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At least 1,009 records · Page 56Linked to original sources
PubMed2001

Prenatal diagnosis and genetic analysis of type I and type II thanatophoric dysplasia.

Thanatophoric dysplasia (TD) is one of the most common neonatal lethal skeletal dysplasias. Prenatal sonographic and molecular genetic diagnoses of three cases of TD type I (TD1) and one case of TD type II (TD2) are presented here. Two fetuses of TD1 were characterized by polyhydramnios, macrocephaly, short limbs, a narrow thoracic cage and curved short femora, but without a cloverleaf skull at 27 and 31 weeks' gestation, respectively. The third fetus with TD1 was, however, not associated with macrocephaly, polyhydramnios, chest narrowing and severe femoral bowing on prenatal ultrasound at 18 weeks' gestation. The TD2 fetus was characterized by polyhydramnios, short limbs, a narrow thoracic cage, straight short femora, hydrocephalus and a cloverleaf skull at 24 weeks' gestation. Three-dimensional ultrasound was able to enhance the visualization of thickened, redundant skin folds and craniofacial and limb deformities associated with TD. Molecular analysis of the fibroblast growth factor receptor 3 (FGFR3) gene by restriction enzyme digestion analysis and direct sequencing using cultured amniotic fluid cells or cord blood cells revealed a missense mutation of 742C-->T (Arg248Cys) in all cases with TD1 and a missense mutation of 1948A-->G (Lys650Glu) in the case with TD2. The present report shows that adjunctive applications of molecular genetic analysis of the FGFR3 gene and three-dimensional ultrasound are useful for prenatal diagnosis of TD.

Adult↗
PubMed1989

Genetic analysis of human deoxyribonuclease I by immunoblotting and the zymogram method following isoelectric focusing.

We have devised two independent detection methods for investigating possible molecular heterogeneity and genetic polymorphism in human DNase I, in terms of both its antigenicity and enzymatic activity. One was an immunoblotting method using an antibody specific to DNase I following polyacrylamide gel isoelectric focusing (IEF-PAGE). The DNase I-specific antibody was raised in a rabbit using purified enzyme from human urine as the immunogen. DNase I in urine was found to exist in multiple forms with different pI values separable by IEF-PAGE within a pH range of 3.5-4.0. This method was able to detect as little as 0.1 micrograms of the purified DNase I and facilitated classification of desialylated urine samples from different individuals into several groups according to differences in DNase I isozyme patterns. About 0.5 ml of the original urine was sufficient for analysis of the isozyme patterns. The other method was the zymogram method, which had a high sensitivity and resolution almost identical to those of the immunoblotting method for analysis of DNase I patterns. It was easier to perform, more time-saving, and more useful since it did not require antibody specific to DNase I. These two methods should prove valuable for biochemical and genetic analysis of DNase I isozymes.

Antibodies↗
PubMed1996

Lens complementation system for the genetic analysis of growth, differentiation, and apoptosis in vivo.

A genetic approach has been established that combines the advantages of blastocyst complementation with the experimental attributes of the developing lens for the functional analysis of genes governing cellular proliferation, terminal differentiation, and apoptosis. This lens complementation system (LCS) makes use of a mutant mouse strain, aphakia (ak), homozygotes of which fail to develop an ocular lens. We demonstrate that microinjection of wild-type embryonic stem (ES) cells into ak/ak blastocysts produces chimeras with normal ES-cell-derived lenses and that microinjection of Rb-/- ES cells generates an aberrant lens phenotype identical to that obtained through conventional gene targeting methodology. Our determination that a cell autonomous defect underlies the aphakia condition assures that lenses generated through LCS are necessarily ES-cell-derived. LCS provides for the rapid phenotypic analysis of loss-of-function mutations, circumvents the need for germ-line transmission of null alleles, and, most significantly, facilitates the study of essential genes whose inactivation is associated with early lethal phenotypes.

Animals↗
PubMed1997

Molecular genetic analysis of two families with keratosis follicularis spinulosa decalvans: refinement of gene localization and evidence for genetic heterogeneity.

X-linked keratosis follicularis spinulosa decalvans (KFSD) is a rare disorder affecting both skin and eyes. In the two extended KFSD families analysed to date, the gene was mapped to Xp22.13-p22.2. By analyzing several new markers in this region, we were able to narrow the candidate region to a 1-Mb interval between DXS7161 and (DXS7593, DXS7105) in the large Dutch pedigree. In addition, we analyzed 23 markers in Xp21.2-p22.2 in a German family with KFSD. Haplotype and recombination analysis positioned the KFSD gene in this family most likely outside the candidate region on Xp22.13-p22.2. This finding is suggestive for genetic heterogeneity: in this pedigree there is either another locus on the X-chromosome, or KFSD is transmitted here as an autosomal dominant trait with variable expression.

Child, Preschool↗
PubMed1997

Defining the asthma phenotype for the purpose of genetic analysis.

In 1991, we began a project to search for the genetic basis of asthma using linkage analysis. We encountered discord between a history of asthma and physiological measures of variable airflow obstruction and sought to examine the frequency of such occurrences and the issues surrounding phenotyping of patients with asthma. We reviewed our experience in ascertaining the asthma phenotype in 50 nuclear families comprised of 219 subjects (110 male, 109 female). Three respiratory physicians reviewed data including a questionnaire, skin testing, objective measures of variable airflow obstruction [increase in FEV1 > or = 15% following salbutamol 400 micrograms of PC20 (methacholine) < or = 4 mg/ml], and serum for IgE. Thirty-eight percent of subjects had both objective and questionnaire data consistent with asthma (++) whereas 39% had negative objective and negative questionnaire findings (--) (i.e., no asthma). A positive history but negative objective findings occurred in 7% of subjects, 2% had a negative history and positive objective findings. Retesting was requested in 13% of subjects; review of historical data was requested in 1% (i.e., childhood asthma but no present asthma). Retesting was requested for either (a) positive history, negative objective if symptoms were seasonal or the subject was using medications known to affect the challenge study, (b) viral infection within 6 weeks of a positive methacholine study, or (c) technically inadequate study. Overall, after the initial assessment, all members of only 22 families could be catagorized as either ++ or --. The diagnostic group requested at least 1 retest in 19 families and a review of historical records in 2 families. We conclude that discordance between self-reported questionnaire data and laboratory measures of variable airflow limitation is common and will increase the numbers of asthmatic subjects in studies that seek to determine the genetic basis of asthma.

Adolescent↗
PubMed2002

Genetic analysis of traits distinguishing outcrossing and self-pollinating forms of currant tomato, Lycopersicon pimpinellifolium (Jusl.) Mill.

The evolution of inbreeding is common throughout the angiosperms, although little is known about the developmental and genetic processes involved. Lycopersicon pimpinellifolium (currant tomato) is a self-compatible species with variation in outcrossing rate correlated with floral morphology. Mature flowers from inbreeding and outcrossing populations differ greatly in characters affecting mating behavior (petal, anther, and style lengths); other flower parts (sepals, ovaries) show minimal differences. Analysis of genetic behavior, including quantitative trait locus (QTL) mapping, was performed on representative selfing and outcrossing plants derived from two contrasting natural populations. Six morphological traits were analyzed: flowers per inflorescence; petal, anther, and style lengths; and lengths of the fertile and sterile portions of anthers. All traits were smaller in the selfing parent and had continuous patterns of segregation in the F(2). Phenotypic correlations among traits were all positive, but varied in strength. Quantitative trait locus mapping was done using 48 RFLP markers. Five QTL total were found involving four of the six traits: total anther length, anther sterile length, style length, and flowers per inflorescence. Each of these four traits had a QTL of major (>25%) effect on phenotypic variance.

Chromosome Mapping↗
PubMed2002

Genetic analysis of multiple sclerosis.

The increased recurrence risk within families indicates a role for genetic factors in the etiology of multiple sclerosis. Genes may influence susceptibility to the development of multiple sclerosis and the subsequent course of the disease. To date, associations have only been demonstrated consistently with class II major histocompatibility complex (MHC) alleles. The relatively low yield from additional candidate gene studies is only modestly advanced by several whole-genome linkage analyses, and by the first in a series of planned whole-genome linkage disequilibrium screens for allelic associations. The aims of linkage and association are to narrow the search for chromosomal regions encoding genes for multiple sclerosis and, with information from the human gene project, suggest new positional candidates. In time, it is expected that these genes will include some that confer susceptibility to the general process of autoimmunity, others that are specific for multiple sclerosis in all populations, some that act only in defined ethic groups, and those that determine particular phenotypes or shape the clinical course. These genetic analyses are predicated on the assumption that multiple sclerosis is one disease; a major part of future studies will be to resolve the question of disease heterogeneity in multiple sclerosis. When eventually in place, the potential of this genetic knowledge for improved understanding of the pathogenesis of multiple sclerosis and designing novel treatments is considerable.

DNA Mutational Analysis↗
PubMed2001

Genetic analysis of intestinal cholesterol absorption in inbred mice.

A genetic mapping strategy was employed to identify chromosomal regions harboring genes that influence the absorption of intestinal cholesterol in the mouse. Analysis of seven inbred strains of male mice (129P3, AKR, BALB/c, C3H/He, C57BL/6, DBA/2, and SJL, all from Jackson Laboratories) revealed substantial differences in their abilities to absorb a bolus of cholesterol delivered by gavage. Crosses between high (AKR, 129) and low (DBA/2, SJL) absorbing strains revealed evidence for the presence of dominant genes that increase and decrease cholesterol absorption. Backcrosses between F1 offspring and parental strains (DBA/2xAKD2F1 and 129xSJL129F1) followed by linkage analyses revealed four quantitative trait loci that influenced cholesterol absorption. Analyses of recombinant inbred strains identified an additional three loci affecting this phenotype. These seven quantitative trait loci, which map to different chromosomes and are termed Cholesterol absorption 1-7 (Chab1-7) loci, together influence the absorption of intestinal cholesterol in mice and are likely to be involved in different steps of this complex pathway.

Animals↗
PubMed1993

Genetic analysis of repeated, biparental, diploid, hydatidiform moles.

A woman presented with five consecutive pregnancies displaying molar morphology. In the fifth pregnancy, a non-malformed, liveborn infant was delivered. Genetic analyses (RFLP analysis, cytogenetics, flow cytometry) were performed in pregnancies II-V. It was demonstrated that these pregnancies originated in separate conceptions, all conceptuses were diploid, and all had maternally as well as paternally derived genetic markers. By cytogenetic analysis, aberrant heteromorphisms were noted; no other abnormalities were observed in chromosome structure or in DNA sequence. Many different causes for the abnormal development can be envisaged, environmental as well as genetic. To conform to current ideas of molar pathogenesis, it is suggested that the present conceptuses might have arisen from imbalances in imprinted genomic regions. This could be a consequence of uniparental disomy in critical regions generated by somatic crossing over. Alternatively, it could be caused by a malfunction in the generation or maintenance of imprinting.

Chromosome Aberrations↗
PubMed2003

Genetic analysis of Agrobacterium tumefaciens susceptibility in Brassica oleracea.

The genetic control and heritability of Agrobacterium tumefaciens susceptibility was investigated using a doubled haploid (DH) mapping population of Brassica oleracea and the associated RFLP map. Preliminary studies were carried out by analysis of an 8 x 8 diallel, for which the parental lines were selected to include a range of susceptibilities to A. tumefaciens. The variation observed within the diallel was attributed to both additive and dominant gene effects, with additive gene effects being more important. A broad sense heritability value of 0.95 suggested that 95% of the observed variation was due to genetic effects, with just 5% attributed to non-genetic or environmental effects. A high narrow-sense heritability value of 0.79 suggested that 79% of this trait was controlled by additive gene effects and, therefore, the potential to introduce this trait into breeding material is high. Fifty-nine DH lines from the mapping population were screened for susceptibility towards A. tumefaciens. Variation in susceptibility was observed across the population. The results of the DH screen were entered into the mapping programme MAPQTL and a highly significant quantitative trait loci (QTL) associated with susceptibility to A. tumefaciens was identified on linkage group 09. The use of substitution lines covering this region confirmed the location of this QTL. This work shows that susceptibility to A. tumefaciens is a heritable trait, and the transfer of susceptibility into resistant lines is demonstrated. These findings may help to overcome genotype restrictions to genetic transformation.

Agrobacterium tumefaciens↗
PubMed2003

Molecular genetic analysis excludes implantation metastasis of basal cell carcinomas.

Basal cell carcinoma (BCC) of the skin is the most common tumor in the white population. A 66-year-old man developed 2 BCCs at the left parietal region of the head and at the helix of the left ear. The 2 lesions matched exactly when pressing the ear against the head, suggesting an implantation metastasis mechanism. Molecular genetic techniques were used to confirm or exclude such a mechanism in this rare clinical constellation. Tumor tissues were precisely microdissected for DNA isolation. Exons 5-9 of the p53 tumor suppressor gene were directly sequenced. In addition, loss of heterozygosity analysis of chromosome 9q was performed using 5 polymorphic microsatellite markers. The BCC of the ear revealed a p53 mutation at codon 273, whereas the other one lacked this mutation. In addition, the smaller BCC of the ear showed loss of heterozygosity at 9q33.3, in contrast with the larger BCC. Interestingly, histologically normal skin of the ear distant from the small BCC had the same deletion, indicating a field defect of this skin patch at 9q33.3. Molecular genetic analysis clearly demonstrated different genetic alterations of the two BCCs and therefore most likely excludes a mechanism of implantation metastasis.

Aged↗
PubMed2005

Localization of bipolar susceptibility locus by molecular genetic analysis of the chromosome 12q23-q24 region in two pedigrees with bipolar disorder and Darier's disease.

OBJECTIVE: The authors previously reported two families (pedigrees 324 and 5501) in which Darier's disease-a rare, autosomal dominant skin disease-and bipolar disorder cosegregate. In each of these families there is complete cosegregation of mood disorder with a segment of chromosome 12q23-q24, consistent with the existence of a highly penetrant dominant variant. Here molecular genetic analyses aimed at localizing and identifying the susceptibility gene in this region are reported. METHOD: In the two families, the authors undertook 1) linkage and haplotype studies using 45 highly polymorphic molecular genetic markers in order to delineate the region of interest and 2) direct analysis of genes within this region. RESULTS: Linkage and haplotype information from the most severely affected individuals defined a region of interest that spanned two neighboring regions of 19 megabases (Mb) (D12S362-D12S1646) and 7 Mb (D12S1718-D12S837). Information from all individuals refined the region of interest to 6.5 Mb (D12S127-D12S1646). Systematic study of the coding and flanking intronic regions of 25 known genes within this latter region failed to identify any highly penetrant autosomal dominant disease-conferring mutations in these pedigrees. CONCLUSIONS: This linkage and haplotype analysis, together with data from several other linkage studies, provides compelling evidence for the existence in the 12q23-q24 region of one or more genes involved in the pathogenesis of bipolar disorder. Further molecular genetic analysis of this region is required to identify the gene(s).

Bipolar Disorder↗
PubMed1996

A genetic analysis of pannier, a gene necessary for viability of dorsal tissues and bristle positioning in Drosophila.

A genetic and phenotypic analysis of the gene pannier is described. Animals mutant for strong alleles die as embryos in which the cells of the amnioserosa are prematurely lost. This leads to a dorsal cuticular hole. The dorsal-most cells of the imagos are also affected: viable mutants exhibit a cleft along the dorsal midline. pannier mRNA accumulates specifically in the dorsal-most regions of the embryo and the imaginal discs. Viable mutants and mutant combinations also affect the thoracic and head bristle patterns in a complex fashion. Only those bristles within the area of expression of pannier are affected. A large number of alleles have been studied and reveal that pannier may have opposing effects on the expression of achaete and scute leading to a loss or a gain of bristles.

Alleles↗
PubMed2000

Regulation of production of the antifungal metabolite 2,4-diacetylphloroglucinol in Pseudomonas fluorescens F113: genetic analysis of phlF as a transcriptional repressor.

The antifungal metabolite 2,4-diacetylphloroglucinol plays a major role in the biocontrol capabilities of Pseudomonas fluorescens. The phloroglucinol biosynthetic locus of P. fluorescens F113 has been isolated previously. From nucleotide sequence data, a putative regulator gene (phlF) was identified upstream and divergently transcribed from the phlACBD phloroglucinol biosynthetic genes. PhlF shows similarity to various transcriptional repressors in the EMBL database and exhibits a helix-turn-helix motif in its amino acid sequence. phlF was cloned into an expression vector and the PhlF protein product was purified. Gel retardation experiments demonstrated PhlF to be a DNA-binding protein and showed that it binds to the phlA-phlF intergenic region. Introduction of phlF into P. fluorescens F113 in multiple copies resulted in repression of phloroglucinol production in this strain. This effect was mediated at the transcription level since the expression of a phloroglucinol biosynthetic gene fusion in this background was equally repressed. Furthermore, the inactivation of phlF results in derepression of phloroglucinol production in this strain.

Antifungal Agents↗
PubMed1996

Genetic analysis of the glucose-6-phosphatase mutation of type 1a glycogen storage disease in a Chinese family.

Type 1a glycogen storage disease (GSD) is an autosomal recessive metabolic disorder caused by a deficiency in glucose-6-phosphatase (G6Pase). Polymerase chain reaction (PCR) and nucleotide sequence analysis were used to identify the location and nature of mutations at the G6Pase locus in two siblings affected with type 1a GSD. Both patients are compound heterozygotes with two different single nucleotide substitutions in the two G6Pase alleles. A guanine to adenine transition was identified at base position 327 in the exon 2, converting an arginine to a histidine at codon 83. The second substitution was a thymine to adenine transversion at base position 1101 in the exon 5, converting an isoleucine to an asparagine at codon 341. Family study reveals that both parents are heterozygous carriers: the father with a mutant G6Pase allele at exon 2, the mother with another mutant G6Pase allele at exon 5. This is the first family study in Taiwan on type 1a GSD identified by molecular analysis. The mutations identified herein are novel substitutions in the G6Pase gene. In addition, an adenine to guanine substitution was observed at base position 653 in the exon 5 of G6Pase gene in both sibling patients and their parents, as well as in 15 normal Chinese subjects and three normal Caucasian subjects.

Child, Preschool↗