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PubMed1991

Ribosomal protein genes are overexpressed in colorectal cancer: isolation of a cDNA clone encoding the human S3 ribosomal protein.

We have isolated a cDNA clone encoding the human S3 ribosomal protein from a normal human colon cDNA library. The clone was identified as one of many that detected genes whose level of expression was increased in adenocarcinoma of the colon relative to normal colonic mucosa. Increased levels of the S3 transcript were present in the tumors of all eight patients examined. Moreover, the S3 mRNA was also more abundant in 7 of 10 adenomatous polyps, the presumed precursor of carcinoma. Additional studies demonstrated that increased levels of mRNAs encoding several other ribosomal proteins, including S6, S8, S12, L5, and P0, were present in colorectal tumors and polyps. These results suggest that there is increased synthesis of ribosomes in colorectal tumors and that this increase is an early event in colon neoplasia.

Adenocarcinoma↗

PubMed1988

Four DNA polymorphisms in the LDL receptor gene: their genetic relationship and use in the study of variation at the LDL receptor locus.

We have studied four different restriction fragment length polymorphisms (RFLPs) for the LDL receptor gene, detected using the restriction enzymes StuI, PvuII, ApaLI, and NcoI, in normal subjects and in patients with familial hypercholesterolaemia (FH) from London. Significant linkage disequilibrium was detected between all four RFLPs. Used together they give a polymorphism information content (PIC) of greater than 0.7 which makes them useful for studying the inheritance of the LDL receptor gene in more than 70% of families with FH. The NcoI and ApaLI RFLPs were found to be the most useful, giving a combined PIC value of 0.6. The allele frequencies of all four polymorphisms were compared in the normal and FH groups and the frequency of the rarer N2 allele of the NcoI RFLP was found to be significantly higher in the FH group. This suggests that a mutation has occurred on the rare NcoI N2 allele and that it may be making a significant contribution to the defects causing FH in this patient group. We have also used these RFLPs to look for evidence that variation at the LDL receptor gene locus contributes to the determination of cholesterol levels in the normal population. People with different RFLP genotypes do not have significantly different levels of serum total or LDL cholesterol. At present we have no evidence that variation at this locus may be determining cholesterol levels in the non-FH population.

Alleles↗

PubMed1996

Molecular analysis of the arylsulphatase A gene in late infantile metachromatic leucodystrophy patients and healthy subjects from Italy.

A molecular analysis of the arylsulphatase A gene was performed on 26 unrelated, Italian, late infantile metachromatic leucodystrophy patients. The frequency of the common disease causing mutations 609A and 2381T was 28.8% and 1.9% respectively. Pseudodeficiency allele frequency in patients was found to be 13.5% and a frequency of 10.1% was found in 89 unaffected normal controls. The frequency of the 609A mutation in Italian late infantile patients is lower than in late infantile patients from northern Europe, suggesting a higher frequency of different sporadic mutations in the Italian population. A cooperative in cis effect in phenotype determination involving arylsulphatase A mutations and the eventual background of the pseudodeficiency allele is proposed.

Alleles↗

PubMed2004

Myocardial infarction: optimization of inversion times at delayed contrast-enhanced MR imaging.

Seventeen patients underwent magnetic resonance (MR) imaging for myocardial viability with a protocol approved by the institutional review board and gave written informed consent. Breath-hold cine inversion-recovery segmented k-space true fast imaging with steady-state precession sequence, referred to as inversion time (TI) mapping, was performed to determine optimal TI for myocardial infarction inversion-recovery imaging. From TI mapping, optimal TI was 180-315 msec 10-15 minutes after administration of 0.15 mmol/kg of gadolinium-based contrast material. At that optimal TI, relative signal intensity of infarcted myocardium compared with uninfarcted myocardium was maximal (mean +/- standard deviation, 297.8% +/- 86.5), whereas signal-to-noise ratio of uninfarcted myocardium was minimal (4.5 +/- 1.2). When applied to conventional myocardial infarction inversion-recovery imaging, optimal TI resulted in nulling of signal intensity of uninfarcted myocardium in all patients and in excellent conspicuity of infarcted myocardium in all nine patients with visible infarction.

Adult↗

PubMed1997

Development and use of a microdissected swine chromosome 6 DNA library.

To facilitate the identification of microsatellite genetic markers from a single swine chromosome, chromosome microisolation and microcloning have been used to generate a swine chromosome 6-specific DNA library. Ten copies of swine chromosome 6 were scraped from metaphase spreads, ligated to custom-prepared adaptors, and amplified by PCR. The purity of the amplified product was verified by fluorescent in situ hybridization. The utility of the chromosome painting probe for heterologous painting was demonstrated and confirmed that swine chromosome 6 is syntenic to human chromosomes 1p and 19q. A small insert genomic library of 1.39 x 10(6) clones was generated from the PCR-amplified chromosome 6 genomic DNA and screened for (GT)n microsatellite genetic markers. Nine (GT)n microsatellite markers were developed and genotyped on a Yorkshire x Meishan swine reference family. All nine markers genetically mapped to chromosome 6, confirming the purity of the microisolation method. The method used here should be adaptable to the microdissection of subchromosomal regions of not only the swine genome but also other livestock genomes.

Animals↗

PubMed1997

Role of the alpha-, beta-, and gamma-subunits of epithelial sodium channel in a model of polygenic hypertension.

The pathophysiological basis of Liddle's syndrome, a rare autosomal dominant form of arterial hypertension, has been found to rest on missense mutations or truncations of the beta- and gamma-subunits of the epithelial sodium channel. The hypothesis has been advanced that molecular variants of these genes might also contribute to the common polygenic forms of hypertension. We tested this hypothesis by performing a cosegregation study in a reciprocal cross between the stroke-prone spontaneously hypertensive rat (SHRSPHD) and a Wistar-Kyoto rat (WKY-1HD) reference strain. We carried out genetic mapping and chromosomal assignment of the alpha-, beta-, and gamma-subunits of the epithelial sodium channel using both linkage analysis and fluorescent in situ hybridization techniques. We demonstrate that in the rat, the beta- and gamma-subunits, as in humans, are in close linkage; they map to rat chromosome 1 and cosegregate with systolic pressure after dietary NaCl (logarithm of the odds [LOD] score, 3.7), although the peak LOD score of 5.0 for this quantitative trait locus was detected 4.4 cM away from the beta-/gamma-subunit locus. The alpha-subunit was mapped to chromosome 4 and exhibited no linkage to blood pressure phenotype. Comparative analysis of the complete coding sequences of all three subunits in the SHRSPHD and WKY-1HD strains revealed no biologically relevant mutations. Furthermore, Northern blot comparison of mRNA levels for all three subunits in the kidney showed no differences between SHRSPHD and WKY-1HD. Our results fail to support a material contribution of the epithelial sodium channel genes to blood pressure regulation in this model of polygenic hypertension.

Animals↗

PubMed1999

Factor V Leiden and thermolabile methylenetetrahydrofolate reductase gene variants in an East Anglian preeclampsia cohort.

Preeclampsia is a heritable condition that develops as a result of widespread vascular endothelial dysfunction. The thrombotic tendency in this condition has suggested a number of candidate genes, and there have been recent reports of positive association with the Leiden variant of factor V and the thermolabile variant of methylenetetrahydrofolate reductase. We attempted to reproduce these results in a large cohort of well-characterized women with preeclampsia, recruited prospectively within the East Anglian region of the United Kingdom. Women in the preeclampsia cohort (n=283) were genotyped for both the Leiden variant (G1691A) of factor V and the thermolabile variant (C677T) of methylenetetrahydrofolate reductase. Genotype and allele frequencies were compared with those of 2 control groups, one consisting of women recruited prospectively (n=100) from the same maternity hospital as the subjects and another consisting of normotensive women (n=100) from East Anglia. No significant differences were detected. Specifically, the carrier rate for the Leiden variant was 5.3% in the preeclampsia group and 5. 5% in the combined control group. T677 homozygotes for methylenetetrahydrofolate reductase were 11% and 11.5% in the 2 groups, respectively. We conclude that there is no evidence of association of preeclampsia with either of these 2 polymorphisms in our study population.

Base Sequence↗

PubMed1994

Gene expression of the cardiac Na(+)-Ca2+ exchanger in end-stage human heart failure.

The regulation of cytosolic Ca2+ concentration during excitation-contraction coupling is altered in the failing human heart. Previous studies have focused on disturbances in Ca2+ release and reuptake from the sarcoplasmic reticulum (SR), whereas functional studies of the cardiac Na(+)-Ca2+ exchanger, another important determinant of myocyte homeostasis, are lacking for the failing human heart. Using a cardiac Na(+)-Ca2+ exchanger cDNA recently cloned from a guinea pig cDNA library, we investigated the gene expression of the cardiac Na(+)-Ca2+ exchanger in relation to the SR Ca(2+)-ATPase. Expression of both genes was quantified in left ventricular myocardium from 24 failing human cardiac explants and 7 control heart samples in relation to beta-myosin heavy chain mRNA by slot blot analysis. Compared with patients with nonfailing hearts, patients with dilated cardiomyopathy (DCM, n = 13) showed a 55% increase in Na(+)-Ca2+ exchanger mRNA levels (P < .05 versus control value) and a 41% increase in patients with coronary artery disease (CAD, n = 11). In the same hearts, SR Ca(2+)-ATPase mRNA levels were decreased by 50% in DCM and by 45% in CAD (P < .05 for both versus control value). There was a positive correlation between Na(+)-Ca2+ exchanger and SR Ca(2+)-ATPase mRNA levels both in normal and failing human hearts, albeit with different slopes and intercepts of the regression line. The Na(+)-Ca2+ exchanger protein levels as assessed by Western blot analysis and normalized to beta-myosin heavy chain protein were increased in DCM and CAD (P < .05 and P < .01 versus control value, respectively), whereas SR Ca(2+)-ATPase protein levels were reduced (P < .05 for both groups versus control values). Thus, the Na(+)-Ca2+ exchanger gene expression is enhanced in failing human hearts and may, in part, compensate for the depressed SR function with regard to diastolic Ca2+ removal.

Adult↗

PubMed2005

No replication of association between estrogen receptor alpha gene polymorphisms and susceptibility to myocardial infarction in a large sample of patients of European descent.

BACKGROUND: The effects of estrogen on blood vessels are partly due to changes in vascular cell gene expression and protein synthesis that are mediated by estrogen receptors. In previous association studies, the -397T/C (rs2234693) and -351A/G (rs9340799) single nucleotide polymorphisms in the estrogen receptor alpha gene (ESR1) have been implicated in the risk of coronary atherosclerosis and myocardial infarction. To test these findings, we examined the relationship of the polymorphisms to myocardial infarction in a large sample of white patients and control individuals of predominantly European descent. METHODS AND RESULTS: The case group included 3657 patients with myocardial infarction, and the control group comprised 1211 individuals with angiographically normal coronary arteries and without signs or symptoms of myocardial infarction. TaqMan assays were used for the determination of genotypes. Genotype distributions of the -397T/C and -351A/G polymorphisms were not significantly different between the control and patient groups (P> or =0.85). The frequencies of haplotypes defined by the -397T/C and -351A/G polymorphisms were similar in the control group and the patient group (P=0.42). In addition, the distributions of haplotype-defined genotypes (diplotypes) were not significantly different between the control group and the patient group (P=0.81). Separate analyses in women and men did not reveal sex-related associations of specific genotypes or haplotypes of the polymorphisms with myocardial infarction (P> or =0.25). CONCLUSIONS: The results indicate that the -397T/C and -351A/G polymorphisms of ESR1 or haplotypes based on these polymorphisms are not associated with myocardial infarction in a white population.

Aged↗

PubMed1990

Frameshift mutation near the 3' end of the COL1A1 gene of type I collagen predicts an elongated Pro alpha 1(I) chain and results in osteogenesis imperfecta type I.

Osteogenesis imperfecta (OI) is a heterogeneous disorder of type I collagen of which OI type I, an autosomal dominant condition, is the mildest and most common form. Affected individuals have blue sclerae, normal stature, bone fragility without significant deformity and osteopenia. Fibroblasts from most affected individuals produce about half the expected amount of structurally normal type I collagen as a result of decreased synthesis of one of its constituent chains, pro alpha 1(I), but the nature of the mutations which result in OI type I are unknown. We describe a three generation family with OI type I in which all affected members have one normal COL1A1 allele and another from which the intragenic Eco RI restriction site near the 3' end of the gene is missing. Amplification by polymerase chain reaction and sequence determination of the normal allele and of the mutant allele in the domain that normally contains the Eco RI site demonstrated a 5-bp deletion from the mutant allele. The deletion changes the translational reading-frame beginning at the Eco RI site and predicts the synthesis of a pro alpha 1(I) chain that extends 84 amino acids beyond the normal termination. Although the mutant pro alpha 1(I) chain is synthesized in an in vitro translation system, we are unable to detect its presence in intact cells, suggesting that it is unstable and rapidly destroyed in one of the cell's degradative pathways. Our analysis of individuals with OI type I from 20 families indicates that this is a unique mutation and suggests that the phenotype can result from multiple mechanisms that decrease the synthesis of normal type I procollagen molecules, including those that alter protein stability.

Adult↗

PubMed1990

Identification of two variant short chain acyl-coenzyme A dehydrogenase alleles, each containing a different point mutation in a patient with short chain acyl-coenzyme A dehydrogenase deficiency.

Two distinct mutant alleles of the precursor (p) short chain acyl-CoA dehydrogenase (SCAD) gene were identified in a SCAD-deficient patient (YH2065) using the polymerase chain reaction to amplify cDNA synthesized from total RNA from her fibroblasts. Cells from this patient had previously been shown to synthesize a labile variant SCAD in contrast to the normal stability of variant SCADs in two other SCAD-deficient cell lines (Naito, E., Y. Indo, and K. Tanaka. 1989. J. Clin. Invest. 84:1671-1674). In the present study, both mutant alleles of YH2065 were found to contain a C----T transition, one at position 136 and the other at position 319 of the coding region of pSCAD cDNA. Clones of cDNA amplified from this region showed only one of the C----T transitions, indicating that each mutation was derived from different pSCAD alleles. Each of these mutations altered a known restriction endonuclease site, and restriction analysis of additional cDNA clones from amplified mutant cDNA and Southern blotting of mutant genomic DNA confirmed the presence of two unique mutant alleles in YH2065, indicating YH2065 is a compound heterozygote. These C----T transitions result in the substitution of Arg-22 and Arg-83 of the mature SCAD with Trp and Cys, respectively.

Acyl-CoA Dehydrogenases↗

PubMed1993

Related individuals with different androgen receptor gene deletions.

We have identified different members of one family affected by androgen insensitivity syndrome who have deletions of different exons of the X-linked androgen receptor (AR) gene. Two affected (XY) siblings have a deletion of exon E of the AR gene and their affected (XY) aunt has a normal exon E, but a deletion of exons F and G of the same gene. The mother and maternal grandmother of the children both carry the exon E deletion, but not the exon F, G deletion. Both deletions are 5 kb in length and have one breakpoint within a 200-bp region in intron 5; however, they extend in opposite directions. The probability that these two different deletions have arisen at random is extremely low, but the cause of this intriguing phenomenon remains to be found.

Adult↗

PubMed1993

Increased radiosensitivity of granulocyte macrophage colony-forming units and skin fibroblasts in human autosomal recessive severe combined immunodeficiency.

We studied the radiosensitivity of granulocyte macrophage colony-forming units (GM-CFU) in patients with a severe combined immunodeficiency (SCID). Three patients lacking both mature T and B cells showed a twofold higher GM-CFU radiosensitivity calculated as the DO value (dose required to reduce survival to 37%), and an identical observation was made with fibroblasts from one of these patients. A patient with an SCID with hypereosinophilia, i.e., Omenn's syndrome characterized by extremely restricted T cell heterogeneity and a lack of B cells, also showed abnormal GM-CFU radiosensitivity. In contrast, GM-CFU from a patient lacking only T cells (X-linked form of SCID) showed normal GM-CFU radiosensitivity. These data further support the similarity between human T(-) B(-) SCID and the murine acid mutation characterized by a defect in T cell receptor and immunoglobulin gene rearrangement, and by an abnormal double-strand DNA break repair function. In addition, they strongly suggest that the Omenn's immunodeficiency syndrome may be a leaky T(-)B(-) SCID phenotype as previously indicated by the coexistence of the two phenotypes in siblings.

Bone Marrow↗

PubMed1993

An inbred line of transgenic mice expressing an internally deleted gene for type II procollagen (COL2A1). Young mice have a variable phenotype of a chondrodysplasia and older mice have osteoarthritic changes in joints.

Studies were carried out on a line of transgenic mice that expressed an internally deleted COL2A1 gene and developed a phenotype resembling human chondrodysplasias (Vandenberg et al. 1991. Proc. Natl. Acad. Sci. USA. 88:7640-7644. Marked differences in phenotype were observed with propagation of the mutated gene in an inbred strain of mice in that approximately 15% of the transgenic mice had a cleft palate and a lethal phenotype, whereas the remaining mice were difficult to distinguish from normal littermates. 1-d- and 3-mo-old transgenic mice that were viable showed microscopic signs of chondrodysplasia with reduced amounts of collagen fibrils in the cartilage matrix, dilatation of the rough surfaced endoplasmic reticulum in the chondrocytes, and decrease of optical path difference in polarized light microscopy. The transgenic mice also showed signs of disturbed growth as evidenced by lower body weight, lower length and weight of the femur, decreased bone collagen, decreased bone mineral, and decreased resistance of bone to breakage. Comparisons of mice ranging in age from 1 d to 15 mo demonstrated that there was decreasing evidence of a chondrodysplasia as the mice grew older. Instead, the most striking feature in the 15-mo-old mice were degenerative changes of articular cartilage similar to osteoarthritis.

Aging↗

PubMed1994

Autoimmune myocarditis induced in mice by cardiac C-protein. Cloning of complementary DNA encoding murine cardiac C-protein and partial characterization of the antigenic peptides.

Autoimmune myocarditis is considered to play a major role in the pathogenesis of dilated cardiomyopathy. A new autoimmune myocarditis model was attained by repeated immunization using murine cardiac C-protein with the immunological adjuvant, Klebsiella pneumoniae O3 lipopolysaccharide. For further analysis of a pathological epitope, the cDNA encoding C-protein was isolated; a fusion protein encoded by part of this cDNA induced myocarditis in SMA mice as well as in three other strains: DBA/1J (H-2q), O20/A (H-2pz1), and SJL (H-2s). The nucleotide sequence and its deduced amino acid analysis revealed that this protein had immunoglobulin-like and fibronectin-like repeats. This study provides a new animal model of autoimmune myocarditis which may shed light on the pathogenesis of dilated cardiomyopathy.

Adult↗

PubMed1995

Calcium-sensing receptor mutations in familial benign hypercalcemia and neonatal hyperparathyroidism.

Familial benign hypercalcemia (FBH) and neonatal hyperparathyroidism (NHPT) are disorders of calcium homeostasis that are associated with missense mutations of the calcium-sensing receptor (CaR). We have undertaken studies to characterize such CaR mutations in FBH and NHPT and to explore methods for their more rapid detection. Nine unrelated kindreds (39 affected, 32 unaffected members) with FBH and three unrelated children with sporadic NHPT were investigated for mutations in the 3,234-bp coding region of the CaR gene by DNA sequencing. Six novel heterozygous (one nonsense and five missense) mutations were identified in six of the nine FBH kindreds, and two de novo heterozygous missense mutations and one homozygous frame-shift mutation were identified in the three children with NHPT. Our results expand the phenotypes associated with CaR mutations to include sporadic NHPT. Single-stranded conformational polymorphism analysis was found to be a sensitive and specific mutational screening method that detected > 85% of these CaR gene mutations. The single-stranded conformational polymorphism identification of CaR mutations may help in the distinction of FBH from mild primary hyperparathyroidism which can be clinically difficult. Thus, the results of our study will help to supplement the clinical evaluation of some hypercalcemic patients and to elucidate further the structure-function relationships of the CaR.

Amino Acid Sequence↗

PubMed1995

A unique genetic and biochemical presentation of fish-eye disease.

This paper describes a novel genetic defect which causes fish-eye disease in four homozygous probands and its biochemical presentation in 34 heterozygous siblings. The male index patient presented with premature coronary artery disease, corneal opacification, HDL deficiency, and a near total loss of plasma lecithin:cholesterol acyltransferase (LCAT) activity. Sequencing of the LCAT gene revealed homozygosity for a novel missense mutation resulting in an Asp131 - Asn (N131D) substitution. Heterozygotes showed a highly significant reduction of HDL-cholesterol and apolipoprotein A-I levels as compared with controls which was associated with a specific decrease of LpA-I:A-II particles. Functional assessment of this mutation revealed loss of specific activity of recombinant LCAT(N131D) against proteoliposomes. Unlike other mutations causing fish-eye disease, recombinant LCAT(N131D) also showed a 75% reduction in specific activity against LDL. These unique biochemical characteristics reveal the heterogeneity of phenotypic expression of LCAT gene defects within a range specified by complete loss of LCAT activity and the specific loss of activity against HDL. The impact of this mutation on HDL levels and HDL subclass distribution may be related to the premature coronary artery disease observed in the male probands.

Aged↗

PubMed2003

Stereotactic radiosurgery associated neurotoxicity.

Stereotactic radiosurgery (SRS) is an evolving therapeutic modality for well demarcated intracranial lesions. Since the inception of stereotactic radiosurgery the types of parenchymal CNS lesions addressed by this mode of treatment has increased. All modern stereotactic radiosurgical procedures employ several common features. Patients are fitted with a stereotactic head frame or fiducial markers followed by radiographic imaging which allows for external reference points and three-dimensional mapping of the intracranial lesion. Armed with this information a highly conformal treatment plan is developed to deliver a high dose of radiation to a sharply defined target, with rapid dose fall-off outside the lesion volume. While an extremely effective therapeutic option, SRS is not without risk of neurotoxicity, with radiation necrosis being the most commonly recognized complication. The neurotoxic effects of SRS are reviewed and discussed.

Brain↗