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Results for “Heterogeneity Mapping”

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PubMed1998

Locus heterogeneity in autosomal dominant congenital external ophthalmoplegia (CFEOM).

Congenital external ophthalmoplegia (CFEOM) is an uncommon autosomal dominant condition that has previously been mapped to the pericentromeric region of chromosome 12 in seven families with no evidence of locus heterogeneity. We report three families with typical CFEOM. One family does not map to this region of chromosome 12 or to other chromosomal locations implicated in disorders of lid or ocular movement. Recombinants in two CFEOM families potentially help to reduce the size of the candidate region on chromosome 12.

Chromosomes, Human, Pair 12↗

PubMed2000

Determination of the origin of charge heterogeneity in a murine monoclonal antibody.

PURPOSE: The aim of this study was to elucidate the molecular basis of charge heterogeneity found in a purified monoclonal IgG1 antibody, MMA383. METHODS: Cation exchange chromatography (CEX) and isoelectric focusing (IEF) were used to monitor charge heterogeneity. CEX in conjunction with carboxypeptidase B digests of the antibody was used to determine the contribution of C-terminal lysines to MMA383 charge heterogeneity. Potential chemical degradation sites were identified by peptide mapping of individual chains, with peptide identification by mass spectrometry (MALDI-TOF MS). Peptide sequencing was used to determine specific deamidation sites. Binding constants of predominant isoforms were compared by surface plasmon resonance (SPR). RESULTS: Extensive charge heterogeneity of purified MMA383 was detected by CEX and IEF. Removal of C-terminal lysines simplified the IEF pattern to nine predominant isoforms. Quantitation of isoaspartate in each of the isoforms indicated deamidation of MMA383 as a major cause of charge heterogeneity. CEX of the individual isoform chains suggested the presence of one deamidation site on each of the heavy and light chains. The two sites of deamidation were identified using peptide mapping, sequencing and mass spectrometry. SPR results showed no significant difference in the binding parameters among the isoforms. CONCLUSIONS: C-terminal lysine microheterogeneity and deamidation of Asn141 in the heavy chain and Asn161 in the light chain are the major causes of MMA383 charge heterogeneity. Identification of the two deamidation sites will allow replacement of these amino acids in order to create a product less susceptible to degradation.

Antibodies, Monoclonal↗

PubMed1998

Homozygosity and physical mapping of the autosomal recessive retinitis pigmentosa locus (RP14) on chromosome 6p21.3.

Retinitis pigmentosa (RP) is a heterogeneous genetic disorder with autosomal dominant, autosomal recessive, and X-linked forms. We previously mapped an additional arRP locus to chromosome 6p21 (RP14) in a single extended kinship from the Dominican Republic. Aided by a second linked RP pedigree from the same region of the Dominican Republic, we have refined the disease locus to a 2-cM region that is homozygous-by-descent in both pedigrees. A complete YAC, and a partial BAC, contig of the RP14 locus was constructed between the markers D6S1560 and D6S291, encompassing approximately 2.1 Mb. The contig contains 12 YACs and 31 BACs and is characterized by 45 markers including 8 microsatellite markers, 6 gene-derived sequences/ESTs obtained from the databases, and 28 new STSs and 4 new ESTs obtained by BLAST search using DNA sequence from the ends of the BAC and YAC inserts. With a STS density of approximately 1 every 20 kilobases, this contig significantly enhances available maps of the region.

Chromosome Mapping↗

PubMed2001

Targeted genome screen of panic disorder and anxiety disorder proneness using homology to murine QTL regions.

Family and twin studies have indicated that genes influence susceptibility to panic and phobic anxiety disorders, but the location of the genes involved remains unknown. Animal models can simplify gene-mapping efforts by overcoming problems that complicate human pedigree studies including genetic heterogeneity and high phenocopy rates. Homology between rodent and human genomes can be exploited to map human genes underlying complex traits. We used regions identified by quantitative trait locus (QTL)-mapping of anxiety phenotypes in mice to guide a linkage analysis of a large multiplex pedigree (99 members, 75 genotyped) segregating panic disorder/agoraphobia. Two phenotypes were studied: panic disorder/agoraphobia and a phenotype ("D-type") designed to capture early-onset susceptibility to anxiety disorders. A total of 99 markers across 11 chromosomal regions were typed. Parametric lod score analysis provided suggestive evidence of linkage (lod = 2.38) to a locus on chromosome 10q under a dominant model with reduced penetrance for the anxiety-proneness (D-type) phenotype. Nonparametric (NPL) analysis provided evidence of linkage for panic disorder/agoraphobia to a locus on chromosome 12q13 (NPL = 4.96, P = 0.006). Modest evidence of linkage by NPL analysis was also found for the D-type phenotype to a region of chromosome 1q (peak NPL = 2.05, P = 0.035). While these linkage results are merely suggestive, this study illustrates the potential advantages of using mouse gene-mapping results and exploring alternative phenotype definitions in linkage studies of anxiety disorder.

Animals↗

PubMed1987

Unusual proopiomelanocortin ribonucleic acids in extrapituitary tissues: intronless transcripts in testes and long poly(A) tails in hypothalamus.

The POMC gene is predominantly expressed in the pituitary gland; it is also expressed in various extrapituitary tissues. While POMC mRNAs of similar size (approximately equal to 1000 nucleotides) are present in the anterior and neurointermediate lobes of the pituitary, other POMC-expressing tissues contain POMC mRNAs of different sizes. Longer POMC mRNAs are observed in the hypothalamus. Using S1 nuclease mapping and mRNA deadenylation by RNase H, we have shown that these large hypothalamic POMC mRNAs have longer poly(A) tails than pituitary POMC transcripts but contain the same transcripted sequences. In contrast, the testes contain POMC transcripts which are smaller than pituitary POMC mRNA. RNase and S1 nuclease mapping analyses suggest that these short transcripts do not contain sequences transcribed from pituitary exons 1 and 2. Indeed, as revealed by primer-extension experiments, these transcripts appear to initiate within exon 3 sequences of the POMC gene. The heterogeneous 5'-ends of these short testicular transcripts map into the NH2-terminal portion of the precursor in the region encoding gamma MSH; if ever translated, these transcripts would produce a form of POMC that would be truncated at the NH2-terminus and therefore would be devoid of any signal peptide sequence. Interestingly, the sequence of the short testicular transcripts corresponds to that of the mouse POMC pseudogene, suggesting that this POMC pseudogene may have derived from genomic integration of testicular transcripts via a cDNA intermediate.

Animals↗

PubMed2006

A new form of congenital muscular dystrophy with joint hyperlaxity maps to 3p23-21.

Congenital muscular dystrophies (CMDS) are a heterogeneous group of disorders. A growing number of CMDS have been found to be associated with joint hyperlaxity. We recruited 14 French-Canadian cases belonging to 11 families affected by a novel autosomal recessive congenital muscular dystrophy with hyperlaxity (CMDH). All cases come from the southwestern part of Quebec, suggesting a new French-Canadian founder effect. All patients present muscle weakness, proximal contractures coexisting with distal joint hyperlaxity. Pathological and genetic studies have excluded that mutations in the three genes coding for collagen VI subunits are responsible for this disease. A genome-wide scan established linkage of two CMDH families to a region on chromosome 3p23-21. Further linkage analysis confirmed that all families are linked to the same region (log of the odds score of 5.3). Haplotype analysis defines a 1.6-cM candidate interval and suggests that two common mutations may account for 78% of carrier chromosomes. This study describes and maps a new form of recessive CMD with joint hyperlaxity distinct from Ullrich and Bethlem myopathies with a founder effect in the French-Canadian population.

Adolescent↗

PubMed1998

Strain analysis and epitope mapping of West Nile virus using monoclonal antibodies.

Monoclonal antibodies (MAbs) against an Indian strain (804994) and an Egyptian strain (E 101) of West Nile virus (WNV) were prepared in mice. Nine MAbs against the 804994 strain and 5 MAbs against E 101 strain were obtained. All 14 MAbs reacted with the envelope (E) protein of WNV in an immunoblot assay. They were tested by an enzyme-linked immunosorbent assay (ELISA) for their cross-reactivity with WNV, Japanese encephalitis virus (JEV) and Dengue-2 virus (DEN-2), and for their reactivity in haemagglutination-inhibition (HAI) test. Based on these results MAbs were broadly grouped into three groups, namely WNV-specific HAI-positive, WNV-JEV cross-reactive HAI-positive, and WNV-JEV cross-reactive HAI-negative MAbs. The antigenic cross-reactivity between twelve WNV strains isolated from different geographical regions and their respective hosts was assessed using these MAbs in HAI and complement fixation (CF) tests. The strain analysis by CF distinguished Indian from South African strains. However, a similarity between some Indian and South African strains in HAI was observed. E 101 strain appeared to have antigenic similarity with Indian as well as South African strains. Overall it appears that antigenically similar strains of WNV are prevalent in India. A single heterogenous domain was apparent on the epitope map of WNV deduced by ELISA additivity test.

Animals↗

PubMed2026

Single-cell transcriptomics reveals heterogeneous stress responses and Mg2+-mediated survival mechanisms in Lactobacillus delbrueckii subsp. bulgaricus during freeze-drying and storage.

Maintaining the viability of lactic acid bacteria during dehydration and subsequent storage remains a significant challenge. Here, we employed single-cell RNA sequencing to reveal the heterogeneous stress responses of Lactobacillus delbrueckii subsp. bulgaricus, identifying seven distinct transcriptional clusters across the liquid culture, freeze-drying, and storage phases. The dominant clusters in the freeze-drying and storage were not completely consistent, showing significant functional differentiation. Genomic stability may be important for survival during freeze-drying and storage, while intracellular energy homeostasis appears important for viability during storage. The magnesium transporter mgtB was highly expressed in clusters tolerant to freeze-drying and storage, suggesting a critical role for Mg2+ homeostasis. Further experimental validation confirmed that Mg2+ treatment significantly bolstered stress resistance, increasing immediate post-freeze-drying survival by over 2-fold (up to 92.90%) and post-storage survival by over 5-fold (up to 5.98%). Proteomic data indicated that Mg2+ supplementation correlated with the maintenance of several biological functions potentially relevant to bacterial survival during freeze-drying and storage, including DNA repair, translation, and central carbon metabolism. These findings provide a map of microbial stress resistance through population heterogeneity and offer a potential strategy that may be adapted for enhancing the stability of other industrial lactic acid bacteria products.

Freeze Drying↗

PubMed2002

Usefulness of sugar mapping by liquid chromatography/mass spectrometry in comparability assessments of glycoprotein products.

We have previously reported that sugar-mapping by liquid chromatography/mass spectrometry (LC/MS) equipped with a graphitized carbon column (GCC) can be useful for structural analysis of carbohydrates in a glycoprotein. In this paper, we evaluated sugar-mapping with regard to its use in comparability assessment of glycoprotein products. Erythropoietins (EPO) produced from three different sources were chosen as models of the closely related glycoprotein products. The two-dimensional displays of sugar maps drawn by LC/MS with GCC clearly showed the differences in carbohydrate heterogeneity with regard to sialylation, acetylation, and sulphation patterns among three EPOs. Exoglycosidase digestion followed by sugar-mapping provided information regarding the structure of characteristic carbohydrates in each EPO. These results demonstrate that LC/MS with GCC can reveal the details of carbohydrate heterogeneity in order to distinguish between closely related glycoprotein products. Our method can thus be useful in comparability assessments of therapeutic glycoproteins.

Animals↗

PubMed1992

Sequence and length heterogeneity of alpha Fc gamma R transcripts in AKR mice.

The murine low-affinity receptors for IgG, Fc gamma RIII and Fc gamma RII, are encoded by the alpha and the beta Fc gamma R genes, respectively. By contrast to the sequence and the molecular polymorphism of human Fc gamma RIII, no heterogeneity of the murine Fc gamma RIII has been reported and a single alpha Fc gamma R transcript was observed. We describe here a double heterogeneity of alpha Fc gamma R transcripts. First, by S1 mapping of alpha transcripts and by cloning of cDNA coding for Fc gamma RIII, we found a strain-related sequence heterogeneity: four amino acids in the coding region and two stretches of nucleotides in the 3' untranslated sequences differ between alpha transcripts of AKR and BALB/c mice. Second, in AKR mice, we found a cell-dependent length heterogeneity: a short 0.9 kb alpha transcript was present in peritoneal thioglycolate-elicited cells (PEC) from AKR mice. This transcript was present neither in mast cells and NK cells from AKR and BALB/c mice nor in PEC from BALB/c mice. A short cDNA, with a deletion of all the 3' untranslated sequences, has been cloned from AKR PEC, and corresponds to the short alpha transcript. All the differences found in the 3' untranslated sequences of AKR alpha transcripts are located within the fifth exon of the mouse alpha Fc gamma R gene.

Amino Acid Sequence↗

PubMed1998

The gene responsible for autoimmune polyglandular syndrome type 1 maps to chromosome 21q22.3 in US patients.

Autoimmune polyglandular syndrome type 1 [APS-1] comprises multiple organ-specific autoimmunities such as acquired hypoparathyroidism and autoimmune Addison's disease, and a predisposition to certain infections such as chronic mucocutaneous candidiasis. An APS-1 candidate gene was assigned to chromosome 21q22.3 by linkage analyses in patients with APS-1 from Finland. To examine the influence of ethnic and geographic differences on the location of the candidate gene locus, we studied 24 US patients with APS-1 by microsatellite marker typing, using five microsatellite markers, D21S49, PFKL, D21S171, D21S1903 and CD18, selected from chromosome 21q22.3. By allelic association analyses, the frequencies of allele number 5 for D21S171 and allele number 8 for D21S1903 were significantly higher in the 24 patients with APS-1 than in 33 controls (33/48 vs. 31/66, P = 0.0207, X2 = 5.35; 12/48 vs. 7/66, P = 0.0418, X2 = 4.15 respectively). The frequency of homozygosity for allele number 5 of D21S171 was also significantly higher in the patients than in controls, 15/24 vs. 9/33 (P = 0.0078, X2 = 7.07). Maximum lod scores detected for the five markers in nine families (containing 15 of the patients with APS-1) were: 2.384 for D21S49, 3.144 for PFKL, 3.506 for D21S171, 4.329 for D21S1903, and 1.130 for CD18. These results confirm the linkage of the candidate APS-1 gene to 21q22.3 in US APS-1 patients, and suggest that the candidate gene is located near the D21S1903 marker. The demonstration of the location of the APS-1 candidate gene to 21q22.3 in an out-bred heterogeneous patient population should promote the physical mapping of the responsible gene.

Alleles↗

PubMed1995

Genetic linkage heterogeneity in myotubular myopathy.

Myotubular myopathy is a severe congenital disease inherited as an X-linked trait (MTM1; McKusick 31040). It has been mapped to the long arm of chromosome X, to the Xq27-28 region. Significant linkage has subsequently been established for the linkage group comprised of DXS304, DXS15, DXS52, and F8C in several studies. To date, published linkage studies have provided no evidence of genetic heterogeneity in severe neonatal myotubular myopathy (XLMTM). We have investigated a family with typical XLMTM in which no linkage to these markers was found. Our findings strongly suggest genetic heterogeneity in myotubular myopathy and indicate that great care should be taken when using Xq28 markers in linkage studies for prenatal diagnosis and genetic counseling.

Chromosome Mapping↗

PubMed2006

Identification of signaling components required for the prediction of cytokine release in RAW 264.7 macrophages.

BACKGROUND: Release of immuno-regulatory cytokines and chemokines during inflammatory response is mediated by a complex signaling network. Multiple stimuli produce different signals that generate different cytokine responses. Current knowledge does not provide a complete picture of these signaling pathways. However, using specific markers of signaling pathways, such as signaling proteins, it is possible to develop a 'coarse-grained network' map that can help understand common regulatory modules for various cytokine responses and help differentiate between the causes of their release. RESULTS: Using a systematic profiling of signaling responses and cytokine release in RAW 264.7 macrophages made available by the Alliance for Cellular Signaling, an analysis strategy is presented that integrates principal component regression and exhaustive search-based model reduction to identify required signaling factors necessary and sufficient to predict the release of seven cytokines (G-CSF, IL-1alpha, IL-6, IL-10, MIP-1alpha, RANTES, and TNFalpha) in response to selected ligands. This study provides a model-based quantitative estimate of cytokine release and identifies ten signaling components involved in cytokine production. The models identified capture many of the known signaling pathways involved in cytokine release and predict potentially important novel signaling components, like p38 MAPK for G-CSF release, IFNgamma- and IL-4-specific pathways for IL-1a release, and an M-CSF-specific pathway for TNFalpha release. CONCLUSION: Using an integrative approach, we have identified the pathways responsible for the differential regulation of cytokine release in RAW 264.7 macrophages. Our results demonstrate the power of using heterogeneous cellular data to qualitatively and quantitatively map intermediate cellular phenotypes.

Analysis of Variance↗

PubMed1992

Immunohistochemical studies on the new type of astrocytic inclusions identified in a patient with brain malformation.

Immunohistochemical studies were carried out on the new type of cerebral cortical astrocytic inclusions recently discovered in a 20-year-old patient with maldeveloped brain and micropolygyria. The inclusions appeared as eosinophilic structures (hematoxylin and eosin stain) and did not exhibit argyrophilia (modified Bielschowsky method). The inclusions were strongly stained by the antibody against S-100 protein (S 100) and to a lesser extent by the antibody to microtubule-associated protein 1B (MAP 1B). In contrast to Rosenthal fibers, the astrocytic inclusions did not react with antibodies to alpha B-crystallin, glial fibrillary acidic protein and ubiquitin. No positive reactions were obtained with antibodies against heat-shock protein 27 (HSP 27), HSP 72, actin, vimentin, desmin, cytokeratin, myelin basic protein, beta-tubulin, MAP 2, tau protein, paired helical filament, phosphorylated neurofilament protein (NFP), nonphosphorylated NFP, synaptophysin, cathepsin D, alpha 1-antichymotrypsin, alpha 1-antitrypsin and basic fibroblast growth factor. By immunoelectron microscopy, the products of the reaction with the anti-S 100 antibody appeared as heterogeneous granular deposits and with the antibody to MAP 1B they were randomly scattered throughout the astrocytic inclusions. Our results demonstrate that the immunohistochemical profile of the recently described inclusions differs from that of Rosenthal fibers. Whether the novel inclusions are involved in congenital astrocyte dysfunction and cerebral malformation remains to be established.

Adult↗

PubMed1996

A general statistical model for detecting complex-trait loci by using affected relative pairs in a genome search.

Scanning of the human genome by use of affected relative pairs and dense sets of highly polymorphic markers or by emerging techniques such as genomic mismatch scanning. (GMS) is making it possible to identify the genetic etiology of a disease through detection of susceptibility loci. We present a general statistical model and test to detect disease genes, using affected relative pairs and either markers or GMS technologies in a genome search. There are an exact test and large-sample normal approximation that control for the elevated probability of false detection of linkage in a genome search. The approach can be used to determine the sample size needed to obtain a prespecified power to detect a disease gene in the presence of etiologic heterogeneity for a single class or mixture of relative classes, with any number of markers, or clones, markers PIC values, or mapping function. The approach is used to examine differences in performance of markers and GMS technologies in a common statistical framework and to provide practical information for designing studies of complex traits.

Alleles↗

PubMed1995

Marked phenotypic heterogeneity associated with expansion of a CAG repeat sequence at the spinocerebellar ataxia 3/Machado-Joseph disease locus.

The spinocerebellar ataxia 3 locus (SCA3) for type I autosomal dominant cerebellar ataxia (ADCA type I), a clinically and genetically heterogeneous group of neurodegenerative disorders, has been mapped to chromosome 14q32.1. ADCA type I patients from families segregating SCA3 share clinical features in common with those with Machado-Joseph disease (MJD), the gene of which maps to the same region. We show here that the disease gene segregating in each of three French ADCA type I kindreds and in a French family with neuropathological findings suggesting the ataxochoreic form of dentatorubropallidoluysian atrophy carries an expanded CAG repeat sequence located at the same locus as that for MJD. Analysis of the mutation in these families shows a strong negative correlation between size of the expanded CAG repeat and age at onset of clinical disease. Instability of the expanded triplet repeat was not found to be affected by sex of the parent transmitting the mutation. Evidence was found for somatic and gonadal mosaicism for alleles carrying expanded trinucleotide repeats.

Adolescent↗

PubMed1999

Twelve novel myosin VIIA mutations in 34 patients with Usher syndrome type I: confirmation of genetic heterogeneity.

Usher syndrome is a heterogeneous autosomal recessive trait and the most common cause of hereditary deaf-blindness. Usher syndrome type I (USH1) is characterised by profound congenital sensorineural hearing loss, vestibular dysfunction, and prepubertal onset of retinitis pigmentosa. Of the at least six different loci for USH1, USH1B maps on chromosome 11q13, and the MYO7A gene has been shown to be defective in USH1B. MYO7A encodes myosin VIIA, an unconventional myosin, and it consists of 48 coding exons. In this study, MYO7A was analysed in 34 unrelated Usher type I patients by single-strand conformation polymorphism analysis and direct sequencing. We identified a total of 12 novel and unique mutations, all single base changes. In addition, we found a previously reported nonsense mutation (C31X) on nine alleles of a total of six patients from Denmark.

Chromosome Mapping↗

PubMed1998

Reduced penetrance, variable expressivity, and genetic heterogeneity of familial atrial septal defects.

BACKGROUND: Secundum atrial septal defect (ASD) is a common congenital heart malformation that occurs as an isolated anomaly in 10% of individuals with congenital heart disease. Although some embryological pathways have been elucidated, the molecular etiologies of ASD are not fully understood. Most cases of ASD are isolated, but some individuals with ASD have a family history of this defect or other congenital heart malformations. METHODS AND RESULTS: Clinical evaluation of three families identified individuals with ASD in multiple generations. ASD was transmitted as an autosomal dominant trait in each family. ASD was the most common anomaly, but other heart defects occurred alone or in association with ASD in individuals from each kindred. Genome-wide linkage studies in one kindred localized a familial ASD disease gene to chromosome 5p (multipoint LOD score=3.6, theta=0.0). Assessment of 20 family members with the disease haplotype revealed that 9 had ASD, 8 were clinically unaffected, and 3 had other cardiac defects (aortic stenosis, atrial septal aneurysm, and persistent left superior vena cava). Familial ASD did not map to chromosome 5p in two other families. CONCLUSIONS: Familial ASD is a genetically heterogeneous disorder; one disease gene maps to chromosome 5p. Recognition of the heritable basis of familial ASD is complicated by low disease penetrance and variable expressivity. Identification of ASD or other congenital heart defects in more than one family member should prompt clinical evaluation of all relatives.

Adult↗