol Model 2009 Mar
PMID:Homology modeling and molecular dynamics study on N-acetylneuraminate lyase. 1905 31


<< Previous 1 2 3 4 Next >>