Polymorphisms and Disease: Hotspots of Inactivation in Methyltransferases

Polymorphisms and Disease: Hotspots of Inactivation in Methyltransferases

Karen Rutherford†§ and Valerie Daggett†‡*

Departments of Biochemistry† and Bioengineering‡, Box 355103

University of Washington, SeattleWA98195-5013

SupplementaryTable S1: Common Coding Polymorphisms in Human Methyltransferases

Methyl-transferase / Function / SNP / Effect Relative to WT / Associated Disease / Ref.
Catechol O-Methyl-transferase / Catechol Metabolism (dopamine, catechol estrogens) / A22S / Decreased activity/stability / Schizophrenia; Breast Cancer; Alcoholism / S1-S4
A52T / NDa
V108M / ~30% less active; decreased stability
Histamine N-Methyl-transferase / Histamine Metabolism / T105I / ~2-fold less active; increased Km (SAM, histamine) / Alcoholism / S5, S6
Protein L-Isoaspartate O-Methyl-transferase / Repair of Damaged Aspartyl/ Asparaginyl Residues / I119V / ~20% less active; decreased thermal stability;
~30% increase in Km (substrates) / Ageing, Spina Bifida / S7, S8
Thiopurine S-Methyl-transferase / Metabolizes thiopurine drugs / A80P / No TPMT protein/ activity / Hematopoietic Toxicity; Leukemia; Inflammatory Bowel Disease; Crohn’s Disease; Multiple Sclerosis / S9-S11
A154T / Decreased activity/ stability
Y240C / Decreased activity/stability
A154T/ Y240C / No TPMT protein/ activity
Glycine N-Methyl-transferase / Folate-Binding Protein;
Regulates SAM:SAH Ratio / L49P / ~90% less active; 2-fold decrease in Km (SAM) / Hyper-methioninaemia; hepatomegaly; mild hepatocellular disease / S12-S15
N140S / No activity
H176N / ~25% less active; 2-fold increase in Km (glycine)
Guanidinoacetate N-Methyl-transferase / Creatine biosynthesis / P40S / ND / Creatine Deficiency: mental retardation, autism, neurological deterioration, epilepsy / S16-S19
V165F / ND
L197P / No activity
T209M / ND
S188C / ND
W276R / ND
Phenylethanol-amine N-Methyl-transferase / Adrenaline Synthesis / T98A / ~95% less protein / ND / S20,S21
R107C / ~90% less active; ~50% less protein
S188C / ND
W276R / ND
Phosphatidyl-ethanolamine N-Methyl-transferase / Phosphatidyl-choline Synthesis / V175M / ~40 % less active / Non-alcoholic fatty liver disease / S22
Arsenic Methyl-transferase / Biotrans-formation of exogenous arsenic / R173W / 69% less active; 80% less protein / Arsenic-dependent carcinogenesis, neurotoxicity, cardiac failure, leucopenia, death / S23, S24
M287T / 350% more active; 190% more protein
T306I / 95% less active; 95% less protein
M287T/ T306I / 94% less active; 92 % less protein

aND, not determined.

References:

S1.Shield, A.J., et al.(2004) Human catechol O-methyltransferase genetic variation: gene resequencing and functional characterization of variant allozymes. Mol Psychiatry 9, 151-160

S2.Chen, J., et al. (2004) Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain. Am J Hum Genet 75, 807-821

S3.Wedren, S., et al. (2003) Catechol-O-methyltransferase gene polymorphism and post-menopausal breast cancer risk. Carcinogenesis 24, 681-687

S4.Karayiorgou, M., et al. (1999) Family-based association studies support a sexually dimorphic effect of COMT and MAOA on genetic susceptibility to obsessive-compulsive disorder. Biol Psychiatry 45, 1178-1189

S5.Preuss, C.V., et al. (1998) Human histamine N-methyltransferase pharmacogenetics: common genetic polymorphisms that alter activity. Mol Pharmacol 53, 708-717

S6.Horton, J.R., et al. (2001) Two polymorphic forms of human histamine methyltransferase: structural, thermal, and kinetic comparisons. Structure 9, 837-849

S7.David, C.L., et al. (1997) Human erythrocyte protein L-isoaspartyl methyltransferase: heritability of basal activity and genetic polymorphism for thermal stability. Arch Biochem Biophys 346, 277-286

S8.DeVry, C.G., and Clarke, S. (1999) Polymorphic forms of the protein L-isoaspartate (D-aspartate) O-methyltransferase involved in the repair of age-damaged proteins. J Hum Genet 44, 275-288

S9.Salavaggione, O.E., et al. (2005) Thiopurine S-methyltransferase pharmacogenetics: variant allele functional and comparative genomics. Pharmacogenet Genomics 15, 801-815

S10.Wang, L., and Weinshilboum, R. (2006) Thiopurine S-methyltransferase pharmacogenetics: insights, challenges and future directions. Oncogene 25, 1629-1638

S11.Tai, H.L., et al. (1999) Enhanced proteasomal degradation of mutant human thiopurine S-methyltransferase (TPMT) in mammalian cells: mechanism for TPMT protein deficiency inherited by TPMT*2, TPMT*3A, TPMT*3B or TPMT*3C. Pharmacogenetics 9, 641-650

S12.Luka, Z., et al. (2002) Mutations in human glycine N-methyltransferase give insights into its role in methionine metabolism. Hum Genet 110, 68-74

S13.Luka, Z., and Wagner, C. (2003) Effect of naturally occurring mutations in human glycine N-methyltransferase on activity and conformation. Biochem Biophys Res Commun 312, 1067-1072

S14.Luka, Z., et al. (2007) Destabilization of human glycine N-methyltransferase by H176N mutation. Protein Sci 16, 1957-1964

S15.Luka, Z., and Wagner, C. (2003) Human glycine N-methyltransferase is unfolded by urea through a compact monomer state. Arch Biochem Biophys 420, 153-160

S16.Item, C.B., et al. (2004) Characterization of seven novel mutations in seven patients with GAMT deficiency. Hum Mutat 23, 524

S17.Saito, S., Iida, A., Sekine, A., Miura, Y., Sakamoto, T., Ogawa, C., Kawauchi, S., Higuchi, S., Nakamura, Y. (2001) Identification of 197 genetic variations in six human methyltransferase genes in the Japanese population. J. Hum. Genet 46, 529-537

S18.Leuzzi, V., et al. (2006) A mutation on exon 6 of guanidinoacetate methyltransferase (GAMT) gene supports a different function for isoform a and b of GAMT enzyme. Mol Genet Metab 87, 88-90

S19.Mercimek-Mahmutoglu, S., et al. (2006) GAMT deficiency: features, treatment, and outcome in an inborn error of creatine synthesis. Neurology 67, 480-484

S20.Ji, Y., et al. (2005) Human phenylethanolamine N-methyltransferase pharmacogenomics: gene re-sequencing and functional genomics. J Neurochem 95, 1766-1776

S21.Ji, Y., et al. (2008) Human phenylethanolamine N-methyltransferase genetic polymorphisms and exercise-induced epinephrine release. Physiol Genomics 33, 323-332

S22.Dong, H., et al. (2007) The phosphatidylethanolamine N-methyltransferase gene V175M single nucleotide polymorphism confers the susceptibility to NASH in Japanese population. J Hepatol 46, 915-920

S23.Wood, T.C., et al. (2006) Human arsenic methyltransferase (AS3MT) pharmacogenetics: gene resequencing and functional genomics studies. J Biol Chem 281, 7364-7373

S24.Hernandez, A., et al. (2008) Role of the Met(287)Thr polymorphism in the AS3MT gene on the metabolic arsenic profile. Mutat Res 637, 80-92