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M C Driscoll

Publications and source records attributed to M C Driscoll.

18 recordsLinked to original sources
PubMed2001

Polymorphisms within the angiotensinogen gene (GT-repeat) and the risk of stroke in pediatric patients with sickle cell disease: a case-control study.

Stroke is one of the most devastating complications of patients with sickle cell disease (SCD). Currently, there are no known molecular or genetic markers that can be used to assess the risk of stroke in this population. We have previously shown that relative hypertension may be one risk factor for stroke in SCD. In a case-control study, we investigated the association between GT-repeat polymorphism within the angiotensinogen (AGT) gene and the risk of stroke in pediatric patients with SCD. After informed consent was obtained, 63 patients (21 stroke subjects and 42 nonstroke control subjects matched according to age and sex) with SCD followed at local pediatric hematology clinics were genotyped to test the association of specific GT-repeat alleles of the AGT gene and occurrence of stroke. There were statistical differences in the distribution of the genotypes among stroke and nonstroke SCD patients (chi(2) = 10.82, df = 11, P < 0.05). We also found GT-repeat alleles A3 and/or A4 of the AGT gene conferred a four-fold increase in the risk of stroke (odds ratio [OR] = 4, P < 0.05). The attributable odds ratio for allele A3 and A4 is 2.24 and 4.33, respectively (P < 0.005). Our results suggest that GT-repeat within the AGT gene may be associated with risk of stroke in pediatric SCD. The relative risk of stroke in the presence of alleles A3 and/or A4 is fourfold greater than in the absence of these alleles. If these data are substantiated in a larger cohort of patients, our results indicate that the determination of GT-repeat of AGT gene may be a useful genetic marker to assess the risk for stroke of patients with SCD. Am. J. Hematol. 68:164-169, 2001. Published 2001 Wiley-Liss, Inc.

Adolescent↗
PubMed1999

Coagulation abnormalities in the carbohydrate-deficient glycoprotein syndrome: case report and review of the literature.

The carbohydrate-deficient glycoprotein syndromes are a group of recently described autosomal recessive, metabolic defects affecting multiple systems. The disorder is caused by inefficient posttranslational glycosylation of glycoproteins. Patients with the syndrome present early in life with psychomotor retardation, seizures, hypotonia, and stroke-like episodes. They also have dysmorphic features including almond-shaped eyes, constant squint, inverted nipples, and buttock fat pads. One of the features of the syndrome is coagulopathy, and we report here a patient who presented with a prolonged activated partial thromboplastin time, and was subsequently diagnosed with the carbohydrate-deficient glycoprotein syndrome. We also summarize the results of five previously published studies of the coagulation system in these patients. Most of the reported patients are deficient in factor XI, protein C, antithrombin III, and protein S. Other coagulation proteins are less frequently affected. Both bleeding and thrombosis have been observed, yet the cause of the stroke-like episodes remains speculative. The carbohydrate-deficient glycoprotein syndrome is an increasingly recognized multisystem disorder affecting hemostasis, and thus will involve clinical hematologists as part of a multidisciplinary team caring for patients with the syndrome.

Blood Coagulation Disorders↗
PubMed1996

Heteroduplex analysis in hemophilia B: detection of two novel factor IX gene mutations.

Heteroduplex analysis of polymerase chain reaction (PCR)-amplified factor IX (FIX) sequences in eight hemophilia B pedigrees localized the causative hemophilia mutation to a single exon in each case. Subsequent PCR-based direct DNA sequence analysis identified two novel FIX mutations and six recurrent mutations. Three of the eight pedigrees represent sporadic hemophilia B, and direct mutation analysis facilitated hemophilia carrier diagnosis in each case.

DNA Mutational Analysis↗
PubMed1990

A deletion of the human beta-globin locus activation region causes a major alteration in chromatin structure and replication across the entire beta-globin locus.

Naturally occurring deletions that remove sequences located approximately 60 kb upstream of the human adult beta-globin gene result in the failure to transcriptionally activate the cis-linked globin genes in erythroid cells. In addition, transfection, transgenic, and somatic cell hybrid studies have revealed that sequences within this region are essential for the developmentally regulated high-level expression of cis-linked globin genes. This regulatory region located at the 5' end of the beta-globin locus has been termed the locus activation region (LAR). Using somatic cell hybrids, we have studied the chromatin structure and timing of DNA replication of the normal human beta-globin locus and a locus containing a de novo 25-kb deletion that removes elements of the LAR. As a result of this deletion, the entire beta-globin locus and sequences approximately 100 kb 5' and 3' of the adult beta-globin gene are DNase I-resistant and do not form characteristic distant hypersensitive sites. These sequences also replicate late in S phase in an erythroid cell background. In contrast, the sequences of the normal locus are DNase I sensitive and early replicating. These results suggest that the LAR is required for both the erythroid-specific chromatin structure and timing of DNA replication over a large physical distance.

Chromatin↗
PubMed1989

A codon 338 nonsense mutation in the factor IX gene in unrelated hemophilia B patients: factor IX338 New York.

Hemophilia B is an X-linked recessive bleeding disorder resulting from a deficiency of the coagulation factor IX (FIX) protein activity, a vitamin K-dependent serine protease active in both the intrinsic and extrinsic coagulation systems. DNA analyses of the factor IX gene in two unrelated patients with severe hemophilia B, with a IX coagulant activity less than 1% and undetectable FIX antigen, detected the loss of the second TaqI site in exon h (VIII) in both individuals. Polymerase chain reaction (PCR) amplification of 576 base pairs of exon h (VIII) with cloning and dideoxy sequencing of cloned DNA from one hemophiliac revealed a single C----T transition in codon 338 that changes an arginine residue codon CGA to a nonsense codon TGA. Allele-specific oligonucleotide probe hybridization with a mutant (C----T) and a wild-type allele confirmed the same mutation in amplified genomic DNA of the second hemophilia patient. The C----T transition represents another example of mutation at a CpG dinucleotide. DNA polymorphism analysis of the FIX gene in both individuals revealed each to be on a separate FIX haplotype; therefore, predicting each to be a separate mutation event.

Amino Acid Sequence↗
PubMed1989

Gamma delta beta-thalassemia due to a de novo mutation deleting the 5' beta-globin gene activation-region hypersensitive sites.

gamma delta beta-Thalassemia is a rare disorder of hemoglobin biosynthesis, characterized molecularly by partial or complete deletions of the beta-globin gene complex of 100 kilobases (kb) or greater. Common to all mutants described has been the deletion of the most-5' sequences of the beta-globin complex. We have used the techniques of pulsed-field gel electrophoresis and polymerase chain reaction to study a patient with a clinical gamma delta beta-thalassemia phenotype. This subject developed a de novo deletion on a maternally inherited beta-globin gene chromosome involving approximately 30 kb of sequences 5' to the epsilon gene; the deletion extends from -9.5 kb to -39 kb 5' of epsilon and includes three of the four DNase I hypersensitive sites (at -10.9 kb, -14.7 kb, and -18 kb 5' of epsilon). The remaining sequences of the beta-globin complex, including the DNase I hypersensitive sites at -6.1 kb and all structural genes in cis to the deletion are physically intact, but presumably nonfunctional, as evidenced by the presence of a beta S-globin gene that is not expressed as a sickle hemoglobin. Deletion of DNase I hypersensitive sites on a previously functional beta-globin gene complex confirms the significance of these sites in regulating globin gene expression.

Base Sequence↗
PubMed1988

A second BamHI DNA polymorphism and haplotype association in the factor IX gene.

A second BamHI DNA polymorphism has been identified in the factor IX gene in an American black population at an allelic frequency of 0.13. This site has been localized within 500 basepairs (bp) 5' to the XmnI intron 3 polymorphic site and increases the heterozygosity of black females at the factor IX gene locus. In addition, haplotype analysis of factor IX genes at five polymorphic loci indicates that although there is conservation of sequences between the races, factor IX genes show more heterogeneity in an American black population and thus more heterozygosity is observed in black females compared with whites. This increased heterogeneity is due to DNA polymorphisms unique to black populations and to linkage equilibrium between the most 5' and 3' polymorphic sites in factor IX genes in blacks.

Alleles↗
PubMed1987

Prenatal diagnosis of sickle hemoglobinopathies: the experience of the Columbia University Comprehensive Center for Sickle Cell Disease.

We report here an evaluation of 55 pregnancies at risk for a sickle hemoglobinopathy prenatally diagnosed by restriction-endonuclease analysis, with the endonucleases MstII and HpaI, of amniocyte DNA. The diagnosis was completed in all cases. Eleven fetuses were predicted to be affected, of which six were terminated. Forty-one of the 55 cases were confirmed. One false-negative was reported in a case predicted to be hemoglobin AS but that was determined to be hemoglobin SS at birth. We estimate that the 55 cases represent only 5% of the pregnancies at risk for a sickle hemoglobinopathy in the New York metropolitan area during the study period. We conclude that the prenatal diagnosis of sickle hemoglobinopathies by molecular methods is reliable. However, the efficiency of utilization and effectiveness of prenatal testing is dependent on the early prospective identification of couples at risk and on the education of communities concerning the significant morbidity of the sickle hemoglobinopathies and the reproductive choices now available to them.

Anemia, Sickle Cell↗
PubMed1985

Structure and expression of two beta genes in a beta thalassemia homozygote.

Two beta globin gene alleles have been cloned and characterized from a patient with beta + thalassemia. Both beta genes have single base mutations in the small intervening sequence (IVS 1); one 6 nucleotides and the other 110 nucleotides from the 5' end of IVS 1. Both genes lead to abnormal splicing of beta globin mRNA precursors when expressed in HeLa cells. Despite the fact that both alleles produce some normal beta globin mRNA transcripts, the patient has clinically severe beta + thalassemia (Cooley's anemia).

Base Sequence↗
PubMed1984

Gene analysis in delta beta and delta (0) thalassemia.

Restriction mapping of the globin genes from a homozygous delta beta thalassemia patient from Israel indicates that at least a 10-kilobase deletion is present extending 3' from within the large intervening sequence (IVS 2) of the delta globin gene and including the entire beta globin gene. Unique bands are seen when cellular DNA from this patient is digested with a variety of restriction endonucleases and hybridized with a probe specific for the delta IVS 2. Extensive analysis of the Israeli delta beta thalassemia DNA as well as material from an Italian delta beta thalassemia homozygote with enzymes which cleave more frequently in delta IVS 2 has localized the 5' end of the deletion to a 107-base pair region within delta IVS 2. This region contains a unique repetitive sequence (TG)4 which has been reported to be a specific recognition signal for recombination and may be involved in the formation of these mutant genes. Two homozygous delta(0) thalassemia DNA samples from Japan were also analyzed for gene rearrangements or other changes by restriction enzyme mapping. No changes from normal were seen using 14 different enzymes indicating the absence of large deletions in the region around the delta globin gene. More specifically, both the 5' and 3' splice junctions of the IVS 2 appear to be normal from hybridization of restriction fragments generated by HphI and AluI, respectively, with a delta IVS 2 specific probe. We have also shown that point mutations which could lead to termination codons are not present at codons 35, 37, 43, 61, and 121, since restriction enzymes which recognize these sites produce normal patterns. The delta(0) thalassemia phenotype in these two subjects is most likely due to a point mutation either at one of the other 24 potential termination codons not accessible to restriction analysis or to other single nucleotide changes which could either decrease delta globin gene transcription or lead to abnormal processing or transport of delta globin mRNA.

Base Sequence↗
PubMed1984

Hemoglobin Miyada: DNA analysis of the anti-Lepore beta delta fusion gene.

Hemoglobin Miyada, an anti-Lepore hemoglobin, represents the protein product of a nonhomologous crossover between beta and delta genes. The mutant globin is beta-like from the N terminus to amino acid 12, and delta-like from amino acid 22 through the C terminus, thus predicting a crossover site in the first coding region of the gene. DNA analysis, using multiple restriction endonucleases and hybridization to delta and beta globin gene-specific probes, confirms that the beta delta hybrid gene 1) is located on a single chromosomal fragment between normal delta and beta genes, and 2) has 5' beta promoter sequences, delta IVS 1 and 2, and 3' coding and flanking sequences.

Base Sequence↗
PubMed1981

A new polymorphism in the human beta-globin gene useful in antenatal diagnosis.

A new polymorphism in the beta-globin is described, using the restriction enzyme Asu I. A radioactive probe specifically representing the large intervening sequence (IVS 2) of the beta-globin gene has been used to detect this polymorphism. Normally, a 0.8-kilobase fragment containing beta-IVS 2 is generated by Asu I; however, a 1.0-kilobase fragment is seen in association with 18% of beta A-genes, and 38% of beta-thalassemia genes in an Israeli population studied. By contrast, the Asu I polymorphism has rarely been seen in blacks examined to date. An additional Asu I change is seen the the delta-globin gene with a delta-IVS probe. The beta-Asu I polymorphism is shown to be useful in the antenatal diagnosis of beta-thalassemia.

Base Sequence↗
PubMed1975

Creative technological aids for the learning-disabled child: an interdisciplinary project.

An interdisciplinary team of engineering students and occupational therapists have developed prototype electromechanical toys to enhance adaptive learning performance of developmentally disabled children. This paper describes the Creative Technological Aids (CTA) project undertaken under the joint auspices of the Undergraduate Research Opportunities Program (UROP) of the Massachusetts Institute of Technology and the Kennedy Memorial Hospital occupational therapy department. Four prototype CTA devices were evaluated in clinical and community settings and preliminary results show that these devices are highly motivational in teaching eye-hand coordination and perceptual-motor skills.

Cerebral Palsy↗
PubMedDate not supplied

Polymerase chain reaction detection of the Dde I polymorphism in the factor 9 gene for fragile X linkage analysis.

We have used the polymerase chain reaction (PCR) to analyze the 50 base pair (bp) insertion/deletion polymorphism in the coagulation factor 9 gene. This procedure is particularly applicable for DNA marker studies in fragile X families. The polymorphism, which can also be detected in Dde I digestions, was detected by the amplification of fragments of 298 and 348 bp. The alleles were distinguished directly by agarose gel electrophoresis. PCR detection of this polymorphism is much simpler, more accurate, and quicker than conventional analysis.

Alleles↗