PROF Congential Heart Disease

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					                  STELLA MITRANI-ROSENBAUM, Ph.D.

Principal Investigator, Goldyne Savad Institute of Gene Therapy

Hadassah University Hospital, the Hebrew University-Hadassah Medical
School, Jerusalem, Israel

1967-1970       B.Sc. in Biology at the University of Barcelona, Spain

1971-1973       M.Sc. in Microbiology, the Hebrew University of Jerusalem,
                Jerusalem, Israel.

1977-1981       Ph.D. in Virology, the Hebrew University of Jerusalem,
                Jerusalem, Israel. Advisors: Prof. N. Goldblum, Department
                of Virology, the Hebrew University of Jerusalem, Jerusalem;
                Prof. George Klein, Karolinska Institute, Stockholm, Sweden.

Research interests
Basic Research on Molecular Genetics mostly focused on muscular diseases


Selected recent publications

Argov Z, Mitrani-Rosenbaum S. 2008. The hereditary inclusion body myopathy
enigma and its future therapy. Neurotherapeutics 5(4):633-7.

Agranat-Meged A, Ghanadri Y, Eisenberg I, Ben Neriah Z, Kieselstein-Gross E,
Mitrani-Rosenbaum S. 2008. Attention deficit hyperactivity disorder in obese
melanocortin-4-receptor (MC4R) deficient subjects: A newly described expression of
MC4R deficiency.. Am J Med Genet B Neuropsychiatr Genet.

Amsili S, Zer H, Hinderlich S, Krause S, Becker-Cohen M, MacArthur DG, North KN,
Mitrani-Rosenbaum        S.    2008.   UDP-N-acetylglucosamine    2-epimerase/N-
acetylmannosamine kinase (GNE) binds to alpha-actinin 1: novel pathways in
skeletal muscle? PLoS ONE. 3(6):e2477.

Argov Z, Mitrani-Rosenbaum S. 2007. Hereditary inclusion body myopathy and
other rimmed vacuolar myopathies. Handb Clin Neurol 86:243-53.

Eisenberg I, Eran A, Nishino I, Moggio M, Lamperti C, Amato AA, Lidov HG, Kang
PB, North KN, Mitrani-Rosenbaum S, Flanigan KM, Neely LA, Whitney D, Beggs
AH, Kohane IS, Kunkel LM. 2007. Distinctive patterns of microRNA expression in
primary muscular disorders. Proc Natl Acad Sci USA. 104(43):17016-21.

Krause S, Aleo A, Hinderlich S, Merlini L, Tournev I, Walter MC, Argov Z, Mitrani-
Rosenbaum S, Lochmuller H. 2007. GNE protein expression and subcellular
distribution are unaltered in HIBM. Neurology 69(7):655-9.

Amsili S, Shlomai Z, Levitzki R, Krause S, Lochmuller H, Ben-Bassat H, Mitrani-
Rosenbaum S. 2007. Characterization of hereditary inclusion body myopathy
myoblasts:      possible     primary   impairment    of    apoptotic   events.
Cell Death Differ 14(11):1916-24.

Nissan A, Jager D, Roystacher M, Prus D, Peretz T, Eisenberg I, Freund HR,
Scanlan M, Ritter G, Old LJ, Mitrani-Rosenbaum S. 2006. Multimarker RT-PCR
assay for the detection of minimal residual disease in sentinel lymph nodes of breast
cancer patients. Br J Cancer 94(5):681-5.

Penner J, Mantey LR, Elgavish S, Ghaderi D, Cirak S, Berger M, Krause S, Lucka L,
Voit T, Mitrani-Rosenbaum S, Hinderlich S. 2006. Influence of UDP-GlcNAc 2-
epimerase/ManNAc kinase mutant proteins on hereditary inclusion body myopathy.
Biochemistry 7;45(9):2968-77.

Krause S, Hinerlich S, Amsili S, Horstkorte R, Wiendl H, Argov Z, Mitrani-
Rosenbaum S, Lochmuller H. 2005. Localization of UDP-G1cNAc 2-
epimerase/ManAc kinase (GNE) in the Gilgi complex and the nucleus of mammalian
cells. Exp Cell Res 304:365-379.

Salama I, Hinderlich S, Shlomai Z, Eisenberg I, Krause S, Yarema K, Argov Z,
Lochmuller H, Reutter W, Dabby R, Sadeh M, Ben-Bassat H, Mitrani-Rosenbaum S.
2005. No overall hyposialylation in hereditary inclusion body myopathy myoblasts
carrying the homozygous M712T GNE mutation. Biochem Biophys Res Commun
Avidor B, Efrat G, Weinberg M, KraOz Z, Satinger J, Mitrani-Rosenbaum S, Yaron
Y, Shulman L, Tepperberg-Oikawa M, Wolf D, Berger SA, Lipitz S, Mendelson E,
Giladi M. 2004. Insight into the intrinsic sensitivity of the PCR assay used to detect
CMV infection in amniotic fluid specimens. J Clin Virol 4:260-70.

Hinderlich S, Salama I, Eisenberg I, Potikha T, Mantey L, Yarema K, Horstkorte R,
Argov Z, Sadeh M, Reutter W, Mitrani-Rosenbaum S. 2004. The homozygous
M712T mutation of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine
kinase results in reduced enzyme activities but not in altered cellular sialylation in
hereditary inclusion body myopathy. FEBS Letters 566:105-109.

Eisenberg I., Grabov-Nardini G., Hochner H., Korner M., Sadeh M., Bertorini T.,
Bushby K., Castellan C., Felice K., Mendell J., Merlini M., Shilling C., Wirguin I., Argov
Z., Mitrani-Rosenbaum S. 2003. Mutations spectrum of the GNE gene in Hereditary
Inclusion Body Myopathy sparing the quadriceps. Hum Mutat 21: 99.

Argov Z., Eisenberg I., Grabov-Nardini G., Sadeh M.,Wirguin I., Soffer D., Mitrani-
Rosenbaum S. 2003. Hereditary Inclusion Body Myopathy: the middle eastern
genetic cluster. Neurology 60:1519-1523.

Hinderlich S., Salama I., Eisenberg I., Mitrani-Rosenbaum, S. 2003. Distal myopathy
with rimmed vacuoles is allelic to hereditary inclusion body myopathy". Neurology

Eisenberg I., Barash M., Kahan T., Mitrani-Rosenbaum S. 2002. Cloning and
characterization of a human novel gene C9orf19 encoding a conserved putative
protein with an SCP-like extracellular protein domain. Gene 293:141-8

Eisenberg 2002. Cloning and characterization of a novel human gene RNF38
encoding a conserved putative protein with a RING finger domain. Biochem Biophys
Res Commun 294:1169-76 I., Hochner H., Levi T., Yelin R., Kahan T.(C), Mitrani-
Rosenbaum S.

Eisenberg I., Hochner H., Sadeh M., Argov Z., Mitrani Rosenbaum S. 2002.
Establishment of the genomic structure and identification of thirteen single-nucleotide
polymorphisms in the human RECK gene. Cytogenet Genome Res 97:58-61.

Research group

Post doc:
Iris Eisenberg, Ph.D., tel 44727,email:

Ph.D. students:
Ilan Salama, tel 44701,
Shira Amsili, tel 44700,

M.Sc students:
Adi Rizansky, tel 44702,
Yulia Luktav, tel 44702,
Michal Becker-Cohen, tel 44716,

Prof Werner Reutter, Dr Stephan Hinderlich, Institut für Biochemie und
Molekularbiologie, Charité Universitätsmedizin, Berlin
Dr Kevin Yarema, Whitaker Institute of Biomedical Engineering The Johns Hopkins
University, Baltimore
Prof Hanns Lochmuller, Genzentrum and Friedrich-Baur-Institute, Ludwig-
Maximilians-University, Munich
Prof Zohar Argov, Hadassah University Hospital
Prof Menachem Sadeh, Wolfson Hospital
Prof Hannah Ben-Bassat
Dr.Aviram Nissan, Hadassah University Hospital
Prof Hani Maayan, Hadassah University Hospital
Dr Ronen Segman, Hadassah University Hospital
Dr Annick Raas Rothschild, Hadassah University Hospital
Dr Azaria Rein, Hadassah University Hospital
Dr Stanley Kurman, Hadassah University Hospital

                               RESEARCH SUMMARY

Hereditary Inclusion Body Myopathy: Characterization of the effects of the
mutated GNE gene in the pathophysiology of muscle tissue.

         Hereditary Inclusion Body Myopathy          (HIBM) is a unique group of
neuromuscular disorders characterized by adult-onset, slowly progressive distal and
proximal muscle weakness, and typical muscle pathology, including rimmed vacuoles
and filamentous inclusions. This disease is the most common form of ethnic-related
familial degenerative myopathy, with a prevalence of 1:1500 in the Jewish Iranian
community. The identification in our laboratory of GNE as the gene causing HIBM, a
form of myopathy till then considered almost exclusively as a Middle Eastern Jewish
disease, allowed the recognition of that same disorder worldwide and a new
classification of this group of diseases.
         UDP-N-acetylglucosamine2-epimerase/ N-acetylmannosamine kinase (GNE)
is a bifunctional enzyme which plays a key role in the biosynthetic pathway of sialic
acid. Because of its terminal position on macromolecules and on cell membranes,
sialic acid is an essential molecule involved in many biological and pathological
         Our research is now aimed towards the understanding of the biochemistry
and biology of GNE in non affected muscle, and subsequently in HIBM muscle
tissue, by investigating different biochemical and biological aspects of the GNE
activity in muscle tissue and cell cultures. Transgenic animals will also be established
bearing the mutated gene. Simultaneously we are investigating the potential partners
of GNE in muscle cells by mass spectrometry, and microchip technology.
        We anticipate that these in vitro and in vivo systems specifically designed for
a genomic and proteomic approach will provide us with the necessary tools to
unravel the mechanisms of GNE protein in normal muscle tissue and possible steps
for the eventual correction of the mutation effect in HIBM.

Identification of genes involved in hereditary cardiomyopathies

        Recently, several transcription factors have been implicated in the complex
biological process of cardiac development. An approach to the understanding of
some of the steps involved is the identification of human mutations that cause
congenital heart disease. In collaboration with Dr Annick Raas Rothschild from the
Department of Human Genetics and Dr Azaria Rein from the Department of Pediatric
Cardiology, we are analyzing various families affected by congenital cardiac

Molecular markers for the detection            of   breast   and    colon   cancer
micrometastases in axillary lymph nodes

        Micrometastases in axillary lymph nodes have been detected by serial
sectioning and immunohistochemistry., and shown to have prognostic significance.
When compared to node-negative disease, the presence of even a single
micrometastasis in a lymph node, is associated with a significant difference in
recurrence and survival, and therefore will determine the nature of the treatment to
follow. In collaboration with Dr Aviram Nissan, from the Department of Surgery at
Mount Scopus, we are developing assays for an increased rate of detection of tumor
involvement within an excised node, by the measurement of differentially expressed
gene transcripts, using a Real Time PCR amplification methods.

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