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Biomedical subjects

J D McDonald

Publications and source records attributed to J D McDonald.

At least 19 recordsLinked to original sources
PubMed1996

Tumor suppressor genes and medulloblastoma.

Although primary intracranial neoplasms are the most common type of solid cancer in children, little is known about their etiology at the molecular genetic level. Recently, studies have shown that a class of genes known as tumor suppressors play an important role in the origin of several different types of human tumors, including those located in the central nervous system (CNS). Using a variety of techniques, selective loss of DNA sequences has been identified in tissue specimens from children with medulloblastoma, one of the most common pediatric brain tumors. The most consistent losses to date have been shown for probes located on distal chromosome arm 17p. Although the known tumor suppressor p53 is located on this chromosome, and deletion and mutation of the p53 gene are the most common genetic events in human cancers of many types, such alterations have been infrequently detected in medulloblastoma specimens. These results suggest that inactivation of another tumor suppressor gene or genes located on 17p is important in medulloblastoma tumorigenesis. Deletion of 17p has also been shown to have implications for clinical management, as the loss of DNA sequences located on this chromosome arm is strongly associated with a negative prognosis for these patients. The identification and cloning of this tumor suppressor gene or genes will aid in understanding of the pathogenesis of medulloblastoma, as well as guiding the development of novel and more effective strategies for a cure.

Cerebellar Neoplasms↗
PubMed1995

Using high-efficiency mouse germline mutagenesis to investigate complex biological phenomena: genetic diseases, behavior, and development.

A valuable approach to investigating a biological process is to study the effect of mutations in the involved genes. By studying a diverse set of such mutations, one can gain important insights into the roles that the given gene product plays in the biological process. Although this approach has long been recognized, the scarcity of mammalian mutations has largely limited such investigations to simple organisms. It has recently been shown that highly efficient mutagenesis of the mouse germline with a random point mutagen can produce mutations that are valuable in several important ways. First, it can produce numerous different types of mutations. Second, it can be used to mutate genes that have yet to be cloned or characterized. Genes that have been marked by mutation can ultimately yield molecular access after mapping to high resolution and cloning from map position. Such new investigative capabilities will ultimately allow one to gain intimate knowledge of the molecular basis of complex biological processes like behavior and development. Third, mutations can be induced that yield animal models of human heritable diseases. Such disease models allow for intensive research into the etiology of the given disease and also permit the facile evaluation of new therapeutic regimens.

Animals↗
PubMed1994

Molecular characterization of HPH-1: a mouse mutant deficient in GTP cyclohydrolase I activity.

GTP cyclohydrolase I catalyzes the initial and rate limiting step of the biosynthesis of tetrahydrobiopterin, the cofactor for aromatic amino acid hydroxylation. The mouse mutant HPH-1, previously generated by chemical mutagenesis, shows a phenylketonuria due to decreased hepatic GTP cyclohydrolase I activity. We show that both parameters GTP cyclohydrolase I activity and tetrahydrobiopterin synthesis significantly increase after weaning, but remain reduced during the lifetime. In the wild type mouse (C57BL/6), interferon-gamma and kit ligand induce GTP cyclohydrolase I activity in primed T-cells and in bone marrow-derived mast cells, respectively. The same is true for the HPH-1 mutant, but the absolute values remain lower throughout. The open reading frame of GTP cyclohydrolase I is not affected by the hph-1 mutation as shown by sequencing. Northern blot analysis demonstrates a marked decrease in the steady state mRNA level specific for GTP cyclohydrolase I.

Animals↗
PubMed1994

Physical mapping of chromosome 17p13.3 in the region of a putative tumor suppressor gene important in medulloblastoma.

Deletion mapping of a medulloblastoma tumor panel revealed loss of distal chromosome 17p13.3 sequences in tumors from 14 of 32 patients (44%). Of the 14 tumors showing loss of heterozygosity by restriction fragment length polymorphism analysis, 14 of 14 (100%) displayed loss of the telomeric marker p144-D6 (D17S34), while a probe for the ABR gene on 17p13.3 was lost in 7 of 8 (88%) informative cases. Using pulsed-field gel electrophoresis, we localized the polymorphic marker (VNTR-A) of the ABR gene locus to within 220 kb of the p144-D6 locus. A cosmid contig constructed in this region was used to demonstrate by fluorescence in situ hybridization that the ABR gene is oriented transcriptionally 5' to 3' toward the telomere. This report provides new physical mapping data for the ABR gene, which has not been previously shown to be deleted in medulloblastoma. These results provide further evidence for the existence of a second tumor suppressor gene distinct from p53 on distal chromosome 17p.

Central Nervous System Neoplasms↗
PubMed1994

Mutagenesis and mapping of a mouse gene, Clock, essential for circadian behavior.

In a search for genes that regulate circadian rhythms in mammals, the progeny of mice treated with N-ethyl-N-nitrosourea (ENU) were screened for circadian clock mutations. A semidominant mutation, Clock, that lengthens circadian period and abolishes persistence of rhythmicity was identified. Clock segregated as a single gene that mapped to the midportion of mouse chromosome 5, a region syntenic to human chromosome 4. The power of ENU mutagenesis combined with the ability to clone murine genes by map position provides a generally applicable approach to study complex behavior in mammals.

Animals↗
PubMed1994

The PKU mouse project: its history, potential and implications.

To produce genetic-based animal models for the human disease phenylketonuria (PKU), we treated mice with the powerful germline mutagen ethylnitrosourea and screened the progeny of these animals for the symptom hyperphenylalaninemia (HPH). Six independent mutant strains have been produced to date that exhibit heritable HPH. The first mutation isolated was found to cause a reduced level of GTP-cyclohydrolase I activity and, as such, yields a model for tetrahydrobiopterin-dependent HPH. The next two mutations have yet to be fully characterized but cause syndromes that appear distinct from any PKU or HPH syndromes yet reported for humans and they are allelic. Next we isolated a mutation that caused a marked reduction in hepatic phenylalanine hydroxylase activity levels. The enzyme deficiency was not sufficient to cause a PKU syndrome but instead produced a mild HPH syndrome. This strain played an instrumental role, however, in the identification of two additional mutant strains that appear to model human PKU very accurately in the laboratory mouse. These latter strains have levels of HPH very similar to human PKU patients, exhibit a phenylalanine-dependent hypopigmentation, and have reproductive difficulties that resemble human maternal PKU.

Animals↗
PubMed1993

Mouse models of human phenylketonuria.

Phenylketonuria (PKU) results from a deficiency in phenylalanine hydroxylase, the enzyme catalyzing the conversion of phenylalanine (PHE) to tyrosine. Although this inborn error of metabolism was among the first in humans to be understood biochemically and genetically, little is known of the mechanism(s) involved in the pathology of PKU. We have combined mouse germline mutagenesis with screens for hyperphenylalaninemia to isolate three mutants deficient in phenylalanine hydroxylase (PAH) activity and cross-reactive protein. Two of these have reduced PAH mRNA and display characteristics of untreated human PKU patients. A low PHE diet partially reverses these abnormalities. Our success in using high frequency random germline point mutagenesis to obtain appropriate disease models illustrates how such mutagenesis can complement the emergent power of targeted mutagenesis in the mouse. The mutants now can be used as models in studying both maternal PKU and somatic gene therapy.

Animals↗
PubMed1991

Infants and atropine: a dangerous mixture.

Colic in infants is a common but short-lived problem. Many different theories and treatment for this distressing ailment have been tried over the years, yet the definitive cure remains elusive. Although the risks associated with the use of atropine and its derivatives are well known, they are still prescribed by some in the management of colic. We report a case of serious side effects from the treatment of colic with an atropine containing mixture, in which an error in preparation was identified. In view of the potential for serious toxicity resulting from either inappropriate prescription, preparation or administration, alternative methods of treatment should be employed.

Atropine↗
PubMed1990

Pahhph-5: a mouse mutant deficient in phenylalanine hydroxylase.

Mutant mice exhibiting heritable hyperphenylalaninemia have been isolated after ethylnitrosourea mutagenesis of the germ line. We describe one mutant pedigree in which phenylalanine hydroxylase activity is severely deficient in homozygotes and reduced in heterozygotes while other biochemical components of phenylalanine catabolism are normal. In homozygotes, injection of phenylalanine causes severe hyperphenylalaninemia and urinary excretion of phenylketones but not hypertyrosinemia. Severe chronic hyperphenylalaninemia can be produced when mutant homozygotes are given phenylalanine in their drinking water. Genetic mapping has localized the mutation to murine chromosome 10 at or near the Pah locus, the structural gene for phenylalanine hydroxylase. This mutant provides a useful genetic animal model affected in the same enzyme as in human phenylketonuria.

Animals↗
PubMed1989

Familial Mediterranean fever in six Australian children.

Six Australian children fulfilled the diagnostic criteria for familial Mediterranean fever. None had a family history of the disease, but five children came from ethnic groups that typically were associated with the disease. The symptoms commenced before five years of age in all the children, and three children underwent unnecessary operations because of the symptoms of recurrent fever and abdominal pain. All six children benefited from colchicine prophylaxis by mouth. More cases can be expected to be recognized in Australia because of the large number of Australian children with a Mediterranean heritage.

Australia↗
PubMed1988

hph-1: a mouse mutant with hereditary hyperphenylalaninemia induced by ethylnitrosourea mutagenesis.

Ethylnitrosourea mutagenesis of spermatogonial stem cells and a three-generation breeding scheme were used to screen for recessive mutations that cause defects in phenylalanine metabolism leading to elevated serum levels of this amino acid. This paper describes the isolation of such a mutation, hph-1, causing a heritable hyperphenylalaninemia in the neonate and weanling and an inability to effectively clear a phenylalanine challenge in the adult. Micro-pedigree analysis of the original mutant mouse and data obtained from crosses of affected and unaffected animals indicate that the mutation segregates in an autosomal recessive manner. An interspecies mouse backcross mapping experiment places the mutant gene locus on mouse chromosome 14 very near Np-1 and a backcross experiment with a conventional inbred mouse strain involving a nearby locus confirms the chromosome 14 assignment. The initial symptomatology of the mutant phenotype suggests this mutant may represent a useful animal model for the study of hyperphenylalaninemia in man.

Amino Acid Metabolism, Inborn Errors↗
PubMed1988

Biochemical defect of the hph-1 mouse mutant is a deficiency in GTP-cyclohydrolase activity.

A hyperphenylalaninemic mouse mutant, hph-1, has been identified in the progeny of mice treated with the mutagen ethylnitrosourea. Phenylalanine hydroxylase activity levels in mutant liver lysates are reduced relative to normal, but correction for the amount of enzyme protein present demonstrates that the specific activity of this enzyme is normal in mutant mice. Quinonoid-dihydropteridine reductase activity is also normal. GTP-cyclohydrolase activity levels are essentially absent early in life and greatly diminished later in life. This finding has significant implications for the study of catecholamine neurotransmitter synthesis because GTP-cyclohydrolase catalyzes an important step in the de novo synthesis of tetrahydrobiopterin, an enzyme cofactor required for the synthesis of 3,4-dihydroxyphenylalanine (DOPA) and serotonin.

Aminohydrolases↗
PubMed1988

Hyperphenylalaninemia in the hph-1 mouse mutant.

A mutation, resulting in a deficiency of liver GTP-cyclohydrolase activity, has been induced in the laboratory mouse. Mice homozygous for this mutation exhibit hyperphenylalaninemia under the following conditions: 1) early in life and 2) throughout life when exposed to phenylalanine. A phenylalanine loading regimen was used to discriminate between mutant and wild type mice on the basis of the resultant phenylalanine and tyrosine serum levels. Subjecting mice to this regimen reveals several distinguishing characteristics. Mutant mice exhibit approximately 2-fold higher peak phenylalanine levels than wild-type mice. In wild-type mice the hyperphenylalaninemic state is transient and rapidly abates while in mutant mice it is persistent and remains for a prolonged period. Mutant mice exhibit normal serum tyrosine levels after a loading challenge, while wild-type mice experience an increase in tyrosine levels. The loading regimen was also used to gauge the response of mutant hyperphenylalaninemic mice to exposure to chemical compounds required for normal phenylalanine catabolism (i.e. pteridine cofactors of the phenylalanine hydroxylase reaction). Mutant mice exposed to native enzyme cofactor or cofactor precursors exhibit a sharp decline in serum phenylalanine levels relative to their uninjected counterparts coupled with a tyrosine increase. By contrast, mutant mice exposed to nonprecursor compounds that are structurally related to the native cofactor, experience no diminution of serum phenylalanine levels.

Aminohydrolases↗
PubMed1988

Molecular biology of brain tumors.

Through the technical advances in molecular biology during the past decade, important new insights into the fundamental chromosomal changes associated with brain tumors have been gained. The pace of such research is accelerating, and most of the published reports have appeared outside the neurosurgical literature. Furthermore, many neurosurgeons may not be sufficiently familiar with the terminology and techniques involved to remain abreast of the field. In this review, we discuss through specific examples of recent work on brain tumors the basic techniques of molecular biology, including the Southern and Northern blots, restriction enzyme digestion of DNA, molecular cloning of genes, and mapping of chromosomal deletions. Gene amplification and rearrangements are discussed through review of recent work on the N-myc gene in neuroblastoma and the epidermal growth factor receptor (EGFR) gene in glioblastoma. The molecular cloning of the gli gene from a glioblastoma illustrates the powerful analytic nature of these laboratory techniques and the investigative potential of a cloned gene. The concept of the "recessive oncogene" is discussed through a summary of recent work analyzing restriction fragment length polymorphisms (RFLPs) in families of patients with meningioma, acoustic neurinoma, and bilateral acoustic neurofibromatosis (BANF; NF-2). Throughout this article, emphasis is placed on ways in which molecular biology may soon affect clinical practice.

Brain Neoplasms↗
PubMed1986

Cloning, sequencing, and evolutionary analysis of the mouse erythropoietin gene.

The gene for mouse erythropoietin was cloned and sequenced. We present here a preliminary analysis of the overall genomic organization of the coding portions and the two flanking regions of the gene. This is the third mammalian erythropoietin for which the sequence is available, but it represents the first from a nonprimate species. We investigated the evolutionary divergence of sequence and structure of the three erythropoietins and identified specific regions of the molecules that are apparently under various degrees, and perhaps different types, of functional constraint.

Amino Acid Sequence↗
PubMed1983

Model emulates human smooth pursuit system producing zero-latency target tracking.

Humans can overcome the 150 ms time delay of the smooth pursuit eye movement system and track smoothly moving visual targets with zero-latency. Our target-selective adaptive control model can also overcome an inherent time delay and produce zero-latency tracking. No other model or man-made system can do this. Our model is physically realizable and physiologically realistic. The technique used in our model should be useful for analyzing other time-delay systems, such as man-machine systems and robots.

Bionics↗
PubMed1983

Smooth pursuit eye movements in response to predictable target motions.

The human smooth pursuit eye movement system has a latency of about 150 msec. However, this study shows that humans can learn to perform zero-latency tracking of targets that move with continuous velocity and amplitude-limited acceleration. Superposition of eye velocity and target velocity records, for our unique target waveforms, demonstrated that the subject was using the correct waveform and not just approximating it with a sinusoid or some other simple waveform. Calculation of the mean square error between target and eye position gave a quantitative measure of how well the human can track. The mean square error between target and eye position was 0.32 deg2 for one thousand seconds of steady-state tracking by seven subjects. For several cycles at a time all subjects were able to reduce this error to less than 0.1 deg2.

Adult↗