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Biomedical subjects

Mary Frances McMullin

Publications and source records attributed to Mary Frances McMullin.

14 recordsLinked to original sources
PubMed2006

Oxygen sensing: recent insights from idiopathic erythrocytosis.

Idiopathic erythrocytosis (IE) is a rare condition in which there is an increase in red cell mass and hematocrit. As it is typically driven by elevated or inappropriately normal erythropoietin (Epo) levels, it has the potential to reveal the identities of proteins involved in the oxygen sensing pathway that regulates the transcription factor, Hypoxia Inducible Factor (HIF), and hence Epo production in humans. One example of this is provided by Chuvash polycythemia, a form of erythrocytosis due to a mutation in the von Hippel Lindau tumor suppressor protein (VHL), a component of an E3 ubiquitin ligase complex that targets hydroxylated HIF for degradation. A recent report of familial erythrocytosis now implicates a different protein, Prolyl Hydroxylase Domain protein 2 (PHD2), which is an enzyme that hydroxylates HIF.

Gene Expression Regulation↗
PubMed2006

A family with erythrocytosis establishes a role for prolyl hydroxylase domain protein 2 in oxygen homeostasis.

The number of red blood cells is normally tightly regulated by a classic homeostatic mechanism based on oxygen sensing in the kidney. Decreased oxygen delivery resulting from anemia induces the production of erythropoietin, which increases red cell production and hence oxygen delivery. Investigations of erythropoietin regulation identified the transcription factor hypoxia-inducible factor (HIF). HIF is now recognized as being a key regulator of genes that function in a comprehensive range of processes besides erythropoiesis, including energy metabolism and angiogenesis. HIF itself is regulated through the alpha-subunit, which is hydroxylated in the presence of oxygen by a family of three prolyl hydroxylase domain proteins (PHDs)/HIF prolyl hydroxylases/egg-laying-defective nine enzymes. Hydroxylation allows capture by the von Hippel-Lindau tumor suppressor gene product, ubiquitination, and destruction by the proteasome. Here we describe an inherited mutation in a mammalian PHD enzyme. We show that this mutation in PHD2 results in a marked decrease in enzyme activity and is associated with familial erythrocytosis, identifying a previously unrecognized cause of this condition. Our findings indicate that PHD2 is critical for normal regulation of HIF in humans.

Adult↗
PubMed2006

Genotyping of thiopurine methyltransferase in patients with acute leukemia using LightCycler PCR.

Patients with acute lymphoblastic leukemia (ALL) are treated with thiopurines. Thiopurine methyltransferase (TPMT) catalyses the S-methylation of thiopurines and is subject to genetic polymorphism. The TPMT genotype was determined in 55 patients with ALL. Three patients were heterozygous for allelic variants of TPMT. We describe an assay for the genotyping of the TPMT polymorphism using real-time fluorescence polymerase chain reaction (PCR) to facilitate rapid processing of samples. This strategy is superior to standard PCR-restriction fragment length polymorphism genotyping methods and provides informative data on TPMT polymorphisms in patients prior to treatment with thiopurines.

Acute Disease↗
PubMed2004

Glucose-6-phosphate dehydrogenase Guadalajara--a case of chronic non-spherocytic haemolytic anaemia responding to splenectomy and the role of splenectomy in this disorder.

Glucose-6-phosphate dehydrogenase (G6PD) is an enzyme of the pentose phosphate shunt pathway a major function of which is to prevent cellular oxidative damage. Deficiency in red blood cells is associated with a number of varied clinical manifestations. Chronic non-spherocytic haemolytic anaemia is uncommon but is usually characterized by chronic haemolysis, often with severe anaemia. In the past splenectomy in this condition has been thought to be of questionable benefit. We report a case of G6PD Guadalajara where splenectomy produced transfusion independence and have reviewed the literature. Those cases with exon 10 mutations often have a severe clinical phenotype, which responds to splenectomy. This procedure should be considered in this condition.

Anemia, Hemolytic, Congenital Nonspherocytic↗
PubMed2003

A common polymorphism in the oxygen-dependent degradation (ODD) domain of hypoxia inducible factor-1alpha (HIF-1alpha) does not impair Pro-564 hydroxylation.

BACKGROUND: The hypoxia-inducible factor (HIF) transcription complex, which is activated by low oxygen tension, controls a diverse range of cellular processes including angiogenesis and erythropoiesis. Under normoxic conditions, the alpha subunit of HIF is rapidly degraded in a manner dependent on hydroxylation of two conserved proline residues at positions 402 and 564 in HIF-1alpha in the oxygen-dependent degradation (ODD) domain. This allows subsequent recognition by the von Hippel-Lindau (VHL) tumor suppressor protein, which targets HIF for degradation by the ubiquitin-proteasome pathway. Under hypoxic conditions, prolyl hydroxylation of HIF is inhibited, allowing it to escape VHL-mediated degradation. The transcriptional regulation of the erythropoietin gene by HIF raises the possibility that HIF may play a role in disorders of erythropoiesis, such as idiopathic erythrocytosis (IE). RESULTS: Patients with IE were screened for changes in the HIF-1alpha coding sequence, and a change in the ODD domain that converts Pro-582 to Ser was identified in several patients. This same change, however, was also detected at a significant frequency, 0.073, in unaffected controls compared to 0.109 in the IE patient group. In vitro hydroxylation assays examining this amino acid change failed to reveal a discernible effect on HIF hydroxylation at Pro-564. CONCLUSION: The Pro582Ser change represents a common polymorphism of HIF-1alpha that does not impair HIF-1alpha prolyl hydroxylation. Although the Pro582Ser polymorphism is located in the ODD domain of HIF-1alpha it does not diminish the association of HIF-1alpha with VHL. Thus, it is unlikely that this polymorphism accounts for the erythrocytosis in the group of IE patients studied.

Binding Sites↗
PubMed2003

Chuvash-type congenital polycythemia in 4 families of Asian and Western European ancestry.

The Chuvash form of polycythemia is an autosomal recessive disorder common to a large number of families in central Russia. Affected individuals have been reported to be homozygous for an Arg200Trp mutation in the von Hippel-Lindau (VHL) gene. We have screened 78 patients with erythrocytosis and found 8 of Bangladeshi and Pakistani origin to be homozygous for the Arg200Trp mutation and another of English descent to be heterozygous. Of these patients, 5 have elevated serum erythropoietin (Epo) levels, while the other 4 have Epo values in the normal range. The heterozygous patient does not fulfill the Chuvash criterion for homozygosity of the Arg200Trp mutation and consequently may harbor a further, as yet uncharacterized, mutation. This mutation has a wider geographic distribution than originally presumed and haplotype analysis suggests a common origin of the Arg200Trp mutation in the 4 families, but it still remains to be established if it has arisen independently of the Chuvash population.

Asia↗
PubMed2003

Global down-regulation of HOX gene expression in PML-RARalpha + acute promyelocytic leukemia identified by small-array real-time PCR.

Acute promyelocytic leukemia (APL) is associated with a reciprocal and balanced translocation involving the retinoic acid receptor-alpha (RARalpha). All-trans retinoic acid (ATRA) is used to treat APL and is a potent morphogen that regulates HOX gene expression in embryogenesis and organogenesis. HOX genes are also involved in hematopoiesis and leukemogenesis. Thirty-nine mammalian HOX genes have been identified and classified into 13 paralogous groups clustered on 4 chromosomes. They encode a complex network of transcription regulatory proteins whose precise targets remain poorly understood. The overall function of the network appears to be dictated by gene dosage. To investigate the mechanisms involved in HOX gene regulation in hematopoiesis and leukemogenesis by precise measurement of individual HOX genes, a small-array real-time HOX (SMART-HOX) quantitative polymerase chain reaction (PCR) platform was designed and validated. Application of SMART-HOX to 16 APL bone marrow samples revealed a global down-regulation of 26 HOX genes compared with normal controls. HOX gene expression was also altered during differentiation induced by ATRA in the PML-RARalpha(+) NB4 cell line. PML-RARalpha fusion proteins have been reported to act as part of a repressor complex during myeloid cell differentiation, and a model linking HOX gene expression to this PML-RARalpha repressor complex is now proposed.

Bone Marrow↗
PubMed2003

Haemoglobin during pregnancy: relationship to erythropoietin and haematinic status.

OBJECTIVE: To investigate the effect of haematinic status on erythropoietin throughout pregnancy in order to assess whether haematinic supplementation is appropriate for all pregnant women or should be reserved for individuals in whom deficiency has been identified. METHODS: A prospective, repeated-measures, longitudinal study of 263 women enrolled at an antenatal clinic in a district general hospital who received standard obstetric management including haematinic supplements. Haematological indices, iron status, folate and B12 status, and erythropoietin levels were measured by standard methods at scheduled intervals throughout pregnancy. The relationships between the measurements were analysed using statistical models which took into account the serial correlation between repeated measurements on the same individuals. RESULTS: Erythropoietin levels rose throughout pregnancy from a mean of 22.8 mU/mL at booking to 43.7 mU/mL at 38 wk. There was a significant relationship between erythropoietin levels and haemoglobin, ferritin, TIBC and folate. The relationship was strongest between erythropoietin and haemoglobin. Erythropoietin levels were influenced by parity but not maternal age. CONCLUSION: Haematinic levels, particularly iron are related to the rise in serum EPO which occurs during pregnancy. Therefore, haematinic deficiency in pregnancy will result in increased stimulation of erythroid progenitor cells by erythropoietin. While haematinic supplementation is not always prescribed throughout pregnancy, haematinic status must be assessed on an individual basis and supplementation provided as required.

Adult↗
PubMed2002

Familial idiopathic methemoglobinemia revisited: original cases reveal 2 novel mutations in NADH-cytochrome b5 reductase.

In 1943, the first description of familial idiopathic methemoglobinemia in the United Kingdom was reported in 2 members of one family. Five years later, Quentin Gibson (then of Queen's University, Belfast, Ireland) correctly identified the pathway involved in the reduction of methemoglobin in the family, thereby describing the first hereditary trait involving a specific enzyme deficiency. Recessive congenital methemoglobinemia (RCM) is caused by a deficiency of reduced nicotinamide adenine dinucleotide (NADH)-cytochrome b5 reductase. One of the original propositi with the type 1 disorder has now been traced. He was found to be a compound heterozygote harboring 2 previously undescribed mutations in exon 9, a point mutation Gly873Ala predicting a Gly291Asp substitution, and a 3-bp in-frame deletion of codon 255 (GAG), predicting loss of glutamic acid. A brother and a surviving sister are heterozygous; each bears one of the mutations. Thirty-three different mutations have now been recorded for RCM. The original authors' optimism that RCM would provide material for future genetic studies has been amply justified.

Amino Acid Sequence↗
PubMedDate not supplied

The V617F JAK2 mutation and the myeloproliferative disorders.

The discovery this year of a single mutation in the Janus Kinase (JAK)-2 gene in a high percentage of cases of polycythaemia vera (PV), essential thrombocythaemia (ET) and myelofibrosis suggests that it maybe the underlying molecular mechanism for these disorders. Different approaches from the inhibition of the tyrosine kinase JAK2, widespread search for mutations in tyrosine kinases, and investigation of the short arm of chromosome 9 where JAK2 is located all led to the discovery of the V617F JAK2 mutation. Substitution of a valine for a phenylalanine destabilizes the JH2 domain of JAK2 causes loss of the auto-inhibitory activity of this domain and explains some of the biological phenomena observed in patients with myeloproliferative disorders (MPD). The V617F JAK2 mutation can be detected by PCR-direct sequencing using DNA from the granulocyte lineage or with increased sensitivity by the amplification refractory mutation system using DNA from unfractionated blood. Pyrosequencing assays can be used to quantitate allele ratios to accurately define homozygote and heterozygote status. This single mutation is widespread having been detected in related MPD and other haematological malignancies. This leads to a number of further questions about the role of this single mutation in the clinical pattern of disease.

Alleles↗