Mucopolysaccharidosis
Morquio A disease

Positions and Honors.

1984-1985, Junior resident, Department of Pediatrics, Gifu University, Gifu, Japan

1986-1988, Graduate Student and research fellow, Institute of Genetic Informationand Experiment, Kyushu University, Fukuoka City, Japan

1989-1991, Senior resident and research fellow, Department of Pediatrics, Gifu
University, Gifu, Japan

1991-1993, Assistant lecturer, Department of Pediatrics, Gifu University, Gifu, Japan

1993- Assistant professor, Department of Pediatrics, Gifu University, Gifu, Japan

1995-2001 Assistant professor, Department of Biochemistry, St. Louis University, St. Louis, MO

2001-2003 Associate professor, Department of Biochemistry, St. Louis University, St. Louis, MO

2003-2008 Associate professor, Department of Pediatrics, St. Louis University, St. Louis, MO

2008-present Professor, Department of Pediatrics, St. Louis University, St. Louis, MO

Honors and Awards

1992, Research Grant Award from Gifu University

1992, Otaka Prize from the Japanese Society of Connective Tissue

1992, Grant-in-Aid for Scientific Research from the Japanese Ministry of Education

1994, Research Grant Award for the Promotion of Inherited Metabolic Disease from

the Japanese Society of Inherited Metabolic Disease

1994, Grant-in-Aid for Scientific Research from the Japanese Ministry of Education

1995, Research Award for the Promotion of the Japanese Society of Human Genetics

1997, Uehara Scholarship

2003, The best presentation Award by Japanese Society of Inherited Metabolic

Disease

Selected peer-reviewed publications (in chronological order).

(Publications selected from 120 peer-reviewed publications for the last three years)

Tomatsu S, Orii KO, Vogler C, Grubb JH, Snella EM, Gutierrez M, Dieter T, Holden CC, Sukegawa K, Orii T, Kondo N, Sly WS. Production of MPS VII mouse (Gus(tm(hE540A.mE536A)Sly)) doubly tolerant to human and mouse beta-glucuronidase. Hum Mol Genet.12:961-73, 2003.

Montano AM, Kaitila I, Sukegawa K, Tomatsu S, Kato Z, Nakamura H, Fukuda S, Orii T, Kondo N. Mucopolysaccharidosis IVA: characterization of a common mutation found in Finnish patients with attenuated phenotype. Hum Genet.113:162-9, 2003.

Tomatsu S, Orii KO, Vogler C, Nakayama J, Levy B, Grubb JH, Gutierrez MA, Shim S, Yamaguchi S, Nishioka T, Montano AM, Noguchi A, Orii T, Kondo N, Sly WS. Mouse model of N-acetylgalactosamine-6-sulfate sulfatase deficiency (Galns-/-) produced by targeted disruption of the gene defective in Morquio A disease. Hum Mol Genet. 12:3349-58, 2003.

Tomatsu S, Orii KO, Fleming RE, Holden CC, Waheed A, Britton RS, Gutierrez MA, Velez-Castrillon S, Bacon BR, Sly WS. Contribution of the H63D mutation in HFE to murine hereditary hemochromatosis. Proc Natl Acad Sci U S A. 100:15788-93, 2003.

Tomatsu S, Okamura K, Taketani T, Orii KO, Nishioka T, Gutierrez MA, Velez-Castrillon S, Fachel AA, Grubb JH, Cooper A, Thornley M, Wraith E, Barrera LA, Giugliani R, Schwartz IV, Frenking GS, Beck M, Kircher SG, Paschke E, Yamaguchi S, Ullrich K, Isogai K, Suzuki Y, Orii T, Kondo N, Creer M, Noguchi A. Development and testing of new screening method for keratan sulfate in mucopolysaccharidosis IVA. Pediatr Res. 55:592-7, 2004.

Tomatsu S, Orii KO, Bi Y, Gutierrez MA, Nishioka T, Yamaguchi S, Kondo N, Orii T, Noguchi A, Sly WS. General Implications for CpG Hot Spot Mutations: Methylation Patterns of the Human Iduronate-2-Sulfatase Gene Locus. Hum Mutat 23:590-8, 2004.

Tomatsu S. Development of Murine Models of Mucopolysaccharidosis IVA and VII and Hereditary Hemochromatosis Japanese J Inherit Metab Dis (in press).

Tomatsu S, Nishioka T, Montano AM, Gutierrez MA, Pena OS, Orii KO, Sly WS, Yamaguchi S, Orii T, Paschke E, Kircher SG, Noguchi A. Mucopolysaccharidosis IVA: identification of mutations and methylation study in GALNS gene. J Med Genet. 41(7):e98, 2004.

Tomatsu S, Filocamo M, Orii KO, Sly WS, Gutierrez MA, Nishioka T, Serrato OP, Di Natale P, Montano AM, Yamaguchi S, Kondo N, Orii T, Noguchi A. Mucopolysaccharidosis IVA (Morquio A): identification of novel common mutations in the N-acetylgalactosamine-6-sulfate sulfatase (GALNS) gene in Italian patients. Hum Mutat. 2004 24:187-8.

Tomatsu S, Dieter T, Schwartz IV, Sarmient P, Giugliani R, Barrera LA, Guelbert N, Kremer R, Repetto GM, Gutierrez MA, Nishioka T, Serrato OP, Montano AM, Yamaguchi S, Noguchi A. Identification of a common mutation in mucopolysaccharidosis IVA: correlation among genotype, phenotype, and keratan sulfate. J Hum Genet 2004 49:490-4.

Tomatsu S. Development of Murine Models of Mucopolysaccharidosis IVA and VII and Hereditary Hemochromatosis Japanese J Inherit Metab Dis 20:27-43, 2004.

Tomatsu S, Okamura K, Taketani T, Orii KO, Nishioka T, Gutierrez MA, Velez-Castrillon S, Fachel AA, Grubb JH, Cooper A, Thornley M, Wraith E, Barrera LA, Giugliani R, Schwartz IV, Frenking GS, Beck M, Kircher SG, Paschke E, Yamaguchi S, Ullrich K, Isogai K, Suzuki Y, Orii T, Kondo N, Creer M, Noguchi A. Keratan sulfate levels in mucopolysaccharidoses and mucolipidoses. J Inherit Metab Dis 2005 28:187-202.

Tomatsu S, Okamura K, Taketani T, Orii KO, Nishioka T, Gutierrez MA, Velez-Castrillon S, Fachel AA, Grubb JH, Cooper A, Thornley M, Wraith E, Barrera LA, Giugliani R, Schwartz IV, Frenking GS, Beck M, Kircher SG, Paschke E, Yamaguchi S, Ullrich K, Isogai K, Suzuki Y, Orii T, Kondo N, Creer M, Noguchi A. Heparan Sulfate Levels in Mucopolysaccharidoses and Mucolipidoses. J Inherit Metab Dis J Inherit Metab Dis. 2005 28:743-57.

Tomatsu S, Montano AM, Nishioka T, Gutierrez MA, Pena OM, Trandafirescu GG, Lopez P, Yamaguchi S, Noguchi A, Orii T. Mutation and polymorphism spectrum of the GALNS gene in mucopolysaccharidosis IVA (Morquio A). Hum Mutat. 2005 26:500-12.

Tomatsu S, Gutierrez M, Nishioka T, Yamada M, Yamada M, Tosaka Y, Grubb JH, Montano AM, Vieira MB, Trandafirescu GG, Pena OM, Yamaguchi S, Orii KO, Orii T, Noguchi A, Laybauer L. Development of MPS IVA mouse (Galnstm(hC79S.mC76S)slu) tolerant to human N-acetylgalactosamine-6-sulfate sulfatase.
Hum Mol Genet. 2005 14:3321-35.

Tomatsu S, Okamura K, Taketani T, Orii KO, Nishioka T, Gutierrez MA, Velez-Castrillon S, Fachel AA, Grubb JH, Cooper A, Thornley M, Wraith E, Barrera LA, Giugliani R, Schwartz IV, Frenking GS, Beck M, Kircher SG, Paschke E, Yamaguchi S, Ullrich K, Isogai K, Suzuki Y, Orii T, Kondo N, Creer M, Noguchi A. Keratan sulfate levels in mucopolysaccharidoses and mucolipidoses. J Inherit Metab Dis. 28:187-202, 2005.

Tomatsu S, Gutierrez MA, Ishimaru T, Pena OM, Montano AM, Maeda H, Velez-Castrillon S, Nishioka T, Fachel AA, Cooper A, Thornley M, Wraith E, Barrera LA, Laybauer LS, Giugliani R, Schwartz IV, Frenking GS, Beck M, Kircher SG, Paschke E, Yamaguchi S, Ullrich K, Isogai K, Suzuki Y, Orii T, Noguchi A. Heparan sulfate levels in mucopolysaccharidoses and mucolipidoses. J Inherit Metab Dis. 28:743-57, 2005.

Tomatsu S, Gutierrez M, Nishioka T, Yamada M, Yamada M, Tosaka Y, Grubb JH, Montano AM, Vieira MB, Trandafirescu GG, Pena OM, Yamaguchi S, Orii KO, Orii T, Noguchi A, Laybauer L. Development of MPS IVA mouse (Galns^{tm(hC79S•mC76S)slu}) tolerant to human N-acetylgalactosamine-6-sulfate sulfatase. Hum Mol Genet. 14:3321-3335, 2005.

Tomatsu S, Montano AM, Nishioka T, Gutierrez MA, Pena OM, Tranda Firescu GG, Lopez P, Yamaguchi S, Noguchi A, Orii T. Mutation and polymorphism spectrum of the GALNS gene in mucopolysaccharidosis IVA (Morquio A). Hum Mutat. 26:500-512, 2005.

Tomatsu S, Sukegawa S, Gutierrez M, Nishioka T, Yamaguchi S, Orii T, Froissart R, Maire I, Chabas A, Cooper A, Di Natale P, Gal A, Noguchi A, Sly WS. Implications for CpG Hot Spot Mutations: Difference of Methylation Pattern in the Methylation Boundary Region of IDS Gene Induces Hunter Syndrome. Eur J Hum Genet 14: 838-845, 2006.

Nishioka T*, Tomatsu S*#, Gutierrez MA, Trandafirescu GG, Lopez P, Grubb JH, Kanai R, Kobayashi H, Yamaguchi S, Gottesman GS, Cahill R, Noguchi A, Miyamoto K, Sly WS. Targeted Drug Delivery to Bone: Characterization of Human Tissue-nonspecific Alkaline Phosphatase Tagged with an Acidic Oligopeptide. Mol Genet Metab 88:244-255, 2006. *Equally contributed, #Corresponding author

Tomatsu S*, Montaño AM*, Lopez P, Trandafirescu GG, Gutierrez MA, Oikawa H, Nishioka T, Vieira MB, Orii T, Noguchi A. Determinant factors of spectrum of missense variants in mucopolysaccharidosis IVA gene. Mol Genet Metab 89:139-149, 2006. *Equally contributed,

Sly WS, Vogler C, Grubb JH, Levy B, Galvin N, Tan Y, Nishioka T, Tomatsu S. Enzyme therapy in mannose receptor-null mucopolysaccharidosis VII mice defines roles for the mannose 6-phosphate and mannose receptors. Proc Natl Acad Sci U S A.103:15172-15177, 2006.

Sukegawa-Hayasaka K, Kato Z, Nakamura H, Tomatsu S, Fukao T, Kuwata K, Orii T, Kondo N. Effect of Hunter disease (mucopolysaccharidosis type II) mutations on molecular phenotypes of iduronate-2-sulfatase: enzymatic activity, protein processing and structural analysis. J Inherit Metab Dis. 29:755-61, 2006.

Tomatsu S, Montano AM, Gutierrez M, Grubb JH, Oikawa H, Dung VC, Ohashi A, Nishioka T, Yamada M, Yamada M, Tosaka Y, Trandafirescu GG, Orii T. Characterization and pharmacokinetic study of recombinant human N-acetylgalactoseamine-6-sulfate sulfatase. Mol Genet Metab 91: 69-78, 2007.

Oguma T, Tomatsu S, Okazaki O. Analytical method for determination of disaccharides derived from keratan sulfates in human serum and plasma by high-performance liquid chromatography/turbo-ionspray ionization tandem mass spectrometry. Biomed Chromatogr 21:356-62, 2007.

Montaño AM^*, Tomatsu S^*#, Gottesman GS, Smith M, Orii T. International Morquio A registry: clinical manifestation and natural course of Morquio A disease. J Inherit Metab Dis 30:165-74, 2007. *Equally contributed, #Corresponding author

Tomatsu S*, Vogler C*, Montaño AM*, Gutierrez M, Trandafirescu GG, Oikawa O, Takarada T, Yamaguchi S, Orii T, Noguchi N. Murine model (Galns^tm(C76S)slu) of MPS IVA with a missense mutation at an active site among sulfatase proteins. Mol Genet Metab 9:251-258, 2007. *Equally contributed

Oguma T, Tomatsu S, Montaño AM, Okazaki O. Analytical method for determination of disaccharides derived from keratan, heparan and dermatan sulfates in human serum and plasma by high-performance liquid chromatography / turbo-ionspray ionization tandem mass spectrometry. Analytical Biochem 368:79-86, 2007.

Montaño AM, Sukegawa K, Kato K, Carrozzo R, Di Natale P, Christensen E, Orii KO, Orii T, Kondo N, Tomatsu S#. Characterization of novel mutations causing attenuated phenotype in Mucopolysaccharidosis IVA J Inherit Metab Dis 5:758-67, 2007. #Corresponding author

Tomatsu S*, Montano AM*, Ohashi A, Oikawa H, Oguma T, Dung VC, Nishioka T, Orii T, Sly WS. Enzyme replacement therapy in a murine model of Morquio A syndrome. Hum Mol Genet 17:815-824, 2008. *Equally contributed.

Montaño AM, Tomatsu S#, Brusius A, Smith M, Orii T. Growth charts for patients affected with Morquio A Disease. Am J Med Genet. 15;146A:1286-95, 2008. #Corresponding author

Montaño AM*, Oikawa H*, Tomatsu*#, Nishioka T, Vogler C, Gutierrez MA, Oguma T, Tan Y, Grubb JH, Dung VC, Ohashi A, Miyamoto K, Orii T, Yoneda Y, Sly WS. Acidic amino acid tag enhances response to enzyme replacement in mucopolysaccharidosis type VII mice. Mol Genet Metab 94:178-89, 2008.. *Equally contributed,#Corresponding author

Takahashi-Nishioka T, Yokogawa K, Tomatsu S, Nomura M, Kobayashi S, Miyamoto K. Targeted drug delivery to bone: pharmacokinetic and pharmacological properties of acidic oligopeptide-tagged drugs. Curr Drug Discov Technol. 5:39-48, 2008.

Ohashi M, Montaño AM, Colón JE, Oguma T, Luisiri A, Tomatsu T. Sacral dimple: Incidental findings                 from newborn evaluation. Acta Paediatrica (in press)

Gutiérrez MA, García-Vallejo F, Tomatsu S, Cerón F, Alméciga-Díaz CJ, Domínguez MC, Barrera LA.                 Construcción de un vector de expresión derivado de virus adenoasociados para corregir in                 vitro el defecto genético de la enfermedad de Morquio A. Biomédica 28:448-59, 2008.

Patent applications

Research Field

I. I have been working on the mucopolysaccharidoses (MPS, which represent 11 diseases) for the past 25 years, from the clinical and basic research aspects, both in Japan and in the United States. This type of lysosomal storage disease has common clinical features that include bone deformities, hepatosplenomegaly, abnormal faces, mental retardation (not MPS IVA), short stature, herniation, hump back, scoliosis, kyphosis, hearing loss, corneal clouding, dysplasia of odontoid process, platyspondyly of the vertebrae, etc. These diverse clinical manifestations result from the storage of mucopolysaccharides in lysosomes of various tissues. Bone, especially, is a target tissue. Most of the bones are destroyed by dysplasia. Because of multiple dysplasia of bones, many patients suffer from hip dislocation, cervical myelopathy, quadriplegia, hump back, restriction of breathing, and gait disturbances. Morquio disease patients will usually die between ages 20 and 30 from pneumonia, valvular heart disease, or neck injuries from a fall. Since 1991, we have cloned the cDNA of the enzyme deficient in MPS IVA (Morquio disease) and identified various mutations in MPS I (Hurler syndrome), II (Hunter syndrome), IVA, and VII (Sly syndrome) patients. In an extensive study, I am making several different mouse models of MPS VII and MPS IVA in humans. Establishing mouse models of MPS diseases and other metabolic diseases like hereditary hemochromatosis is expected to lead to clarification of the pathogenesis, advanced therapy (BMT, gene therapy, and enzyme replacement therapy [ERT]), and genotype/phenotype correlations. To date, we have established five different types of mouse models for MPS VII and five different types of hereditary hemochromatosis. Three different MPS IVA mice (Morquio disease mouse) are currently established. After establishment of these mouse models, we now study the response to enzyme replacement treatment on affected mice using a purified beta-glucuronidase (GUSB) for MPS VII and N-acetyl-galactoseamine-6-6sulfate sulfatase (GALNS) for MPS IVA.

Moreover, recently we and our collaborators developed the bone targeting system (a new drug delivery system) in conjunction with enzyme replacement therapy or other types of molecules. This DDS would lead to an additive effectiveness and could be applied to a variety of genetic bone diseases whose enzyme is deficient. Thus, this unique strategy has allowed us to open the new field such as treatment of congenital bone diseases (hypoparathoidism, hypopohspatasia, achondodysplasia etc). Our new DDS is also applicable to any systematic bone diseases such as osteoporosis, infection, cancer, and other genetic diseases.

II. Glycosaminoglycans (GAGs) are accumulated in both mucopolysaccharidoses (MPS). Each type of MPS stores a different type(s) of GAG(s): MPS I and II patients by dermatan sulfate (DS) and heparan sulfate (HS); MPS III by HS; MPS IV by keratan sulfate (KS) and chondroitin-6-sulfate (C6S); MPS VI by DS and C4S; MPS VII by DS, HS, and CS. Recent successful achievements of treatment on MPS patients by bone marrow transplantation and enzyme replacement therapy made it possible to improve the clinical manifestations. However, most patients treated are already at a progressive stage and some clinical features involving brain and bone are irreversible. Since MPS patients appear normal at birth, it is impossible to separate normal healthy newborns and MPS newborns. Therefore, if an appropriate treatment has been done at newborns, the quality of life of the MPS patients will be dramatically improved. In spite of the importance of early diagnosis and early treatment, no newborn screening is available. To develop a newborn screening system, we will establish the tandem mass spectrometry (TMS) method to assay KS, HS, and DS levels in blood and have compared each GAG level between control group and each type of MPS group.

Morquio Dream Team July 2008

New Research Building Oct 2007 at SLU