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PubMed1994

Two long QT syndrome loci map to chromosomes 3 and 7 with evidence for further heterogeneity.

Cardiac arrhythmias cause sudden death in 300,000 United States citizens every year. In this study, we describe two new loci for an inherited cardiac arrhythmia, long QT syndrome (LQT). In 1991 we reported linkage of LQT to chromosome 11p15.5. In this study we demonstrate further linkage to D7S483 in nine families with a combined lod score of 19.41 and to D3S1100 in three families with a combined score of 6.72. These findings localize major LQT genes to chromosomes 7q35-36 and 3p21-24, respectively. Linkage to any known locus was excluded in three families indicating that additional heterogeneity exists. Proteins encoded by different LQT genes may interact to modulate cardiac repolarization and arrhythmia risk.

Base Sequence↗

PubMed1986

Primary structure of human ribosomal protein S14 and the gene that encodes it.

Chinese hamster ribosomal protein S14 cDNA was used to recognize homologous human cDNA and genomic clones. Human and Chinese hamster S14 protein sequences deduced from the cDNAs are identical. Two overlapping human genomic S14 DNA clones were isolated from a Charon 28 placental DNA library. A fragment of single-copy DNA derived from an intron region of one clone was mapped to the functional RPS14 locus on human chromosome 5q by using a panel of human X Chinese hamster hybrid cell DNAs. The human S14 gene consists of five exons and four introns spanning 5.9 kilobase pairs of DNA. Polyadenylated S14 transcripts purified from HeLa cell cytoplasma display heterogeneous 5' ends that map within noncoding RPS14 exon 1. This precludes assignment of a unique 5' boundary of RPS14 transcripts with respect to the cloned human genomic DNA. Apparently HeLa cells either initiate transcription at multiple sites within RPS14 exon 1, or capped 5' oligonucleotides are removed from most S14 mRNAs posttranscription. In contrast to the few murine ribosomal protein and several other mammalian housekeeping genes whose structures are known, human RPS14 contains a TATA sequence (TATACTT) upstream from exon 1. Three related short sequence motifs, also observed in murine and yeast ribosomal protein genes, occur in this region of the RPS14 gene. RPS14 introns 3 and 4 both contain Alu sequences. Interestingly, the Alu sequence in intron 3 is located slightly downstream from a chromosome 5 deletion breakpoint in one human X hamster hybrid clone analyzed.

Amino Acid Sequence↗

PubMed1987

Monoclonal antibodies reveal the global organization of the cerebellar cortex.

Electrophysiological mapping of the rat cerebellar cortex has revealed an elaborate functional somatotopy that tract tracing procedures have shown to correlate with specific patterns of afferent and efferent connectivity that encompass the cerebellum as a whole. In contrast, most anatomical and biochemical procedures suggest that the cerebellar cortex is remarkably uniform. To unmask covert molecular heterogeneity underlying the functional map, it is appropriate to use monoclonal antibody technology to search for antigenic epitopes whose cerebellar distribution reflects or encodes the positional information. Given that no preconditions can be set on the biochemical nature of the putative epitopes, a shotgun approach to immunization and screening is required. The construction of monoclonal antibodies and screening for specificities that reveal positional information is discussed with examples from an anti-cerebellar antibody library.

Antibodies, Monoclonal↗

PubMed2003

Liposome entrapment and immunogenic studies of a synthetic lipophilic multiple antigenic peptide bearing VP1 and VP3 domains of the hepatitis A virus: a robust method for vaccine design.

Multiple antigen peptides (MAP) have been demonstrated to be efficient immunological reagents for the induction of immune responses to a variety of infectious agents. Several peptide domains of the hepatitis A virus (HAV) capsid proteins, mainly VP1 and VP3, are the immunodominant targets for a protective antibody response. In the present study we analyse the immunogenic properties of a tetrameric heterogeneous palmitoyl-derivatised MAP containing two defined HAV peptide sequences, VP1(11-25) and VP3(102-121), in rabbits immunised with either Freund's adjuvant or multilamellar liposomes. The immune response was evaluated with a specific enzyme immunoassay using MAP[VP1+VP3], VP1 and VP3 as targets. The avidity of the immune response was measured by a non-competitive enzyme-linked immunosorbent assay and by the surface plasmon resonance technology. Antisera raised against the lipo-MAP peptide entrapped in liposomes demonstrated high avidity of binding with affinity rate constants approximately one order of magnitude greater than those obtained with the Freund's protocol.

Amino Acid Sequence↗

PubMed1999

Sex-based linkage analysis of alcoholism.

A high degree of locus heterogeneity is likely in alcoholism, and linkage heterogeneity analysis may be helpful in mapping susceptibility loci. The genetic contribution to alcoholism in females may be higher than in males, and therefore sex of affected individuals was used in linkage analysis. Families with female alcoholics demonstrated evidence for linkage to chromosomes 10p11-p15 and 21q22.1-q22.2 while those with male alcoholics did not provide evidence for linkage to these regions. Sharing of maternal and paternal alleles was also investigated separately, and evidence for linkage of maternal alleles on chromosomes 1 and 8, and paternal alleles on chromosome 2 was observed, suggesting parental origin effects. Mapping of complex traits may benefit from tests of linkage heterogeneity based on sex, and parental origin.

Alcoholism↗

PubMed1983

Characterization of tissue culture-induced heterogeneity in DNAs of independent isolates of JC virus.

After several serial passages at low multiplicities of infection in primary human foetal glial cells at 37 degrees C, the DNA of prototype (MAD-1) JC virus and that of MAD-2 and MAD-3 are typically heterogeneous in size, but DNAs of MAD-4 and MAD-6 are relatively homogeneous. A similar dichotomy was observed in the DNAs of six isolates propagated more recently in glial cultures at 39 degrees C under similar conditions of brief passage in vitro at low multiplicities of infection: the DNAs of two (MAD-9 and -10) were heterogeneous, but the DNAs of four others (MAD-8, -11, -12 and -14) were homogeneous. Therefore, the propensity of the viral genome to sustain deletions was an intrinsic property of each isolate. However, actual induction and maintenance of the presumably defective DNAs was influenced by the relative proportions of permissive spongioblasts and semi-permissive astrocytes in the glial cultures and by the multiplicity of infection. Deletions in MAD-1 DNA were confined to the presumptive early region and spanned the BamHI cleavage site (map position 0.505). The heterogeneity was more complex in the DNAs of MAD-2 and MAD-3, but again most of the deletions, which ranged up to 12% of full-length DNA, spanned the BamHI site. We propose that the differential susceptibility to deletion among isolates is a consequence of natural genetic variation in JC virus.

Chromosome Deletion↗

PubMed2005

Evidence for clinical and genetic heterogeneity of syndactyly type I: the phenotype of second and third toe syndactyly maps to chromosome 3p21.31.

There is good evidence from the medical literature that type I syndactyly, the most common form of the nonsyndromic syndactylies, is clinically heterogeneous. We therefore propose to group the condition into four subtypes, which are all autosomal dominantly inherited. Subtype 1, zygodactyly (cutaneous webbing of second and third toe without hand involvement) is the mildest and most common form. The phenotype varies from unilateral minor impression of webbing to bilateral complete webbing of second and third toe including a fusion of nails. Bony involvement is never observed. Subtype 2 is characterized by bilateral cutaneous and/or bony webbing of third and fourth finger, and second and third toe. The phenotype maps on chromosome 2q34-q36 and was designated as SD1 (ie syndactyly 1). The hallmark of subtype 3 is bilateral cutaneous or bony webbing of third and fourth finger, while subtype 4 shows bilateral cutaneous webbing of fourth and fifth toe. Both, subtype 3 and 4, are rare entities. Here, we present clinical and molecular data of a large Pakistani family with zygodactyly that was mapped to a new locus on chromosome 3p21.31 by genome-wide linkage analysis. The highest LOD score (Zmax=3.38) was obtained with microsatellite marker D3S2409. The disease interval is flanked by markers Chr3_4919 and Chr3_4940 encompassing about 0.20 Mb. Since the same phenotype appears not to be linked to this locus in a German family, we predict genetic heterogeneity in zygodactyly and propose to designate the 3p21.31 locus as ZD1 (i.e., zygodactyly 1).

Chromosome Mapping↗

PubMed1979

BamI, KpnI, and SalI restriction enzyme maps of the DNAs of herpes simplex virus strains Justin and F: occurrence of heterogeneities in defined regions of the viral DNA.

We present the locations of the cleavage sites for the BamI, KpnI, and SalI restriction endonucleases within the DNA molecules of herpes simplex virus type 1 (HSV-1) strains Justin and F. These restriction enzymes cleave the HSV-1 DNA at many sites, producing relatively small fragments which should prove useful in future studies of HSV-1 gene structure and function. The mapping data revealed the occurrence of heterogeneity within three regions of the viral genome including (i) the region spanning map coordinates 0.74--0.76, (ii) the ends of the large (L) DNA component, and (iii) the junction between the large (L) and the small (S) components. The heterogeneity in the ends of L and the S-L junctions of HSV-1 (Justin) and HSV-1 (F) DNAs was grossly similar to that previously reported to occur in the ends of L and the S-L junctions of the HSV-1 (KOS) DNA (M. J. Wagner and W. C. Summers, J. Virol. 27:374--387, 1978). Thus, cleavage of these regions with restriction endonucleases yielded sets of minor fragments differing in size by constant increments. However, the various strains of HSV-1 differed with respect to the numbers, size increments, and relative molarities of the various minor fragments, suggesting that the parameters of the heterogeneity are inherited in the structural makeup of the HSV-1 genome. The strain dependence of the pattern of heterogeneity can be most easily explained in terms of variable sizes of the terminally reiterated a sequence, contained in the DNA molecules of these three strains of HSV-1.

Base Sequence↗

PubMed2005

Ordered subset analysis supports a glaucoma locus at GLC1I on chromosome 15 in families with earlier adult age at diagnosis.

Open angle glaucoma (OAG) is a complex disorder with varying etiologies due to multiple genes and environmental effects. This genetic heterogeneity can confound efforts to map loci. Increased homogeneity in a sample can be achieved using either ordered subset analysis (OSA) which groups families, or individual OSA (IOSA), which groups individuals based on disease related covariates. Recently, GLC1I was mapped to 15q11-13 in families with early adult onset of OAG. We tested for linkage to GLC1I in an independent sample of 167 individuals in 25 multiplex OAG families of European descent. We carried out nonparametric linkage analysis on the complete set of 25 families and obtained a maximum LOD score of 1.00 at 9.0 cM. Using mean age at diagnosis (AAD) across the affected individuals within each family to order the families as a proxy for age at onset, we found a maximum OSA LOD score of 2.09 (p=0.021) at 26.1 cM. The mean (+/-s.d.) AAD across the 14 earlier AAD families that contributed to the OSA LOD score was 50.6 years (+/-5.38); the mean AAD for the other 1210 later AAD families that did not contribute to the OSA LOD score (the high-AAD) was 61.7 years (+/-3.50). We also ran IOSA on our families using AAD as our covariate on which to subset affected individuals. The maximum LOD score was 1.01 at 14.3 cM when ordering subjects from early to late AAD. Ordered subset analysis of this sample has provided evidence of linkage close to the previously identified GLC1I glaucoma locus on 15q11-13 in families with middle-aged mean age at diagnosis.

Adolescent↗

PubMed1992

Evidence for clonal heterogeneity of the expression of six protein kinase C isoforms in murine B and T lymphocytes.

Protein kinase C (PKC), which plays a pivotal role in lymphocyte activation, represents a homologous family of at least nine proteins. Seven genes that encode PKC proteins have been identified. Since the regulatory properties and substrate specificities of the isoforms are not identical in vitro, it is possible that each isoform plays a unique role in cell activation. Toward an understanding of the role of PKC isoforms in lymphocyte activation we have studied the expression of mRNA encoding six of the isoforms (alpha, beta, gamma, delta, epsilon, and zeta) in T cell clones and B cell lines. PKC isoform phenotyping was done by MAPPing using isoform-specific primers and slot-blot analyses of mRNA were performed using specific probes. T cell clones and B cell lines were determined to express levels of the delta, epsilon, and zeta isoforms of PKC that were detectable by MAPPing. Plasmacytomas did not express PKC-beta message detectable by MAPPing. Slot blot analyses and Western blot analyses with peptide-specific antibody confirmed that B cell plasmacytomas did not express PKC-beta mRNA or protein. T cell clones and B cell lines were similar in that none expressed PKC-gamma. In cells that expressed PKC isoforms that were detectable by the MAPPing protocol, there was heterogeneity in the relative abundance of isoform mRNA (PKC-delta and -beta) and protein (PKC-beta and -epsilon). Such diversity of isoform expression could be responsible for the differential responsiveness of lymphocyte clones to activating stimuli.

Animals↗

PubMed1999

[Gly380Arg and Asn540Lys mutations of fibroblast growth factor receptor 3 in achondroplasia and hypochndroplasia in the Spanish population].

BACKGROUND: Achondroplasia, the most common type of genetic dwarfism characterised by disproportionate short stature and other skeletal anomalies, results from a defect in the maturation of the chondrocytes in the growth plate cartilage. Hypochondroplasia, considered allelic to achondroplasia is clinically and genetically heterogeneous. Recent studies have mapped the gene on chromosome 4p16.3, and frequent mutations in the fibroblast growth factor 3 (FGFR3) have been described in these diseases in other populations. PATIENTS AND METHODS: Analysis of the FGFR3 gene mutations Gly380Arg and Asn540Lys in 20 Spanish patients (10 achondroplasic, 6 hypochondroplasic and 4 with skeletal dysplasias with some phenotypic and radiological characteristics of hypochondroplasia) by PCR and restriction analysis. RESULTS: All the achondroplasic patients have shown the same mutation (Gly380Arg) in the transmembrane domain of the receptor. Five hypochondroplasic patients presented the mutation Asn540Lys in the proximal thirosine kinase domain. CONCLUSIONS: Achondroplasia in this sample from Spanish patients is also homogeneous in its molecular basis. Genetic heterogeneity has been found in hypochondroplasia corresponding with the phenotypic diversity in this disease. Molecular analysis of FGFR3 may be an additional diagnostic tool and facilitates genetic counselling in these chondrodysplasias.

Achondroplasia↗

PubMed2002

Present status on the genetic studies of asthma.

Asthma, one of the most common chronic diseases, is a complex and heterogeneous disorder. The results of genome screens for asthma-related traits in 11 different populations identified at least 18 regions of the genome that probably house asthma/atopy genes. The most consistently replicated regions are on chromosomes 2q, 5q, 6p, 12q and 13q. Positional cloning projects are ongoing in laboratories around the world to identify the asthma susceptibility loci in these regions. In addition, many candidate genes have been associated with asthma phenotypes, such as the genes in the IL-4/IL-13 pathway.

Animals↗

PubMed2006

Empirical modeling of atmospheric deposition in mountainous landscapes.

Atmospheric deposition has long been recognized as an important source of pollutants and nutrients to ecosystems. The need for reliable, spatially explicit estimates of total atmospheric deposition (wet + dry + cloud) is central, not only to air pollution effects researchers, but also for calculation of input-output budgets, and to decision makers faced with the challenge of assessing the efficacy of policy initiatives related to deposition. Although atmospheric deposition continues to represent a critical environmental and scientific issue, current estimates of total deposition have large uncertainties, particularly across heterogeneous landscapes such as montane regions. We developed an empirical modeling approach that predicts total deposition as a function of landscape features. We measured indices of total deposition to the landscapes of Acadia (121 km2) and Great Smoky Mountains (2074 km2) National Parks (USA). Using approximately 300-400 point measurements and corresponding landscape variables at each park, we constructed a statistical (general linear) model relating the deposition index to landscape variables measured in the field. The deposition indices ranged over an order of magnitude, and in response to vegetation type and elevation, which together explained approximately 40% of the variation in deposition. Then, using the independent landscape variables available in GIS data layers, we created a GIS-relevant statistical nitrogen (N) and sulfur (S) deposition model (LandMod). We applied this model to create park-wide maps of total deposition that were scaled to wet and dry deposition data from the closest national network monitoring stations. The resultant deposition maps showed high spatial heterogeneity and a four- to sixfold variation in "hot spots" and "cold spots" of N and S deposition ranging from 3 to 31 kg N x ha(-1) x yr(-1) and from 5 to 42 kg S x ha(-1) x yr(-1) across these park landscapes. Area-weighted deposition was found to be up to 70% greater than NADP plus CASTNET monitoring-station estimates together. Model-validation results suggest that the model slightly overestimates deposition for deciduous and coniferous forests at low elevation and underestimates deposition for high-elevation coniferous forests. The spatially explicit deposition estimates derived from LandMod are an improvement over what is currently available. Future research should test LandMod in other mountainous environments and refine it to account for (currently) unexplained variation in deposition.

Air Pollutants↗

PubMed1997

[Cardiomyopathies].

Cardiomyopathies, and more specifically hypertrophic cardiomyopathy, have opened the route to what is now called genetic cardiology. Hypertrophic cardiomyopathy (HCM) is characterized by unexplained left and/or right ventricular hypertrophy, and disorganisation of tissular architecture. Approximately 60% of HCM are transmitted as an autosomal dominant trait. The clinical aspects of HCM vary markedly, and several morphological variants were described, depending on the localization of hypertrophy. This pathology is often complicated by cardiac failure, but the major risk is sudden death, and the predictive factors are presently very unrefined. Several pathogenic hypotheses were forwarded in the past, and one surprising result of genetic analyses is that none of these hypotheses was confirmed. Four disease genes were identified, and they encode sarcomeric proteins, cardiac myosin heavy chain, troponin T, tropomyosin and cardiac myosin binding protein C. To this high intergenic heterogeneity is associated a high intragenic heterogeneity. A major fall out of these genetic findings is the recent discovery of adult healthy carriers, around 30% in our experience. Genetype/phenotype relationships are being performed, and this is the first approach to a prognostic evaluation based on genetic localisation. The work on hypertrophic cardiomyopathy is currently being used as a model to analyse dilated cardiomyopathies, characterized by dilatation and impaired contraction of the left or both ventricles. The mode of inheritance of these forms of cardiomyopathies is complex. Five families with an autosomal inheritance were analyzed since two years, the loci were found, but the disease genes are not identified yet. Identification of patients at high risk and early treatment or prevention are the current goals.

Cardiomyopathies↗

PubMed1997

Mapping of peptides and protein fragments in human urine using liquid chromatography-mass spectrometry.

A method for the mapping of peptide mixtures, heterogeneous with respect to the concentration and the size of individual peptides, was established with the aim of obtaining a comprehensive analysis of human urine peptides. Peptide extraction and fractionation were optimized to achieve a two-step analysis, using reversed-phase and ion-exchange chromatography. Highly sensitive detection of peptides was performed by coupling microbore HPLC with electrospray mass spectrometry (ESI-MS). Peptides such as urodilatin, angiotensin and fragments of psoriasin, granulin and uromodulin were isolated and sequenced. The procedure presented here is a tool for the analysis of complex peptide mixtures from human urine.

Amino Acid Sequence↗

PubMed2003

Physical map and haplotype analysis of 16q-linked autosomal dominant cerebellar ataxia (ADCA) type III in Japan.

Autosomal dominant cerebellar ataxia (ADCA) is a group of heterogeneous neurodegenerative disorders. We previously mapped a gene locus for ADCA with pure cerebellar syndrome (ADCA type III) to a 3-cM region in chromosome 16q, and found a common haplotype among affected individuals. This region was exactly within the locus for another ADCA, spinocerebellar ataxia type 4 (SCA4). To identify the gene causing 16q-linked ADCA type III, we constructed a contig with 38 bacterial artificial chromosome clones between D16S3043 and D16S3095. The size of this contig was estimated to be 4.8 Mb. We found more than 500 nucleotide tandem repeats, including 9 CAG/CTG repeats in this candidate region, although none of the 94 tandem repeats analyzed were expanded in affected individuals. However, we found 11 new polymorphic markers, giving 22 markers spanning the candidate region. By typing these markers on eight Japanese families with ADCA type III, including two new families, we found that a common "founder" haplotype is seen in a more restricted 3.8-Mb region, spanning markers GGAA05 and D16S3095. We present here a newly refined critical interval of 16q-ADCA type III/SCA4. Data of 11 new DNA markers on 16q22.1 would also be useful for other research of genes mapped to this region.

Cerebellar Ataxia↗

PubMed1998

Population genetic diversity in relation to microsatellite heterogeneity.

Nine populations (Germans, Turks, Moroccans, Ovambos, Ugandans, Chinese, Japanese, Papuans, and Australian Aborigines) were investigated using six microsatellite systems (HumCD4, Hum F13B, HumFES/FPS, HumTH01, HumVWA, and D21S11), so-called STRs (short tandem repeats). Allele frequency data and sequencing results were used to compare the population genetic diversity among these populations. The genetic differences varied depending on the STR applied. According to the systems investigated, we defined three categories of STR microvariation: LOMs (low microvariation systems), INMs (intermediate microvariation systems), and HIMs (high microvariation systems). LOMs (STRs: CD4, FES, F13B, TH01) are characterised by a number of repeats between 5-15 and a stable repeat sequence. INMs and HIMs each showed an increasing number of repeats and additional sequence variation in the repeat motifs. The rate of new mutations was associated with the extent of microvariation. The reconstruction of phylogenetic trees led to a clustering in an early split of the African populations followed by further branching of the Asian/Melanesian and the Caucasian groups.

Africa↗

PubMed1996

A locus for Fanconi anemia on 16q determined by homozygosity mapping.

We report the results of a genomewide scan using homozygosity mapping to identify genes causing Fanconi anemia, a genetically heterogeneous recessive disorder. By studying 23 inbred families, we detected linkage to a locus causing Fanconi anemia near marker D16S520 (16q24.3). Although -65% of our families displayed clear linkage to D16S520, we found strong evidence (P = .0013) of genetic heterogeneity. This result independently confirms the recent mapping of the FAA gene to chromosome 16 by Pronk et al. Family ascertainment was biased against a previously identified FAC gene on chromosome 9, and no linkage was observed to this locus. Simultaneous search analysis suggested several additional chromosomal regions that could account for a small fraction of Fanconi anemia in our families, but the sample size is insufficient to provide statistical significance. We also demonstrate the strong effect of marker allele frequencies on LOD scores obtained in homozygosity mapping and discuss ways to avoid false positives arising from this effect.

Chromosome Mapping↗