Overview

My research program involves molecular biological approaches to studying inherited metabolic disorders. My overall aim has been to identify and characterize causative mutations and their application to diagnosis, to examine the diverse consequences of missense mutations, and to determine the potential for pharmacological intervention with small molecule chemical chaperones.

Publications

SNP Variants in RET and PAX2 and Their Possible Contribution to the Primary Hyperoxaluria Type 1 Phenotype
Biochemical Genetics
Marion B. Coulter-Mackie
DOI: 10.1007/s10528-015-9667-z
04/2015

Overexpression of recombinant human antiquitin in E. coli: Partial enzyme activity in selected ALDH7A1 missense mutations associated with pyridoxine-dependent epilepsy
Molecular Genetics and Metabolism
Marion B. Coulter-Mackie and Sylvia Tiebout and Clara van Karnebeek and Sylvia Stockler
DOI: 10.1016/j.ymgme.2014.02.010
04/2014

Mitochondrial Carbonic Anhydrase VA Deficiency Resulting from CA5A Alterations Presents with Hyperammonemia in Early Childhood
The American Journal of Human Genetics
Clara D. van Karnebeek and William S. Sly and Colin J. Ross and Ramona Salvarinova and Joy Yaplito-Lee and Saikat Santra and Casper Shyr and Gabriella A. Horvath and Patrice Eydoux and Anna M. Lehman and Virginie Bernard and Theresa Newlove and Henry Ukpeh and Anupam Chakrapani and Mary Anne Preece and Sarah Ball and James Pitt and Hilary D. Vallance and Marion Coulter-Mackie and Hien Nguyen and Lin-Hua Zhang and Amit P. Bhavsar and Graham Sinclair and Abdul Waheed and Wyeth W. Wasserman and Sylvia Stockler-Ipsiroglu
DOI: 10.1016/j.ajhg.2014.01.006
03/2014

Overexpression of human antiquitin in E. coli: Enzymatic characterization of twelve ALDH7A1 missense mutations associated with pyridoxine-dependent epilepsy
Molecular Genetics and Metabolism
Marion B. Coulter-Mackie and Ailin Li and Qun Lian and Eduard Struys and Sylvia Stockler and Paula J. Waters
DOI: 10.1016/j.ymgme.2012.06.008
08/2012

Variability of Phenotype in Two Sisters with Pyridoxine Dependent Epilepsy
The Canadian Journal of Neurological Sciences
Majid Alfadhel and Sandra Sirrs and Paula J. Waters and András Szeitz and Eduard Struys and Marion Coulter-Mackie and Sylvia Stockler-Ipsiroglu
DOI: 10.1017/s0317167100014050
07/2012

Profound Neonatal Hypoglycemia and Lactic Acidosis Caused by Pyridoxine-Dependent Epilepsy
PEDIATRICS
S. Mercimek-Mahmutoglu and G. A. Horvath and M. Coulter-Mackie and T. Nelson and P. J. Waters and M. Sargent and E. Struys and C. Jakobs and S. Stockler-Ipsiroglu and M. B. Connolly
DOI: 10.1542/peds.2011-0123
04/2012

Hemiplegic migraine, seizures, progressive spastic paraparesis, mood disorder, and coma in siblings with low systemic serotonin
Cephalalgia
Gabriella A Horvath and Kathryn Selby and Ken Poskitt and Keith Hyland and Paula J Waters and Marion Coulter-Mackie and Sylvia G Stockler-Ipsiroglu
DOI: 10.1177/0333102411420584
10/2011

Pyridoxine dependent epilepsy and antiquitin deficiency
Molecular Genetics and Metabolism
Sylvia Stockler and Barbara Plecko and Sidney M. Gospe and Marion Coulter-Mackie and Mary Connolly and Clara van Karnebeek and Saadet Mercimek-Mahmutoglu and Hans Hartmann and Gunter Scharer and Eduard Struijs and Ingrid Tein and Cornelis Jakobs and Peter Clayton and Johan L.K. Van Hove
DOI: 10.1016/j.ymgme.2011.05.014
09/2011

Late-onset nonketotic hyperglycinemia caused by a novel homozygous missense mutation in the GLDC gene
Molecular Genetics and Metabolism
Catherine Brunel-Guitton and Brett Casey and Marion Coulter-Mackie and Hilary Vallance and Deborah Hewes and Sylvia Stockler-Ipsiroglu and Saadet Mercimek-Mahmutoglu
DOI: 10.1016/j.ymgme.2011.02.009
06/2011

Primary hyperoxaluria type 1: update and additional mutation analysis of theAGXTgene
Human Mutation
Emma L. Williams and Cecile Acquaviva and Antonio Amoroso and Francoise Chevalier and Marion Coulter-Mackie and Carla G. Monico and Daniela Giachino and Tricia Owen and Angela Robbiano and Eduardo Salido and Hans Waterham and Gill Rumsby
DOI: 10.1002/humu.21021
06/2009

Partial trypsin digestion as an indicator of mis-folding of mutant alanine:glyoxylate aminotransferase and chaperone effects of specific ligands. Study of a spectrum of missense mutants
Molecular Genetics and Metabolism
M.B. Coulter-Mackie and Q. Lian
DOI: 10.1016/j.ymgme.2008.03.010
07/2008

Mutation-based diagnostic testing for primary hyperoxaluria type 1: Survey of results
Clinical Biochemistry
Marion B. Coulter-Mackie and Qun Lian and Derek A. Applegarth and Jennifer Toone and Paula J. Waters and Hilary Vallance
DOI: 10.1016/j.clinbiochem.2008.01.018
05/2008

4-Hydroxyproline metabolism and glyoxylate production: A target for substrate depletion in primary hyperoxaluria?
Kidney International
M.B. Coulter-Mackie
DOI: 10.1038/sj.ki.5001987
2006

Consequences of missense mutations for dimerization and turnover of alanine:glyoxylate aminotransferase: Study of a spectrum of mutations
Molecular Genetics and Metabolism
M.B. Coulter-Mackie and Q. Lian
DOI: 10.1016/j.ymgme.2006.07.013
2006

The major allele of the alanine:glyoxylate aminotransferase gene: Nine novel mutations and polymorphisms associated with primary hyperoxaluria type 1
Molecular Genetics and Metabolism
Marion B. Coulter-Mackie and Qun Lian and Derek Applegarth and Jennifer Toone
DOI: 10.1016/j.ymgme.2005.05.005
09/2005

Overexpression of human alanine:glyoxylate aminotransferase in Escherichia coli: renaturation from guanidine–HCl and affinity for pyridoxal phosphate co-factor
Protein Expression and Purification
Marion B. Coulter-Mackie and Qun Lian and Steve G. Wong
DOI: 10.1016/j.pep.2004.11.004
05/2005

Preliminary Evidence for Ethnic Differences in Primary Hyperoxaluria Type 1 Genotype
American Journal of Nephrology
Marion B. Coulter-Mackie
DOI: 10.1159/000086356
2005

Genetic heterogeneity in primary hyperoxaluria type 1: impact on diagnosis
Molecular Genetics and Metabolism
Marion B. Coulter-Mackie and Gill Rumsby
DOI: 10.1016/j.ymgme.2004.08.009
09/2004

Evaluation of mutation screening as a first line test for the diagnosis of the primary hyperoxalurias
Kidney International
DOI: 10.1111/j.1523-1755.2004.00842.x
09/2004

The major allele of the alanine:glyoxylate aminotransferase gene: seven novel mutations causing primary hyperoxaluria type 1
Molecular Genetics and Metabolism
M Coulter-Mackie
DOI: 10.1016/j.ymgme.2004.02.001
05/2004

Molecular genetic and potential biochemical characteristics of patients with T-protein deficiency as a cause of glycine encephalopathy (NKH)
Molecular Genetics and Metabolism
Jennifer R Toone and Derek A Applegarth and Harvey L Levy and Marion B Coulter-Mackie and Gary Lee
DOI: 10.1016/s1096-7192(03)00115-x
08/2003

Spectrum of mutations in the arylsulfatase A gene in a Canadian DNA collection including two novel frameshift mutations, a new missense mutation (C488R) and an MLD mutation (R84Q) in cis with a pseudodeficiency allele
Molecular Genetics and Metabolism
M Coulter-Mackie
DOI: 10.1016/s1096-7192(03)00077-5
06/2003

The AGT gene in Africa: a distinctive minor allele haplotype, a polymorphism (V326I), and a novel PH1 mutation (A112D) in black Africans
Molecular Genetics and Metabolism
Marion B Coulter-Mackie and Andrew Tung and Howard E Henderson and Jennifer R Toone and Derek A Applegarth
DOI: 10.1016/s1096-7192(02)00204-4
01/2003

Novel mutations in the P-protein (glycine decarboxylase) gene in patients with glycine encephalopathy (non-ketotic hyperglycinemia)
Molecular Genetics and Metabolism
Jennifer R. Toone and Derek A. Applegarth and Shigeo Kure and Marion B. Coulter-Mackie and Payam Sazegar and Kanako Kojima and Akiko Ichinohe
DOI: 10.1016/s1096-7192(02)00041-0
07/2002

Molecular prenatal diagnosis of non-ketotic hyperglycinemia (glycine encephalopathy)
Prenatal Diagnosis
Derek A. Applegarth and Marie-Odile Rolland and Jennifer R. Toone and Marion Coulter-Mackie and Robert Saura
DOI: 10.1002/pd.293
2002

Three Novel Deletions in the Alanine:Glyoxylate Aminotransferase Gene of Three Patients with Type 1 Hyperoxaluria
Molecular Genetics and Metabolism
Marion B. Coulter-Mackie and Gillian Rumsby and Derek A. Applegarth and Jennifer R. Toone
DOI: 10.1006/mgme.2001.3222
11/2001

Multiple metachromatic leucodystrophy alleles in an unaffected subject: a case of dispermic chimaerism
Journal of Medical Genetics
M B Coulter-Mackie
DOI: 10.1136/jmg.38.5.e15
05/2001

Recurrent Mutations in P- and T-Proteins of the Glycine Cleavage Complex and a Novel T-Protein Mutation (N145I): A Strategy for the Molecular Investigation of Patients with Nonketotic Hyperglycinemia (NKH)
Molecular Genetics and Metabolism
Jennifer R. Toone and Derek A. Applegarth and Marion B. Coulter-Mackie and Erick R. James
DOI: 10.1006/mgme.2001.3158
04/2001

Variable onset of metachromatic leukodystrophy in a Vietnamese family
Pediatric Neurology
Laura T Arbour and Kenneth Silver and Peter Hechtman and Eileen P Treacy and Marion B Coulter-Mackie
DOI: 10.1016/s0887-8994(00)00164-8
08/2000

Biochemical and Molecular Investigations of Patients with Nonketotic Hyperglycinemia
Molecular Genetics and Metabolism
Jennifer R. Toone and Derek A. Applegarth and Marion B. Coulter-Mackie and Erick R. James
DOI: 10.1006/mgme.2000.3000
06/2000

Identification of the first reported splice site mutation (IVS7-1G?A) in the aminomethyltransferase (T-protein) gene (AMT) of the glycine cleavage complex in 3 unrelated families with nonketotic hyperglycinemia
Human Mutation
Jennifer R. Toone and Derek A. Applegarth and Marion B. Coulter-Mackie and Erick R. James
DOI: 10.1002/1098-1004(2001)17:13.0.co;2-0
2000

Identification of 6 new mutations in the iduronate sulfatase gene
Human Mutation
Hilary D. Vallance and Lynn Bernard and Michael Rashed and Doris Chiu and Grace Le and Jenny Toone and Derek A. Applegarth and Marion Coulter-Mackie
DOI: 10.1002/(sici)1098-1004(1999)13:43.0.co;2-3
1999

A protocol for detection of mitochondrial DNA deletions: characterization of a novel deletion
Clinical Biochemistry
Marion B Coulter-Mackie and Derek A Applegarth and Jennifer R Toone and Liane Gagnier
DOI: 10.1016/s0009-9120(98)00074-5
11/1998

Two novel mutations in the arylsulfatase A gene associated with juvenile (R390Q) and adult onset (H397Y) metachromatic leukodystrophy
Human Mutation
Marion B. Coulter-Mackie and Liane Gagnier
DOI: 10.1002/humu.1380110181
1998

Two new polymorphisms in the arylsulfatase A gene and their haplotype associations with normal, metachromatic leukodystrophy and pseudodeficiency alleles
American Journal of Medical Genetics
Marion Coulter-Mackie and Liane Gagnier
DOI: 10.1002/(sici)1096-8628(19971128)73:13.0.co;2-r
11/1997

Metachromatic leucodystrophy in three families from Nova Scotia, Canada: a recurring mutation in the arylsulphatase A gene.
Journal of Medical Genetics
M B Coulter-Mackie and L Gagnier and M J Beis and D A Applegarth and D E Cole and K Gordon and M D Ludman
DOI: 10.1136/jmg.34.6.493
06/1997

DNA-based diagnosis of arylsulfatase A deficiencies as a supplement to enzyme assay: A case in point
Clinical Biochemistry
Marion B. Coulter-Mackie and Derek A. Applegarth and Jennifer Toone and Hilary Vallance
DOI: 10.1016/s0009-9120(96)00124-5
02/1997

A five-basepair deletion (7118 delTTTTA) identified within neurofibromatosis NF1 exon 39
Human Mutation
David I. Rodenhiser and Jack H. Jung and Jane M.R. Gillet and Ken Hovland and Joseph Andrews and Peter J. Ainsworth and Marion Coulter-MAckie and Shiva M. Singh
DOI: 10.1002/(sici)1098-1004(1997)9:53.3.co;2-h
1997

Metachromatic leucodystrophy (MLD) in a patient with a constitutional ring chromosome 22
Journal of Medical Genetics
M B Coulter-Mackie and J Rip and M D Ludman and J Beis and D E C Cole
DOI: 10.1136/jmg.32.10.787
10/1995

A genetic study of neurofibromatosis type 1 (NF1) in south-western Ontario. II. A PCR based approach to molecular and prenatal diagnosis using linkage.
Journal of Medical Genetics
D I Rodenhiser and P J Ainsworth and M B Coulter-Mackie and S M Singh and J H Jung
DOI: 10.1136/jmg.30.5.363
05/1993

Evidence of DNA methylation in the neurofibromatosis type 1 (NF1) gene region of 17q11.2
Human Molecular Genetics
David I. Rodenhiser and Marion B. Coulter-Mackie and Shiva M. Singh
DOI: 10.1093/hmg/2.4.439
1993

Purification and structure of human liver aspartylglucosaminidase
Biochemical Journal
J W Rip and M B Coulter-Mackie and C A Rupar and B A Gordon
DOI: 10.1042/bj2881005
1992

A genetic study of neurofibromatosis 1 in south-western Ontario. I. Population, familial segregation of phenotype, and molecular linkage.
Journal of Medical Genetics
D I Rodenhiser and M B Coulter-Mackie and J H Jung and S M Singh
DOI: 10.1136/jmg.28.11.746
11/1991

A method for transforming lymphocytes from very small blood volumes suitable for paediatric samples
Human Genetics
J. Elliott and M.B. Coulter-Mackie and J.H. Jung and D.I. Rodenhiser and S.M. Singh
DOI: 10.1007/bf00201551
04/1991

Diagnostic single strand conformational polymorphism, (SSCP): a simplified non-radioisotopic method as applied to a Tay-Sachs B1 variant
Nucleic Acids Research
P.J. Ainsworth and L.C. Surh and M.B. Coulter-Mackie
DOI: 10.1093/nar/19.2.405
1991

In vivo and in vitro models of demyelinating diseases
Virus Research
Marion Coulter-Mackie and Richard Adler and Greame Wilson and Samuel Dales
DOI: 10.1016/0168-1702(85)90049-8
10/1985

In vivo and in vitro models of demyelinating disease X. A Schwannoma-L-2 somatic cell hybrid persistently yielding high titres of mouse hepatitis virus strain JHM
Virus Research
M.B. Coulter-Mackie and W.F. Flintoff and S. Dales
DOI: 10.1016/0168-1702(84)90005-4
09/1984

In vivo and in vitro models of demyelinating disease IX. Progression of JHM virus infection in the central nervous system of the rat during overt and asymptomatic phases
Virology
O. Sorensen and M.B. Coulter-Mackie and S. Puchalski and S. Dales
DOI: 10.1016/0042-6822(84)90227-7
09/1984

In Vivo and In Vitro Models of Demyelinating Diseases — VIII: Genetic, Immunologic and Cellular Influences on JHM Virus Infection of Rats
Molecular Biology and Pathogenesis of Coronaviruses
O. Sorensen and S. Beushausen and S. Puchalski and S. Cheley and R. Anderson and M. Coulter-Mackie and S. Dales
DOI: 10.1007/978-1-4615-9373-7_29
1984

Measles virus encephalitis and retinopathy in the Wistar rat
Experimental and Molecular Pathology
D.H. Percy and M. Coulter-Mackie
DOI: 10.1016/0014-4800(82)90072-7
06/1982

In vivo and in vitro Models of Demyelinating Diseases
Intervirology
Andrew Massalski and Marion Coulter-Mackie and Robert L. Knobler and Michael J. Buchmeier and Samuel Dales
DOI: 10.1159/000149316
1982

In Vivo and in Vitro Models of Demyelinating Diseases
Biochemistry and Biology of Coronaviruses
Ole Sorensen and Marion Coulter-Mackie and Dean Percy and Samuel Dales
DOI: 10.1007/978-1-4757-0456-3_22
1981

Assembly of Mouse Hepatitis Virus Strain JHM
Biochemistry and Biology of Coronaviruses
Andrew Massalski and Marion Coulter-Mackie and Samuel Dales
DOI: 10.1007/978-1-4757-0456-3_9
1981

In vivo and in vitro models of demyelinating diseases IV. Isolation of Hallé measles virus-specific RNA from BGMK cells and preparation of complementary DNA
Virology
Marion B. Coulter-Mackie and Wayne C. Bradbury and Samuel Dales and Wayne F. Flintoff and Vincent L. Morris
DOI: 10.1016/0042-6822(80)90100-2
04/1980

The noncoordinate expression of muscle-specific proteins in mutant rat skeletal myoblasts and reinitiation of differentiation in hybrids
Somatic Cell Genetics
Jackilynn Rogers and Marion Coulter and S. K. Ng and B. D. Sanwal
DOI: 10.1007/bf01542927
09/1978

In vivo and in vitro models of demyelinating diseases II. Persistence and host-regulated thermosensitivity in cells of neural derivation infected with mouse hepatitis and measles viruses
Virology
Alexandra Lucas and Marion Coulter and Robert Anderson and Samuel Dales and Wayne Flintoff
DOI: 10.1016/0042-6822(78)90289-1
07/1978

Apparent dominance of serine auxotrophy and the absence of expression of muscle-specific proteins in rat myoblast ¿ mouse L-cell hybrids
Somatic Cell Genetics
M. J. P. Dufresne and Jackilynn Rogers and Marion B. Coulter and Eric Ball and Theodore Lo and B. D. Sanwal
DOI: 10.1007/bf01542689
11/1976

Inhibition of myogenesis in a rat myoblast line by 5-bromodeoxyuridine
Nature
JACKILYNN ROGERS and STEPHEN K. C. NG and MARION B. COULTER and B. D. SANWAL
DOI: 10.1038/256438a0
07/1975

In vitro synthesis and detection of deoxyribonucleic acids with covalently linked complementary sequences
Biochemistry
Marion Coulter and Wayne Flintoff and Verner Paetkau and David Pulleyblank and A. Richard Morgan
DOI: 10.1021/bi00705a008
04/1974

Enzymic synthesis of deoxyribonucleic acids with repeating sequences. New repeating trinucleotide deoxyribonucleic acid, d(T-C-C)n·d(G-G-A)n
Biochemistry
A. Richard Morgan and Marion B. Coulter and Wayne F. Flintoff and Verner H. Paetkau
DOI: 10.1021/bi00705a007
04/1974

Thymine · guanine base pairing during transcription of polydeoxypyrimidines in vitro
Journal of Molecular Biology
Verner Paetkau and Marion B. Coulter and Wayne F. Flintoff and A.Richard Morgan
DOI: 10.1016/0022-2836(72)90352-x
11/1972

Research

Specific Projects
1. Primary hyperoxaluria type 1: This is a genetic disease caused by a deficiency of the peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT), a PLP-requiring enzyme. In the most common form of PH1, AGT is active but is incorrectly targeted to the mitochondria, where it is physically separated from its substrate. In this form of PH1, supplementation with pyridoxine, precursor to PLP, is used effectively in the management of the disease. We have demonstrated that this is at least partly due to an altered Km for PLP in the mutant protein. For several other mutations we have demonstrated decreased protein turnover in the presence of PLP. We have also demonstrated effects on oligomerization and stability of selected mutant recombinant AGTs with several other small molecule stabilizers.

2. Metabolic epilepsies: PDE is caused by a deficiency of the enzyme antiquitin (ALDH7A1), an essential enzyme in the metabolism of lysine. Severe seizures are brought under control with pyridoxine supplementation. GAMT deficiency results in creatine deficiency and consequent seizures. Supplementation with creatine relieves seizures. We have developed recombinant genes for expression of both human antiquitin and human GAMT. We are initiating expression studies for normal and mutant enzymes using the approaches outlined above. Although metabolic supplementation in these diseases is effective in bringing seizures under control, there are frequently other long term consequences to these enzyme deficiencies. Therefore additional pharmacological therapeutic strategies are desirable.