ABSTRACT
Congenital generalized lipodystrophy (CGL) is an autosomal recessive disorder characterized by extreme lack of body fat and severe insulin resistance since birth. Recently, mutations have been reported in 1-acylglycerol-3-phosphate-O-acyltransferase 2 (AGPAT2) and Berardinelli-Seip congenital lipodystrophy 2 (BSCL2 or Seipin) genes in affected subjects from pedigrees linked to chromosomes 9q34 and 11q13, respectively. The AGPAT2 catalyses the acylation of the lysophosphatidic acid at the sn-2 position to form phosphatidic acid, a key intermediate in the biosynthesis of triacylglycerol and glycerophospholipids. High expression of AGPAT2 mRNA in adipose tissue compared to other isoforms suggests that the mutations might affect the adipose tissue the most. The function of BSCL2 remains unknown. Several CGL pedigrees reveal no mutation in either of the above genes and are not linked to these loci, suggesting additional genetic loci for CGL. Thus, several distinct mechanisms can lead to extreme lack of adipose tissue in humans and cause CGL.
Subject(s)
Lipodystrophy/congenital , Lipodystrophy/genetics , 1-Acylglycerol-3-Phosphate O-Acyltransferase , Acyltransferases/genetics , GTP-Binding Protein gamma Subunits/genetics , Humans , Insulin Resistance/genetics , MutationABSTRACT
Balanced translocations with breakpoints in a critical region of the X chromosome, Xq13-->q26, are associated with premature ovarian failure (POF). Translocations may cause POF either by affecting expression of specific X-linked genes essential for maintenance of normal ovarian function or by a chromosomal effect such as inhibition of meiotic pairing or altered X inactivation. We previously mapped seven Xq translocation breakpoints associated with POF to approximately 75-kb intervals. One translocation disrupted an aminopeptidase gene, XPNPEP2. We have now refined the map location of the remaining six breakpoints with respect to known genes and transcription units predicted from the draft human genome sequence. Only one of the six breakpoints disrupts a gene, DACH2, the human ortholog of a mouse gene expressed in embryonic nervous tissue, sensory organs, and limbs. DACH2 has no obvious relationship to ovarian function. The other five breakpoints fall in apparently intragenic regions. Our results are most consistent with models for POF associated with X;autosome translocations that involve generalized chromosome effects.
Subject(s)
Primary Ovarian Insufficiency/genetics , Translocation, Genetic , X Chromosome/genetics , Amino Acid Sequence , Animals , Base Sequence , Chromosome Mapping , DNA/genetics , DNA Mutational Analysis , DNA-Binding Proteins , Female , Genetic Linkage , Humans , In Situ Hybridization, Fluorescence , Mice , Models, Genetic , Molecular Sequence Data , Nuclear Proteins/genetics , Transcription FactorsABSTRACT
The interplay of multiple genes and environmental factors generates interindividual variation in plasma low density lipoprotein-cholesterol (LDL-C) concentrations. As a result, it has been difficult to identify individual genes that contribute to variation in plasma LDL-C levels using classical linkage analysis. We have exploited a genetic defect in the gene encoding the LDL receptor that is associated with a dramatically elevated plasma LDL-C level to unmask an allele at another locus that lowers plasma LDL-C levels. The existence of such an allele was implied by the analysis of a human pedigree with familial hypercholesterolaemia in which a third of the familial hypercholesterolaemia heterozygotes had normal levels of LDL-C. To develop an animal model of this LDL-C lowering effect and to identify genes that modify the plasma LDL-C level, we crossed LDL receptor-deficient mice with other strains of mice.
Subject(s)
Cholesterol/genetics , Lipoproteins, LDL/genetics , Alleles , Animals , Cholesterol/blood , Genes, Dominant , Genetic Linkage , Genetic Variation , Humans , Hypercholesterolemia/genetics , Lipoproteins, LDL/blood , Mice , Mice, Inbred Strains , Models, Genetic , Multigene Family , Mutation , Pedigree , Phenotype , Puerto RicoABSTRACT
We have constructed a 2.0 centiMorgan (cM) resolution genetic linkage map for chromosome 15q that contains 55 polymorphic satellites and 3 RFLPs that have placed on the map with odds for order of at least 1,000:1. Genotypes from 67 polymorphic loci (64 polymorphic microsatellites) were used to construct the map. Nine genes are included in the 1,000:1 map and 37 markers have heterozygosities of at least 70%. The sex-equal map length is 128 cM and the largest genetic interval is 11 cM (15.5 cM on the female map). The female and male map lengths are 150 cM and 106 cM, respectively. The map was constructed with 'MultiMap' and is based on the CEPH reference pedigrees and includes over 12,000 new genotypes. A sub-set of 12 markers spanning the length of the linkage map were genotyped in a somatic cell hybrid panel with breakpoints that divided 15q into five segments. Cytogenetic placement agreed with the linkage positions for each of the microsatellites tested with the exception of one (ACTC) which failed to give consistent results. Ten spontaneous new mutations were identified from a subset of 42 polymorphic microsatellites (out of a total of 20,420 transmissions), giving an apparent observed spontaneous mutation rate of 5 x 10(-4) per locus. An integrated map of chromosome 15q was also constructed with the microsatellite markers described here and previously genotyped RFLP-based markers. The sex average map spans 144.7 cM with an average distance between unique map locations of 3.5 cM and a maximum intermarker distance of 11.5 cM. These genetic linkage maps can be considered baseline maps for 15q which will be useful for physical mapping and the localization of disease genes and other genes of interest.
Subject(s)
Chromosomes, Human, Pair 15 , DNA, Satellite/genetics , Polymorphism, Genetic , Base Sequence , Chromosome Mapping , DNA Primers , Female , Genetic Linkage , Genetic Markers , Genotype , Humans , Male , Molecular Sequence Data , Mutation , Polymerase Chain Reaction , Polymorphism, Restriction Fragment Length , Recombination, Genetic , Sex CharacteristicsABSTRACT
The CEPH consortium map of chromosome 13 is presented. This map contains 59 loci defined by genotypes generated from CEPH family DNAs with 94 different probe and restriction enzyme combinations contributed by 9 laboratories. A total of 25 loci have been placed on the map with likelihood support of at least 1000:1. The map extends from loci in the centromeric region of chromosome 13 to the terminal band of the long arm. Multipoint linkage analyses provided estimates that the male, female, and sex-averaged maps extend for 158, 203, and 178 cM respectively. The largest interval is 24 cM and is between D13Z1 (alpha RI) and ATP1AL1. The mean genetic distance between the 25 uniquely placed loci is 7 cM.
Subject(s)
Chromosome Mapping , Chromosomes, Human, Pair 13 , Databases, Factual , Genetic Linkage , Genome, Human , Female , France , Genes, Retinoblastoma , Genetic Markers , Humans , Male , Reference StandardsABSTRACT
The monoamine oxidase A (MAOA) and B (MAOB) genes have been localized to chromosome Xp11.3. Recently-defined polymorphisms and linkage analysis have shown tight linkage between MAOA and MAOB, with a distance of approximately 2.7 cM between them.
Subject(s)
Genetic Linkage , Monoamine Oxidase/genetics , X Chromosome , Base Sequence , Genotype , Humans , Lod Score , Molecular Sequence Data , Oligodeoxyribonucleotides , Polymerase Chain Reaction , Polymorphism, GeneticABSTRACT
The CEPH consortium map of chromosome 15q is presented. The map contains 41 loci defined by genotypes generated from CEPH family DNAs with 45 different probe and restriction enzyme combinations contributed by 10 laboratories. A total of 29 loci have been placed on the map with likelihood support of at least 1000:1. The map extends from 15q13 to 15q25-qter. Multipoint linkage analyses provided estimates that the male, female, and sex-averaged maps extend for 127, 190, and 158 cM, respectively. The largest interval is 21 cM and is between D15S37 and D15S74. The on-average locus spacing is 5.6 cM and the mean genetic distance between the 21 uniquely placed loci is 8 cM.
Subject(s)
Chromosomes, Human, Pair 15 , Genetic Linkage , Chromosome Mapping , DNA , Female , Genotype , Humans , Male , Polymerase Chain Reaction , Recombination, GeneticABSTRACT
An insertion/deletion polymorphism between exons 7 and 8 of the pepsinogen C gene (PGC), previously detectable with Southern analysis, was formatted for detection with PCR. Alleles were rapidly typed by UV irradiation of ethidium bromide-stained agarose gels. Whereas Southern analysis revealed two alleles, the smaller fragments generated with PCR allowed the resolution of three alleles that were previously scored as a single allele and increased the heterozygosity of the system from 0.20 to 0.53. After a set of reference families was genotyped with the PCR-based polymorphism, a linkage map around the PGC gene on chromosome 6 was constructed. This included the HLA cluster and the highly informative D6S223 locus. PGC lies 22 cM proximal to HLA-DPB and between D6S5 and D6S4 at distances of 4.5 and 13.1 cM, respectively.
