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A Kessling

Publications and source records attributed to A Kessling.

15 recordsLinked to original sources
PubMed2000

Organization and conservation of the GART/SON/DONSON locus in mouse and human genomes.

The SON gene, which maps to human chromosome 21q22.1-q22.2, encodes a novel regulatory protein. Here we describe the organization of the Son locus in the mouse genome. The mouse Son gene spans a region of approximately 35 kb. The coding region is more than 8 kb in length and has been completely sequenced. The gene is organized into 11 coding exons and 1 noncoding 3'UTR exon, with over 70% of the coding region residing in one 5.7-kb exon. The gene contains at least one alternative exon, N/C exon 1, which can be used, by splicing, to generate a truncated form of the SON protein. Further investigation of the mouse Son locus has identified the genes directly flanking Son. The glycinamide ribonucleotide formyltransferase gene, Gart, is encoded 5' of Son in a head-to-head arrangement, with the start of both genes lying within 899 bp. Sequence comparison with the expressed sequence tagged database identified a novel gene within 65 bp of the 3' end of Son, which we have named Donson. In this unusually compact gene cluster, we have found overlap in the pattern of expression between Gart, Son, and Donson. However, at least two of these genes have very different functions. While GART is involved in purine biosynthesis, we find that SON shows the characteristics of "SR- type" proteins, which are involved in mRNA processing and gene expression.

Amino Acid Sequence↗
PubMed1999

A high-resolution physical map of human chromosome 21p using yeast artificial chromosomes.

The short arm of human chromosome 21 (21p) contains many different types of repetitive sequences and is highly homologous to the short arms of other acrocentric chromosomes. Owing to its repetitive nature and the lack of chromosome 21p-specific molecular markers, most physical maps of chromosome 21 exclude this region. We constructed a physical map of chromosome 21p using sequence tagged site (STS) content mapping of yeast artificial chromosomes (YACs). To this end, 39 STSs located on the short arm or near the centromere of chromosome 21 were constructed, including four polymorphic simple tandem repeats (STRs) and two expressed sequence tags (ESTs). Thirty YACs were selected from the St. Louis YAC library, the chromosome 21-enriched ICRF YAC library, and the CEPH YAC and megaYAC libraries. These were assembled in a YAC contig map ranging from the centromere to the rDNA gene cluster at 21p12. The total size of the region covered by YACs is estimated between 2.9 and 5 Mb. The integrity of the YAC contig was confirmed by restriction enzyme fingerprinting and fluorescence in situ hybridization (FISH). One gap with an estimated size of 400 kb remained near the telomeric end of the contig. This YAC contig map of the short arm of human chromosome 21 constitutes a basic framework for further structural and functional studies of chromosome 21p.

Chromosomes, Artificial, Yeast↗
PubMed1995

Prevalence of alleles encoding defective lipoprotein lipase in hypertriglyceridemic patients of French Canadian descent.

It has previously been estimated that due to genetic "founder effects," 97% of lipoprotein lipase (LPL) gene alleles conferring type I hyperlipoproteinemia (HLP) in French Canadians encode one of the following mutant LPL forms: Gly188-->Glu, Pro207-->Leu, or Asp250-->Asn. Although the genetic basis of type I HLP is known to be homozygosity for LPL deficiency, that for other forms of HLP, especially types IV, and V HLP, is not clear. It is also unclear whether hypertriglyceridemia due to very low density lipoprotein (VLDL) overproduction can be distinguished phenotypically from that due to defective catabolism of plasma lipoprotein triglycerides. The present study took advantage of the unique circumstances inherent in the relatively genetically isolated French Canadian population to address these questions. This study was carried out in order to determine the prevalence of these three mutant LPL alleles, and of a fourth encoding LPL Asn291-->Ser, in French Canadian patients with hypertriglyceridemia. The prevalence of heterozygosity for one of the four LPL mutant alleles in nondiabetic, nonobese hypertriglyceridemic subjects was 16 of 95 type IV HLP (17%) and 4 of 26 type V HLP cases (15%). These alleles were not found in over 150 normotriglyceridemic subjects, supporting the likelihood that the mutant alleles were at least partially responsible for HLP. In addition, heterozygosity for LPL deficiency due to one of these mutations apparently did not contribute to hypoalphalipoproteinemia, and was observed in 3 of 39 subjects with type III HLP. The results suggest that in French Canadians, 15-20% of type IV and V HLP cases are associated with these genetic defects in plasma triglyceride catabolism.

Adult↗
PubMed1992

Diabetes secondary to genetic disorders.

Diabetes may be associated with many genetic disorders. The scientific importance of these often rare disorders resides in the insight they may provide into the possible mechanisms of common diabetes. The type of diabetes varies in these syndromes. Non-insulin-dependent diabetes (NIDDM), clinically similar to common NIDDM, may be found in some syndromes (e.g. Werner's syndrome). In others there may be considerable insulin resistance, such as that present in ataxia telangiectasia. Extreme insulin resistance due to abnormal insulin receptor function is found in the Mendenhall syndrome. The mechanism of diabetes is more obscure in acute intermittent porphyria (AIP), although haem deficiency affecting the cytochrome chain raises interesting possibilities. In glycogen storage disease type I, the diabetes is associated with insulinopenia, following an earlier period in the disease when hypoglycaemia is the rule. IDDM, clinically similar to the common form, is present in the autoimmune polyglandular syndromes. Although a change in the lean:fat ratio is common in many neuromuscular disorders, mechanisms other than insulin resistance would seem to operate. The increased incidence of diabetes in heterozygotes for some of these genetic disorders raises the possibility that many common diabetics are, in fact, heterozygotes for some other disorder. The increased frequency of diabetes in Klinefelter's syndrome, Turner's syndrome and possibly Down's syndrome leads to the hypothesis that non-disjunction may, in some way be associated with the predisposition to diabetes. In several syndromes there is an increased incidence of diabetes in otherwise unaffected relatives of individuals with these syndromes. It is impossible to assess what proportion of common NIDDM or IDDM is made up of heterozygotes for these genetic syndromes.

Diabetes Mellitus↗
PubMed1992

Patterns of association between genetic variability in apolipoprotein (apo) B, apo AI-CIII-AIV, and cholesterol ester transfer protein gene regions and quantitative variation in lipid and lipoprotein traits: influence of gender and exogenous hormones.

Patterns of RFLP association were studied, to identify gene regions influencing quantitative variation in lipid and lipoprotein traits (coronary artery disease [CAD] risk factors or metabolically related traits). Subjects (118 female and 229 male; age 20-59 years) were selected for health. Multiple RFLPs were used to sample variability in regions around genes for apolipoprotein (apo) B (restriction enzymes HincII, PvuII, EcoRI, and XbaI), apo AI-CIII-AIV (BamHI, XmnI, TaqI, PstI, SstI, and PvuII) and cholesterol ester transfer protein (TaqI). Separate analyses were done by gender. The sample was truncated at mean +/- 4 SD, to remove extreme outliers. There was no significant gender difference in RFLP genotype frequency distribution. After trait-level adjustment to maximize removal of concomitant variability, analysis of variance was used to estimate the percentage trait phenotypic variance explained by measured variability in the gene regions studied. Fewer gene regions were involved in men, with less influence on quantitative trait variation than in women, in whom hormone use affected association patterns. Gender differences imply that pooling genders or adjusting data for gender effects removes genetic information and should be avoided. The association patterns show that variability around the candidate genes modulates trait levels: the genes are contributors to the genetics of CAD risk variables in a healthy sample.

Adult↗
PubMed1990

G to A substitution in the promoter region of the apolipoprotein AI gene is associated with elevated serum apolipoprotein AI and high density lipoprotein cholesterol concentrations.

We have determined the sequence of 250 bases 5' of the transcriptional start site of the apolipoprotein AI gene in a human individual with high serum concentrations of apo AI. One of the alleles contained a G to A substitution at position -75, between the CACAT sequence and the TAAATA box, creating a tandem repeat, CAGGGC-CA*GGGC. The substitution destroys an MspI cutting site, and the polymerase chain reaction and MspI digestion were used to identify the presence of the A or G base. The frequency of the A substitution in 96 healthy men from Bristol was 0.11 and this was increased to 0.25 in men with serum apo AI concentrations greater than 180 mg/dl. Men with the A allele had significantly higher serum concentrations of apo AI, high density lipoprotein (HDL) cholesterol and HDL2 than those with the G allele. In this sample, variation associated with the G to A substitution accounted for 6% and 4.6% of the total variance in apo AI and HDL cholesterol concentrations, respectively. Although there is as yet no functional proof, it is possible that the A substitution may be having a direct positive effect on the rate of apo AI gene transcription and thus be associated with increased apo AI and HDL cholesterol concentrations because of increased production of apo AI protein from the liver or intestine.

Alleles↗
PubMed1988

A cladistic analysis of phenotype associations with haplotypes inferred from restriction endonuclease mapping. II. The analysis of natural populations.

Genes that code for products involved in the physiology of a phenotype are logical candidates for explaining interindividual variation in that phenotype. We present a methodology for discovering associations between genetic variation at such candidate loci (assayed through restriction endonuclease mapping) with phenotypic variation at the population level. We confine our analyses to DNA regions in which recombination is very rare. In this case, the genetic variation at the candidate locus can be organized into a cladogram that represents the evolutionary relationships between the observed haplotypes. Any mutation causing a significant phenotypic effect should be imbedded within the same historical structure defined by the cladogram. We showed, in the first paper of this series, how to use the cladogram to define a nested analysis of variance (NANOVA) that was very efficient at detecting and localizing phenotypically important mutations. However, the NANOVA of haplotype effects could only be applied to populations of homozygous genotypes. In this paper, we apply the quantitative genetic concept of average excess to evaluate the phenotypic effect of a haplotype or group of haplotypes stratified and contrasted according to the nested design defined by the cladogram. We also show how a permutational procedure can be used to make statistical inferences about the nested average excess values in populations containing heterozygous as well as homozygous genotypes. We provide two worked examples that investigate associations between genetic variation at or near the Alcohol dehydrogenase (Adh) locus and Adh activity in Drosophila melanogaster, and associations between genetic variation at or near some apolipoprotein loci and various lipid phenotypes in a human population.

Alcohol Dehydrogenase↗
PubMed1985

DNA polymorphisms flanking the apo A-1 and insulin genes and type III hyperlipidaemia.

Two alleles identified by DNA restriction fragment length polymorphisms around the apo A-1/C-III and insulin genes have been shown to be associated with Type IV and V hyperlipidaemia. We have genotyped 19 patients with Type III hyperlipidaemia to establish whether this association is also found in the disorder. Our data show that these associations are not responsible for the majority of cases of Type III hyperlipidaemia, but cannot exclude the possibility that a small proportion (less than 50%) of cases of Type III are caused by interaction between these alleles and the apolipoprotein E2 phenotype.

Adult↗
PubMed1985

Linkage relationships of the gene for apolipoprotein CII with loci on chromosome 19.

Two common restriction fragment length polymorphisms detected with cloned gene probes for apolipoprotein CII (apo CII) have been used to study the inheritance of the gene in families segregating for loci on chromosome 19. Lod scores for APOC2 with the gene for complement component 3 (C3) exclude close linkage and give a maximum at a male recombination fraction of 0.25-0.30. Lod scores for APOC2 and FHC, the gene causing familial hypercholesterolaemia, are negative in males and suggest the genes may not be linked. However, it appears that APOC2 may be closely linked to the blood group loci Lutheran (Lu) and Secretor (Se), and probably less closely linked to Lewis (Le). These data are consistent with the gene order: FHC-----C3-----(Lu, Se, APOC2)

Apolipoprotein C-II↗
PubMed1983

A DNA polymorphism adjacent to the human apolipoprotein CII gene.

We have used a cDNA clone for human apolipoprotein CII (apo CII) to detect a common DNA polymorphism with the enzyme TaqI. This polymorphism is probably caused by a single base change approximately 2000 base-pairs from the 3' end of the structural gene. In the normal population (n = 90) the frequency of the less common allele is approximately 0.44. No significant differences were observed in the allele frequency in individuals with type IIa, IIb, III, IV and V lipoprotein patterns. There does not seem to be any population association between the TaqI polymorphism and factors that predispose an individual to hyperlipidaemia.

Adult↗