Thursday, September 3, 2009

Amis FSH Europe - Research News

FSHD Alert - September 1st

Exp Neurol, August 12, 2009; .
Engraftment of Embryonic Stem Cell-Derived Myogenic Progenitors in a Dominant Model of Muscular Dystrophy.
Radbod Darabi, June Baik, Mark Clee, Michael Kyba, Rossella Tupler, and Rita C R Perlingeiro
Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas-TX, USA; Lillehei Heart Institute, Department of Medicine, University of Minnesota, Minneapolis-MN, USA.

Muscular dystrophies (MD) consist of a genetically heterogeneous group of disorders, recessive or dominant, characterized by progressive skeletal muscle weakening. To date, no effective treatment is available. Experimental strategies pursuing muscle regeneration through the transplantation of stem cell preparations have brought hope to patients affected by this disorder. Efficacy has been demonstrated in recessive MD models through contribution of wild-type nuclei to the muscle fiber heterokaryon, however to date, there has been no study investigating the efficacy of a cell therapy in a dominant model of MD. We have recently demonstrated that Pax3-induced embryonic stem (ES) cell- derived myogenic progenitors are able to engraft and improve muscle function in mdx mice, a recessive mouse model for Duchenne MD. To assess whether this therapeutic effect can be extended to a dominant type of muscle disorder, here we transplanted these cells into FRG1 transgenic mice, a dominant model that has been associated with Facioscapulohumeral muscular dystrophy.

Our results show that Pax3-induced ES-derived myogenic progenitors are capable of significant engraftment after intramuscular or systemic transplantation into Frg1 mice. Analyses of contractile parameters revealed functional improvement in treated muscles of male mice, but not females, which are less severely affected.
This study is the first to use Frg1 transgenic mice to assess muscle regeneration as well as to support the use of a cell-based therapy for autosomal dominant types of MD.
Permanent muscle weakness in MCArdle disease.
Aleksandra A Nadaj-Pakleza, Carlo M Vincitorio, Pascal Laforet, Bruno Eymard, Elisabeth Dion, Susana Teijeira, Irene Vietez, Marc Jeanpierre, Carmen Navarro, and Tanya Stojkovic
Muscle Nerve, August 7, 2009; .

Institute of Myology, Pitié-Salpêtrière Hospital, 47-83, Boulevard de l'Hôpital, 75651 Paris Cedex 13, France.
McArdle disease is an autosomal recessive muscle glycogenosis. In the typical clinical presentation, only exercise-related symptoms are noted. Nevertheless, permanent weakness may occur, usually late in life. In this study we report on the clinical and genetic features of fixed muscle weakness in McArdle disease. Among the 80 McArdle patients being followed at the Institute of Myology of the Salpêtrière Hospital, 9 patients have permanent weakness. The diagnosis of McArdle disease was confirmed by muscle biopsy and genetic investigations. Two patterns of muscle weakness and wasting were noted: (1) proximal and symmetric in 5patients; and (2) asymmetric, mimicking facioscapulohumeral dystrophy (FSHD) in 4 patients. Computerized tomography scan showed fatty infiltration in the shoulder and pelvic girdle muscles. There was no clear correlation between genotype and the severity of muscle weakness.
Proximal muscle weakness appeared after the age of 40 years and affected 11% of subjects in our series of 80 McArdle patients. Among patients over 40 years of age, 37.5% had muscle weakness. Muscle Nerve, 2009.

Macrosatellite epigenetics: the two faces of DXZ4 and D4Z4.
Brian P Chadwick - Chromosoma, August 19, 2009; .
Department of Biological Science, Florida State University, 3090 King Life Sciences Building, Tallahassee, FL, 32306, USA,

Almost half of the human genome consists of repetitive DNA. Understanding what role these elements have in setting up chromatin states that underlie gene and chromosome function in complex genomes is paramount. The function of some types of repetitive DNA is obvious by virtue of their location, such as the alphoid arrays that define active centromeres. However, there are many other types of repetitive DNA whose evolutionary origins and current roles in genome biology remain unknown. One type of repetitive DNA that falls into this class is the macrosatellites. The relevance of these sequences to disease is clearly demonstrated by the 4q macrosatellite (D4Z4), whereupon contraction in the size of the array is associated with the onset of facioscapulohumeral muscular dystrophy.

Here, I describe recent findings relating to the chromatin organization of D4Z4 and that of the X-linked macrosatellite DXZ4, highlighting the fact that these enigmatic sequences share more than a similar name.
Identification of a perinuclear positioning element in human subtelomeres that requires A-type lamins and CTCF.
A Ottaviani, C Schluth-Bolard, S Rival-Gervier, A Boussouar, D Rondier, AM Foerster, J Morere, S Bauwens, S Gazzo, E Callet-Bauchu, E Gilson, and F Magdinier
EMBO J, August 19, 2009; 28(16): 2428-36.

Laboratoire de Biologie Moléculaire de la Cellule, Ecole Normale Supérieure de Lyon, CNRS UMR 5239, UCBL1, Lyon Cedex, France.

The localization of genes within the nuclear space is of paramount importance for proper genome functions. However, very little is known on the cis-acting elements determining subnuclear positioning of chromosome segments. We show here that the D4Z4 human subtelomeric repeat localizes a telomere at the nuclear periphery. This perinuclear activity lies within an 80 bp sequence included within a region known to interact with CTCF and A-type Lamins. We further show that a reduced level of either CTCF or A-type Lamins suppresses the perinuclear activities of D4Z4 and that an array of multimerized D4Z4 sequence, which has lost its ability to bind CTCF and A-type Lamins, is not localized at the periphery. Overall, these findings reveal the existence of an 80 bp D4Z4 sequence that is sufficient to position an adjacent telomere to the nuclear periphery in a CTCF and A-type lamins-dependent manner.

Strikingly, this sequence includes a 30 bp GA-rich motif, which binds CTCF and is present at several locations in the human genome.
Biochem Biophys Res Commun. 2009 Aug 27.
Reduction of a 4q35-Encoded Nuclear Envelope Protein in Muscle Differentiation.
Ostlund C, Guan T, Figlewicz DA, Hays AP, Worman HJ, Gerace L, Schirmer EC.
Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA; Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Muscular dystrophy and peripheral neuropathy have been linked to mutations in genes encoding nuclear envelope proteins; however, the molecular mechanisms underlying these disorders remain unresolved. Nuclear envelope protein p19A is a protein of unknown function encoded by a gene at chromosome 4q35. p19A levels are significantly reduced in human muscle as cells differentiate from myoblasts to myotubes; however, its levels are not similarly reduced in all differentiation systems tested. Because 4q35 has been linked to facioscapulohumeral muscular dystrophy (FSHD) and some adjacent genes are reportedly misregulated in the disorder, levels of p19A were analyzed in muscle samples from patients with FSHD. Although p19A was increased in most cases, an absolute correlation was not observed.

Nonetheless, p19A downregulation in normal muscle differentiation suggests that in the cases where its gene is inappropriately re-activated it could affect muscle differentiation and contribute to disease pathology.


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