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PubMed1995

Intragenomic complementation of a 3AB mutant in dicistronic polioviruses.

We report the construction of a poliovirus genome [pPVM-VPg(3F4A)] harboring a double mutation in VPg. This mutant, in which the tyrosine and the threonine at residues 3 and 4 of the VPg region were replaced by phenylalanine and alanine, respectively, is lethal, that is, all RNA synthesis was abolished and no revertants could be isolated. Using the properties of dicistronic polioviruses (with the general genotype PV 5'NTR-3AB-EMCV IRES-PV ORF-3'NTR), we have observed that the defect in RNA synthesis of the VPg(3F4A) mutant could be rescued by providing wild-type protein 3AB from the first open reading frame in trans. We conclude that the 3AB provided by the first cistron of the dicistronic construct was capable of "intragenomic complementation." Intragenomic complementation, however, was inefficient. Thus, the dicistronic RNAs were only quasi-infectious, and even first-passage viruses were found to have reverted to a functioning VPg in the polyprotein. This phenomenon underlines the role of polypeptide 3AB in multiple functions of viral proliferation. First-passage viruses, all of which expressed a small-plaque phenotype, had retained the original dicistronic genotype. At the fourth passage, however, all isolates were monocistronic, and they displayed complex genetic rearrangements revealing interesting information regarding IRES function.

Amino Acid Sequence↗
PubMed2001

A novel protein involved in the functional assembly of the oxygen-evolving complex of photosystem II in Synechocystis sp. PCC 6803.

Mutation of Glu69 to Gln in the D2 protein of photosystem II is known to lead to a loss of photoautotrophic growth in Synechocystis sp. PCC 6803. However, second-site mutants (pseudorevertants) with restored photoautotrophic growth but still maintaining the E69Q mutation in D2 are easily obtained. Using a genomic mapping technique involving functional complementation, the secondary mutation was mapped to slr0286 in two independent mutants. The mutations in Slr0286 were R42M or R394H. To study the function of Slr0286, mutants of E69Q and of the wild-type strain were made that lacked slr0286. Deletion of slr0286 did not affect photoautotrophic capacity in wild type but led to a marked decrease in the apparent affinity of Ca(2+) to its binding site at the water-splitting system of photosystem II and to a reduced heat tolerance of the oxygen-evolving system, particularly in E69Q. Moreover, a small increase in the half-time for photoactivation of the oxygen-evolving complex of photosystem II for both wild type and the E69Q mutant was observed in the absence of Slr0286. The accumulation of photosystem II reaction centers, dark stability of the oxygen-evolving apparatus, stability of oxygen evolution, and the kinetics of charge recombination between Q(A)(-) and the donor side were not affected by deletion of slr0286. Slr0286 lacks clear functional motifs, and no homologues are apparent in other organisms, even not in other cyanobacteria. In any case, Slr0286 appears to help the functional assembly and stability of the water-splitting system of photosystem II.

Amino Acid Sequence↗
PubMed2003

Genome scan for childhood and adolescent obesity in German families.

OBJECTIVE: Several genome scans have been performed for adult obesity. Because single formal genetic studies suggest a higher heritability of body weight in adolescence and because genes that influence body weight in adulthood might not be the same as those that are relevant in childhood and adolescence, we performed a whole genome scan. METHODS: The genome scan was based on 89 families with 2 or more obese children (sample 1). The mean age of the index patients was 13.63 +/- 2.75 years. A total of 369 individuals were initially genotyped for 437 microsatellite markers. A second sample of 76 families was genotyped using microsatellite markers that localize to regions for which maximum likelihood binomial logarithm of the odd (MLB LOD) scores on use of the concordant sibling pair approach exceeded 0.7 in sample 1. RESULTS: The regions with MLB LOD scores >0.7 were on chromosomes 1p32.3-p33, 2q37.1-q37.3, 4q21, 8p22, 9p21.3, 10p11.23, 11q11-q13.1, 14q24-ter, and 19p13-q12 in sample 1; MLB LOD scores on chromosomes 8p and 19q exceeded 1.5. In sample 2, MLB LOD scores of 0.68 and 0.71 were observed for chromosomes 10p11.23 and 11q13, respectively. CONCLUSION: We consider that several of the peaks identified in other scans also gave a signal in this scan as promising for ongoing pursuits to identify relevant genes. The genetic basis of childhood and adolescent obesity might not differ that much from adult obesity.

Adolescent↗
PubMed2005

Mutation of DNAJC19, a human homologue of yeast inner mitochondrial membrane co-chaperones, causes DCMA syndrome, a novel autosomal recessive Barth syndrome-like condition.

BACKGROUND: A novel autosomal recessive condition, dilated cardiomyopathy with ataxia (DCMA) syndrome, has been identified in the Canadian Dariusleut Hutterite population, characterised by early onset dilated cardiomyopathy with conduction defects, non-progressive cerebellar ataxia, testicular dysgenesis, growth failure, and 3-methylglutaconic aciduria. OBJECTIVE: To map DCMA syndrome and identify the mutation underlying this condition. METHODS: A genome wide scan was undertaken on consanguineous Hutterite families using a homozygosity mapping approach in order to identify the DCMA associated chromosomal region. Mutation analysis was carried out on positional candidate genes in this region by sequencing. Reverse transcriptase polymerase chain reaction and bioinformatics analyses were then used to characterise the mutation and determine its effect on the protein product. RESULTS: The association of DCMA syndrome with a 2.2 Mb region of chromosome 3q26.33 was found. A disease associated mutation was identified: IVS3-1 G-->C in the DNAJC19 gene, encoding a DNAJ domain containing protein of previously unknown function (Entrez Gene ID 131118). CONCLUSIONS: The DNAJC19 protein was previously localised to the mitochondria in cardiac myocytes, and shares sequence and organisational similarity with proteins from several species including two yeast mitochondrial inner membrane proteins, Mdj2p and Tim14. Tim14 is a component of the yeast inner mitochondrial membrane presequence translocase, suggesting that the unique phenotype of DCMA may be the result of defective mitochondrial protein import. It is only the second human disorder caused by defects in this pathway that has been identified.

Abnormalities, Multiple↗
PubMed1998

The mouse genome contains two expressed intronless retroposed pseudogenes for the sentrin/sumo-1/PIC1 conjugating enzyme Ubc9.

The ubiquitin conjugating (ubc) E2 enzyme ubc-9 conjugates the ubiquitin-like peptide sentrin/SUMO-1/PIC1 to target proteins which include the Fas antigen. We show that the mouse genome contains four copies of the ubc-9 gene. These include a structural ubc-9 gene consisting of seven exons which encode a protein identical to human ubc-9, and three intronless processed pseudogenes. The open reading frames (ORF) of two of the pseudogenes, ubc9-psi1 and ubc9-psi2, correspond to the cDNA of ubc-9 and encode for proteins which differ from ubc9 by three and one amino acid substitutions respectively. The third pseudogene, ubc9-psi3, contains many mutations and stop codons. ubc9-psi1 and ubc9-psi2 are flanked by 5'- and 3'-untranslated (UT) regions homologous to those of the structural ubc-9 gene. Both genes contain a polyA tail and direct repeats at both ends suggesting that they arose by mRNA retroposition. Both ubc9-psi1 and ubc9-psi2 are transcribed into mRNA in murine cells. In contrast to ubc9, the protein products of ubc9-psil and ubc9-psi2 fail to bind Fas and to complement an yeast conditional ubc9 mutant. These results suggest that ubc9-psi1 and ubc9-psi2 encode for proteins that may interact with targets that differ from those recognized by ubc-9.

Amino Acid Sequence↗
PubMed1995

Cloning of a Candida albicans peptide transport gene.

A Candida albicans peptide transport gene, CaPTR2, was cloned from a C. albicans genomic library by functional complementation of a peptide transport deficient mutant (strain ptr2-2) of Saccharomyces cerevisiae. CaPTR2 restored peptide transport to transformants as determined by uptake of radiolabelled dileucine, growth on dipeptides as sources of required amino acids, and restoration of growth inhibition by toxic peptides. Plasmid curing experiments demonstrated that the peptide transport phenotype was plasmid borne. CaPTR2 was localized to chromosome R of C. albicans by contour-clamped homologous electric field gel chromosome blots. Deletion subclones and frameshift mutagenesis were used to narrow the peptide transport complementing region to a 5.1 kb DNA fragment. DNA sequencing of the complementing region identified an ORF of 1869 bp containing an 84 nucleotide intron. The deduced amino acid sequence predicts a protein of 70 kDa consisting of 623 amino acids with 12 hydrophobic segments. A high level of identity was found between the predicted protein and peptide transport proteins of S. cerevisiae and Arabidopsis thaliana. This study represents the first steps in the genetic characterization of peptide transport in C. albicans and initiates a molecular approach for the study of drug delivery against this pathogen.

Amino Acid Sequence↗
PubMed2001

Genomic localization, organization and amplification of the human zinc transporter protein gene, ZNT4, and exclusion as a candidate gene in different clinical variants of acrodermatitis enteropathica.

Acrodermatitis enteropathica is an inherited disorder of zinc metabolism, the molecular basis of which is currently unknown. Recent transgenic mouse studies have highlighted the potential significance of certain zinc transport proteins, for example ZnT4, in providing clues to the pathogenesis of zinc-related disorders such as acrodermatitis enteropathica. Specifically, mice of any genotype suckled on ZnT4-deficient mice fail to absorb intestinal zinc and ZnT4-deficient mice also develop dermatitis, alopecia and stunted growth. Therefore, to assess human ZnT4 as a candidate gene/protein in acrodermatitis enteropathica or related disorders, we characterized the intron-exon organization of the human ZNT4 gene, which comprises seven distinct exons spanning approximately 38.7 kb. High-resolution radiation hybrid mapping placed ZNT4 on 15q21.1. We also developed a PCR-based mutation detection strategy using primers placed on flanking introns followed by direct sequencing of the PCR products. Using this approach, we sequenced DNA from five individuals with acrodermatitis enteropathica; no mutations were identified. Thus, ZNT4 is unlikely to be the correct candidate gene for this disorder. We also identified and characterized two common single nucleotide polymorphisms in exon 5 and in the 3' UTR of ZNT4, which will be useful for future genetic linkage studies in assessing ZNT4 as a candidate gene for other inherited disorders of zinc metabolism.

Acrodermatitis↗
PubMed2003

A whole-genome screen of a quantitative trait of age-related maculopathy in sibships from the Beaver Dam Eye Study.

Age-related maculopathy (ARM) is a leading cause of visual impairment among the elderly in Western populations. To identify ARM-susceptibility loci, we genotyped a subset of subjects from the Beaver Dam (WI) Eye Study and performed a model-free genomewide linkage analysis for markers linked to a quantitative measure of ARM. We initially genotyped 345 autosomal markers in 325 individuals (N=263 sib pairs) from 102 pedigrees. Ten regions suggestive of linkage with ARM were observed on chromosomes 3, 5, 6, 12, 15, and 16. Prior to fine mapping, the most significant regions were an 18-cM region on chromosome 12, near D12S1300 (P=.0159); a region on chromosome 3, near D3S1763, with a P value of.0062; and a 6-cM region on chromosome 16, near D16S769, with a P value of.0086. After expanding our analysis to include 25 additional fine-mapping markers, we found that a 14-cM region on chromosome 12, near D12S346 (located at 106.89 cM), showed the strongest indication of linkage, with a P value of.004. Three other regions, on chromosomes 5, 6, and 15, that were nominally significant at P< or =.01 are also appropriate for fine mapping.

Adult↗
PubMed2003

Identification of novel imprinted genes in a genome-wide screen for maternal methylation.

A characteristic of imprinted genes is that the maternal and paternal alleles show differences in methylation. To perform a genome-wide screen for novel imprinted loci, we applied methylation-sensitive representational difference analysis (Me-RDA) to parthenogenetic mouse embryos, to identify differentially methylated regions (DMRs) methylated specifically on the maternal allele. We isolated a total of 26 distinct clones from known and novel DMRs and identified three novel imprinted genes. Nap1l5 is located on proximal chromosome 6 and encodes a protein with homology with nucleosome assembly proteins (NAPs); it has tissue-specific imprinting with expression from the paternal allele. We identified two DMRs on chromosome 15, a chromosome that was not thought to contain imprinted loci, and demonstrated that each is associated with a paternally expressed transcript. Peg13 gives rise to a noncoding RNA that is highly expressed in the brain and imprinted in all tissues examined. A DMR was also identified at the chromosome 15 Slc38a4 gene, which encodes a system A amino acid transporter; we show that Slc38a4 is imprinted in a tissue-specific manner. Interestingly, two of the three novel genes identified in this screen are located within the introns of other genes; their identification indicates that such "microimprinted" domains may be more common than previously thought.

Alleles↗
PubMed2003

Evaluating the context-dependent effect of family history of stroke in a genome scan for hypertension.

BACKGROUND AND PURPOSE: Hypertension is an important risk factor for stroke, and the 2 diseases may share susceptibility genes in common. We sought to identify genomic regions influencing susceptibility to both hypertension and stroke. SUBJECTS AND METHODS: Genome-wide linkage scans were performed in samples of 338 white and 265 black hypertensive sibships recruited by the Genetic Epidemiology Network of Arteriopathy Study of the NHLBI Family Blood Pressure Program (FBPP). The hypertensive sibships were stratified by positive (+FH) or negative (-FH) family history of stroke. Genome-wide scans were repeated in each stratum, and the results were compared within each ethnic group by a regression-based analysis of heterogeneity. RESULTS: In whites, the best evidence for linkage was found on chromosome 16 in the unstratified sample of hypertensive sibpairs (logarithm of odds [LOD]=1.85 at 71 cM). In blacks, the best evidence for linkage was found on chromosome 2 in the unstratified sample of hypertensive sibpairs (LOD=1.95 at 230 cM). Additional evidence for linkage (LOD >or=1.5) was observed among white hypertensive sibpairs with a -FH on chromosome 13 and among black hypertensive sibpairs with a +FH of stroke on chromosome 19. CONCLUSIONS: Significant evidence for linkage heterogeneity among hypertensive sibpairs stratified by family history of stroke suggests the presence of genes influencing susceptibility to both hypertension and stroke on chromosomes 13 (whites) and 19 (blacks). Although no significant evidence of heterogeneity was observed on chromosome 16 in whites and chromosome 2 in blacks, these chromosomes do provide evidence of linkage to hypertension.

Adult↗
PubMed2005

Sensitive multistep clinical molecular screening of 180 unrelated individuals with retinoblastoma detects 36 novel mutations in the RB1 gene.

Retinoblastoma (RB) is a neoplasm of retinal origin caused by mutations in RB1, the retinoblastoma tumor suppressor gene. To facilitate genetics counseling and patient management, we adopted a multistep molecular screening assay for detecting RB1 mutations. This assay included DNA sequencing to identify mutations within coding exons and immediate flanking intronic regions, Southern blot analysis to characterize genomic rearrangements, and transcript analysis to characterize potential splicing mutations buried within introns. In a pilot investigation of 180 patients from North America, we identified germline RB1 mutations in 77 out of 85 bilateral RB patients (91%), 7 out of 10 familial unilateral (70%), and 6 out of 85 unilateral patients with no family history of RB (7%). Mutations included 36 novel alterations spanning the entire RB1 gene. Seven of these novel changes were missense or silent mutations. Sequence analysis predicted that, in five out of seven cases, the changes can cause aberrant splicing. This was confirmed by transcript analysis in four out of five cases. In addition, four intronic point mutations within nonconsensus sites activated cryptic splice sites. Without the transcript analysis, the significance of these 11 mutations would have remained undefined. In a separate investigation of a subset of unilateral RB tumors, we identified somatic biallelic RB1 gene inactivation in 34 out of 56 cases (61%) cases. In 14 tumors, only one of the two RB1 mutations could be detected, and in eight tumors, no mutations were detected. The absence of detectable RB1 mutations in eight bilateral cases and eight unilateral tumors suggests that alternative genetic mechanisms may underlie the development of RB in certain individuals.

DNA Mutational Analysis↗
PubMed1996

The human serotonin 7 (5-HT7) receptor gene: genomic organization and systematic mutation screening in schizophrenia and bipolar affective disorder.

In the present study, we evaluated the possible contribution of genetic variation of the serotonin 5-HT7 receptor to the development of schizophrenia and bipolar affective disorder. Cloning and characterization of exon-flanking intronic sequences enabled us to investigate the whole coding region and the exon-intron boundaries of the human 5-HT7 receptor gene. Using single-strand conformational analysis, we screened for presence of DNA sequence variation in a sample of 137 unrelated individuals including 45 schizophrenic and 46 bipolar affective patients, as well as 46 healthy controls. We detected two rare naturally occurring receptor variants (Pro-279-Leu, Thr-92-Lys) and a silent nucleotide substitution (A-->G) at position +1233. The occurrence of the Pro-279-Leu and Thr-92-Lys substitutions was studied in an extended sample of patients (n = 462) and controls (n = 335). The Leu-279 variant was found in similar frequency in all groups, indicating that presence of this variant is not causally related to the development of schizophrenia or bipolar affective disorder. The Lys-92 variant was found in a single individual who suffered from bipolar affective disorder. Investigation of the patient's family revealed independent segregation between the Lys-92 variant and psychiatric illness. Our data suggests that genetic variation of the 5-HT7 receptor does not play a major role in the development of bipolar affective disorder and schizophrenia.

Bipolar Disorder↗
PubMed2005

Genome-wide scan for myopia in the Old Order Amish.

PURPOSE: To identify myopia susceptibility genes influencing common myopia in 34 Old Order Amish families, a genetically well-defined founder population. DESIGN: A prospective study of families with myopia consisting of a minimum of two individuals affected with myopia. METHODS: Extended families consisting of at least two siblings affected with myopia were ascertained. A genome-wide linkage scan using 387 markers was conducted by the Center for Inherited Disease Research (CIDR). Linkage analyses were conducted with parametric (autosomal dominant, fixed penetrance model) and nonparametric methods. Model-free linkage analysis was also performed maximizing over penetrance and over dominance (that is, fitting a wide range of both dominant and recessive models). RESULTS: Under the fixed penetrance model, the maximum two-point heterogeneity LOD score (HLOD) was 1.59 at D20S451 and the maximum multipoint HLOD was 1.92 at D6S1021. The nonparametric maximum multipoint (NPL) at D3S2427 had a P-value of .0005. Under the model-free analysis, multipoint heterogeneity LOD scores of 2.03 were observed on both chromosomes 8 (under a recessive model between D8S1130 and D8S1106) and X (under a recessive model between DXS6800 and DXS6789). Reanalyses of chromosomes 3, 6, 8, 20, and X using the best penetrance models resulted in maximum multipoint HLODs of 1.84 at D3S3053; 1.84 at D3S2427; 2.04 at D8S1130; and 2.34 at DXS6800. CONCLUSIONS: The locus on chromosome 8p23 independently confirms a report by Hammond and associates mapping a myopia quantitative trait loci (QTL) to this region.

Adolescent↗
PubMed1998

trans-Complementation of flavivirus RNA polymerase gene NS5 by using Kunjin virus replicon-expressing BHK cells.

A BHK cell line persistently expressing a Kunjin (KUN) virus replicon RNA (repBHK, similar to our recently described ME/76Neo BHK cell line [A. A. Khromykh and E. G. Westaway, J. Virol. 71:1497-1505, 1997]) was used for rescue and propagation of KUN viruses defective in the RNA polymerase gene (NS5). A new infectious full-length KUN virus cDNA clone, FLSDX, prepared from our previously described cDNA clone pAKUN (A. A. Khromykh and E. G. Westaway, J. Virol. 68:4580-4588, 1994) and possessing approximately 10(5)-fold higher specific infectivity than that of pAKUN, was used for preparation of defective mutants. Deletions of the predicted RNA polymerase motif GDD (producing FLdGDD) and of one of the predicted methyltransferase motifs (S-adenosylmethionine [SAM] binding site, producing FLdSAM) were introduced separately into FLSDX. Transcription and transfection of FLdGDD and FLdSAM RNAs into repBHK cells but not into normal BHK cells resulted in their replication and the recovery of defective viruses able to replicate only in repBHK cells. Reverse transcription-PCR and sequencing analyses showed retention of the introduced deletions in the genomes of the recovered viruses. Retention of these deletions, as well as our inability to recover viruses able to replicate in normal BHK cells after prolonged incubation (for 7 days) of FLdGDD- or FLdSAM-transfected repBHK cells, excluded the possibility that recombination had occurred between the deleted defective NS5 genes present in transfected RNAs and the functional NS5 gene present in the repBHK cells. An RNA with a point mutation in the GDD motif (FLGVD) was also complemented in transfected repBHK cells, and defective virus was recovered by day 3 after transfection. However, in contrast to the results with FLdGDD and FLdSAM RNAs, prolonged (4 days or more) incubation of FLGVD RNA in normal BHK cells allowed recovery of a virus in which the GVD mutation had reverted via a single base change to the wild-type GDD sequence. Overall, these results represent the first demonstration of trans-complementation of defective flavivirus RNAs with deleterious deletions in the flavivirus RNA polymerase gene NS5. The complementation system described here may prove to be useful for the in vivo complementation of deletions and mutations affecting functional domains or the essential secondary structure in any of the other flavivirus nonstructural proteins.

Animals↗
PubMed2007

Mutations in the TPsiC loop of E. coli tRNALys,3 have varied effects on in trans complementation of HIV-1 replication.

BACKGROUND: Human immunodeficiency virus (HIV-1) exclusively selects and utilizes tRNALys,3 as the primer for initiation of reverse transcription. Several elements within the TPsiC stem loop of tRNALys,3 are postulated to be important for selection and use in reverse transcription. The post-transcriptional modification at nucleotide 58 could play a role during plus-strand synthesis to stop reverse transcriptase from re-copying the tRNA primer. Nucleotides 53 and 54 within the TPsiC stem loop of the tRNA have been shown to be important to form the complex between tRNA and the HIV-1 viral genome during initiation of reverse transcription. RESULTS: To further delineate the features of the TPsiC stem loop of tRNALys,3 in reverse transcription, we have developed a complementation system in which E. coli tRNALys,3 is provided in trans to an HIV-1 genome in which the PBS is complementary to this tRNA. Successful selection and use of E. coli tRNALys,3 results in the production of infectious virus. We have used this single round infectious system to ascertain the effects that different mutants in the TPsiC stem loop of tRNALys,3 have on complementation. Mutants were designed within the TPsiC loop (nucleotide 58) and within the stem and loop of the TPsiC loop (nucleotides 53 and 54). Analysis of the expression of E. coli tRNALys,3 mutants revealed differences in the capacity for aminoacylation, which is an indication of intracellular stability of the tRNA. Alteration of nucleotide 58 from A to U (A58U), T54G and TG5453CC all resulted in tRNALys,3 that was aminoacylated when expressed in cells, while a T54C mutation resulted in a tRNALys,3 that was not aminoacylated. Both the A58U and T54G mutated tRNALys,3 complemented HIV-1 replication similar to wild type E. coli tRNALys,3. In contrast, the TG5453CC tRNALys,3 mutant did not complement replication. CONCLUSION: The results demonstrate that post-transcriptional modification of nucleotide 58 in tRNALys,3 is not essential for HIV-1 reverse transcription. In contrast, nucleotides 53 and 54 of tRNALys,3 are important for aminoacylation and selection and use of the tRNALys,3 in reverse transcription.

Base Sequence↗
PubMed2006

Pooled association genome scanning for alcohol dependence using 104,268 SNPs: validation and use to identify alcoholism vulnerability loci in unrelated individuals from the collaborative study on the genetics of alcoholism.

Association genome scanning can identify markers for the allelic variants that contribute to vulnerability to complex disorders, including alcohol dependence. To improve the power and feasibility of this approach, we report validation of "100k" microarray-based allelic frequency assessments in pooled DNA samples. We then use this approach with unrelated alcohol-dependent versus control individuals sampled from pedigrees collected by the Collaborative Study on the Genetics of Alcoholism (COGA). Allele frequency differences between alcohol-dependent and control individuals are assessed in quadruplicate at 104,268 autosomal SNPs in pooled samples. One hundred eighty-eight SNPs provide (1) the largest allele frequency differences between dependent versus control individuals; (2) t values >or= 3 for these differences; and (3) clustering, so that 51 relatively small chromosomal regions contain at least three SNPs that satisfy criteria 1 and 2 above (Monte Carlo P = 0.00034). These positive SNP clusters nominate interesting genes whose products are implicated in cellular signaling, gene regulation, development, "cell adhesion," and Mendelian disorders. The results converge with linkage and association results for alcohol and other addictive phenotypes. The data support polygenic contributions to vulnerability to alcohol dependence. These SNPs provide new tools to aid the understanding, prevention, and treatment of alcohol abuse and dependence.

Alcoholism↗
PubMed1999

Genome-wide scan for CAG/CTG repeat expansions in Pimas with early onset of type 2 diabetes mellitus.

The expansion of polymorphic CAG/CTG repeats in specific genes causes several neurodegenerative disorders and in many instances the length of the disease-causing repeat correlates with the onset age and/or severity of symptoms. Type 2 diabetes mellitus has features in common with diseases resulting from trinucleotide repeat expansion, including a variable age of disease onset and penetrance. We have investigated whether CAG/CTG repeat expansion contributes to the genetic etiology of type 2 diabetes in the Pima Indians, a population with the highest reported prevalence of this disease. Using the Repeat Expansion Detection (RED) method, we determined the size range in nondiabetic Pimas to be between (CAG)20 and (CAG)130 (mean repeat length = 195 bp), which is significantly larger than the mean size reported in Caucasians (150 bp). We compared the distribution of CAG/CTG repeat lengths among 40 Pimas with an early onset of type 2 diabetes (<22 years) and 38 nondiabetic subjects (>55 years). A 240-bp CAG/CTG RED product was found more frequently in early onset diabetics relative to nondiabetic controls (26% vs 11%), whereas a 210-bp band was more prominent in unaffected subjects (29% vs 13%); however, these differences were not statistically significant. In one Pima kindred, we also identified large RED products (>/=360 bp) that displayed intergenerational instability among family members. However, these expansions were not associated with diabetes or any other clinical abnormalities in the carriers. We conclude that this unstable CAG/CTG repeat may represent a novel locus, consisting of large, but apparently nonpathogenic, unstable sequences.

Age of Onset↗
PubMed2002

A whole genome screen for linkage disequilibrium in multiple sclerosis confirms disease associations with regions previously linked to susceptibility.

Linkage analysis in multiplex families has provisionally identified several genomic regions where genes influencing susceptibility to multiple sclerosis are likely to be located. It is anticipated that association mapping will provide a higher degree of resolution, but this more powerful approach is limited by the substantial genotyping effort required. Here, we describe the first use of DNA pooling to screen the whole genome for association in multiple sclerosis based on a 0.5 cM map of microsatellite markers and using four DNA pools derived from cases (n = 216), controls (n = 219) and trio families (n = 745 affected individuals and their 1490 parents). The 10 markers showing the greatest evidence for association with multiple sclerosis that emerge from this analysis include three from the HLA region on chromosome 6p (D6S1615, D6S2444 and TNFa), providing a positive control for the method, four from regions previously identified by linkage analysis in UK multiplex families (two mapping to chromosome 17q GCT6E11 and D17S1535; one to chromosome 1p GGAA30B06; and one to 19q D19S585), and three from novel sites with respect to linkage analysis (D1S1590 at 1q; D2S2739 at 2p; and D4S416 at 4q). Our results thus provide further supporting evidence for the candidature of 6p, 17q, 19q and 1p as regions encoding susceptibililty genes for multiple sclerosis. The protocol used in this UK-based study is now being extended to 18 additional sites in Europe in order to search for susceptibility genes shared between populations of common ancestry, as well as those that exert ethnically more restricted effects.

Adult↗