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Int J Clin Exp Pathol 2010;3(4):386-400
Original Article
Testing the effects of FSHD candidate gene expression in vertebrate muscle
development
Ryan D. Wuebbles, Steven W. Long, Meredith L. Hanel, Peter L. Jones
Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, 601 S. Goodwin Ave, B107 Chemical and Life
Sciences Laboratory, Urbana, IL 61801 USA
Received March 1, 2010; accepted March, 2010; available online March, 2010
Abstract: The genetic lesion leading to facioscapulohumeral muscular dystrophy (FSHD) is a dominant deletion at the 4q35 locus. The
generally accepted disease model involves an epigenetic dysregulation in the region resulting in the upregulation of one or more
proximal genes whose overexpression specifically affects skeletal muscle. However, multiple FSHD candidate genes have been proposed
without clear consensus. Using Xenopus laevis as a model for vertebrate development our lab has studied the effects of overexpression of the
FSHD candidate gene ortholog, frg1 (FSHD region gene 1), showing that increased levels of frg1 systemically led specifically to an abnormal
musculature and increased angiogenesis, the two most prominent clinical features of FSHD. Here we studied the overexpression effects of
three other promising FSHD candidate genes, DUX4, DUX4c, and PITX1 using the same model system and methods for direct comparison.
Expression of even very low levels of either DUX4 or pitx1 early in development led to massive cellular loss and severely abnormal
development. These abnormalities were not muscle specific. In contrast, elevated levels of DUX4c resulted in no detectable adverse affects on
muscle and DUX4c levels did not alter the expression of myogenic regulators. This data supports a model for DUX4 and PITX1 in FSHD only as
pro-apoptotic factors if their expression in FSHD is confined to cells within the myogenic pathway; neither could account for the vascular
pathology prevalent in FSHD. Taken together, increased frg1 expression alone leads to a phenotype that most closely resembles the
pathophysiology observed in FSHD patients..(IJCEP1003001).
Key words: facioscapulohumeral muscular dystrophy, FSHD, DUX4, DUX4c, PITX1, FRG1
Full text PDF
Address all correspondence to:
Peter L. Jones, PhD
Department of Cell and Developmental Biology
University of Illinois at Urbana-Champaign
601 S. Goodwin Ave, B107 Chemical and Life Sciences Laboratory,
Urbana, IL 61801
USA.
Tel: (217) 265-6462
Fax: (217) 244-1648
E-mail: pljones@life.illinois.edu
Original Article
Testing the effects of FSHD candidate gene expression in vertebrate muscle
development
Ryan D. Wuebbles, Steven W. Long, Meredith L. Hanel, Peter L. Jones
Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, 601 S. Goodwin Ave, B107 Chemical and Life
Sciences Laboratory, Urbana, IL 61801 USA
Received March 1, 2010; accepted March, 2010; available online March, 2010
Abstract: The genetic lesion leading to facioscapulohumeral muscular dystrophy (FSHD) is a dominant deletion at the 4q35 locus. The
generally accepted disease model involves an epigenetic dysregulation in the region resulting in the upregulation of one or more
proximal genes whose overexpression specifically affects skeletal muscle. However, multiple FSHD candidate genes have been proposed
without clear consensus. Using Xenopus laevis as a model for vertebrate development our lab has studied the effects of overexpression of the
FSHD candidate gene ortholog, frg1 (FSHD region gene 1), showing that increased levels of frg1 systemically led specifically to an abnormal
musculature and increased angiogenesis, the two most prominent clinical features of FSHD. Here we studied the overexpression effects of
three other promising FSHD candidate genes, DUX4, DUX4c, and PITX1 using the same model system and methods for direct comparison.
Expression of even very low levels of either DUX4 or pitx1 early in development led to massive cellular loss and severely abnormal
development. These abnormalities were not muscle specific. In contrast, elevated levels of DUX4c resulted in no detectable adverse affects on
muscle and DUX4c levels did not alter the expression of myogenic regulators. This data supports a model for DUX4 and PITX1 in FSHD only as
pro-apoptotic factors if their expression in FSHD is confined to cells within the myogenic pathway; neither could account for the vascular
pathology prevalent in FSHD. Taken together, increased frg1 expression alone leads to a phenotype that most closely resembles the
pathophysiology observed in FSHD patients..(IJCEP1003001).
Key words: facioscapulohumeral muscular dystrophy, FSHD, DUX4, DUX4c, PITX1, FRG1
Full text PDF
Address all correspondence to:
Peter L. Jones, PhD
Department of Cell and Developmental Biology
University of Illinois at Urbana-Champaign
601 S. Goodwin Ave, B107 Chemical and Life Sciences Laboratory,
Urbana, IL 61801
USA.
Tel: (217) 265-6462
Fax: (217) 244-1648
E-mail: pljones@life.illinois.edu
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