HAL Id: hal-01907613
https://hal.archives-ouvertes.fr/hal-01907613
Submitted on 9 Nov 2018
HAL is a multi-disciplinary open access
archive for the deposit and dissemination of
sci-entific research documents, whether they are
pub-lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.
L’archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d’enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.
DUX 4 and DUX4 downstream target genes are
expressed in fetal FSHD muscles
M Ferreboeuf, V. Mariot, B. Bessières, A Vasiljevic, Tania Attié-Bitach, S
Collardeau, Stéphane Roche, Frédérique Magdinier, Jérôme Robin-Ducellier,
P Rameau, et al.
To cite this version:
M Ferreboeuf, V. Mariot, B. Bessières, A Vasiljevic, Tania Attié-Bitach, et al..
DUX 4
and DUX4 downstream target genes are expressed in fetal FSHD muscles.
18th International
Congress of The World Muscle Society, Oct 2013, Pacific Grove, CA, United States.
pp.823,
�10.1016/j.nmd.2013.06.640�. �hal-01907613�
P.16.2
The DUX4 promoter is expressed in FSHD-affected tissues L. Wallace, J. Liu, S. Garwick-Coppens, S. Guckes, S. Harper The Research Institute at Nationwide Children’s Hospital, Center for Gene Therapy, Columbus, United States
Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disorder with a 1 in 7500 incidence. Symptoms typically arise in young adulthood and most patients show clinical features before age 30. FSHD is most commonly characterized by progressive wasting and weakness of facial and shoulder-girdle muscles, although no consistent pattern of penetrance or severity exists, even within affected families. A hallmark characteristic of FSHD is asymmetrical muscle weakness. There are also non-muscular features including retinal vasculopathy and high frequency hearing loss. Several recent breakthroughs now support a model in which mis-expression of the myotoxic DUX4 gene is a primary patho-genic event underlying FSHD. We hypothesized that there was a direct correlation between DUX4 expression patterns and the involvement of selected muscles (and ear and retinal pathologies) in FSHD. In short, we proposed that if DUX4 over-expression is indeed an underlying path-ogenic event in FSHD, it must be preferentially expressed in FSHD-affected regions. To test this hypothesis, we developed transgenic reporter mice containing a putative DUX4 promoter cloned upstream of GFP. We generated three separate lines of DUX4 promoter-GFP mice. We found the DUX4 promoter directed GFP expression in the face and limbs of newborn and adult mice, as well as multiple cell types in the retina. Essen-tially all other organs were GFP negative with a few exceptions including the pancreas and brain (cerebellum, olfactory bulb, and hippocampus). Strikingly, all lines showed asymmetrical expression and variable pene-trance in all GFP-positive tissues, even within individual litters. We con-clude that our mice faithfully recapitulate expected DUX4 expression patterns in regions of FSHD pathology, and further suggest the role of DUX4 as pathogenic insult in FSHD. We are now using a modified but analogous system to inducibly express DUX4.
http://dx.doi:10.1016/j.nmd.2013.06.639
P.16.3
DUX 4 and DUX4 downstream target genes are expressed in fetal FSHD muscles
M. Ferreboeuf1, V. Mariot1, B. Bessie`res2, A. Vasiljevic3, T. Attie´-Bitach2, S. Collardeau3, S. Roche4, F. Magdinier4, J. Robin-Ducellier5, P. Rameau6, S. Whalen7, S. Sacconi8, V. Mouly1, G. Butler-Browne1,
J. Dumonceaux1
1Universite´ Pierre et Marie Curie, Paris, France; 2Universite´ Paris
Descartes, Paris, France; 3CHU-Lyon, Bron, France; 4Faculte´ de
Me´de-cine de la Timone, Marseille, France; 5UT Southwestern Medical Center,
Dallas, United States; 6Institut Gustave Roussy, Villejuif,
France; 7Groupe hospitalier Pitie´-Salpe´trie`re, Paris, France; 8Nice
Uni-versity Hospital, Nice, France
The facio scapulo humeral dystrophy (FSHD) is the third most preva-lent muscular dystrophy. The common clinical signs usually appear during the second decade of life but when the first molecular dysregulations occur is still unknown. Our aim was to determine whether molecular dysregula-tions can be identified during FSHD fetal muscle development. We com-pared 2 muscle biopsies coming from one FSHD fetus and the cells derived from these biopsies with biopsies and cells coming from control fetuses. We mainly focus on DUX4 isoform expression since the expression of DUX4 has been confirmed in both FSHD cells and biopsies by several laboratories.
We measured by qRT-PCR DUX4 isoforms expression in fetal FSDH myotubes treated or not with a shRNA directed against DUX4 mRNA. We also analyzed DUX4 downstream genes expression in myotubes and fetal or adult FSDH and control quadriceps biopsies.
We show that DUX4-FL is not expressed in control myotubes whereas it is expressed FSHD myotubes. Interestingly, DUX4-FL expression level is much lower in trapezius than in quadriceps myotubes which is con-firmed by the level of expression of DUX4 downstream genes: We observed that TRIM43 and MBD3L2 are already overexpressed in FSHD fetal quadriceps biopsies, at similar levels at those observed in adult FSHD quadriceps biopsies.
These results indicate that molecular markers of the disease are already expressed during fetal life, raising the question as to the role of DUX4 in the onset and progression of FSHD.
http://dx.doi:10.1016/j.nmd.2013.06.640
P.16.4
Psychoanalysis impact to facioscapulohumeral (FSHD) patients
J. Forbes1, T. Genesini1, C. Riolfi1, E. Macedo2, D. Ru¨diger2, L. Lise2,
A. Mouzat2, R.C.M. Pavanello3, M. Zatz3
1Human Genome Research Center – University of Sa˜o Paulo and Institute
of Lacanian Psychoanalysis – IPLA, Biosciences Institute, Sa˜o Paulo, Brazil; 2Human Genome Research Center – University of Sa˜o Paulo and Institute of Lacanian Psychoanalysis – IPLA, Biosciences Institute, Sa˜o Paulo, Brazil; 3Human Genome Research Center– University of Sa˜o Paulo, Biosciences Institute, Sa˜o Paulo, Brazil
Among 67 neuromuscular patients searching for psychoanalysis treat-ment (in the Psychoanalysis Clinic, Human Genome Center), facioscapu-lohumeral (FSHD) patients constitute an important group. Ten patients with clinical course ranging for very mildly to severely affected have asked for treatment with complaints of depression to date. Two patients, L. and J., described below, both with a family history of FSHD whose diagnosis were confirmed by molecular analysis, illustrate the positive effect of such approach.
L., aged 45, father of three children was only mildly affected. He never told his family that he had a genetic disorder. When his younger son started to show clinical signs of FSHD he found out he could not hide it any more but did not know how to deal with this situation. After 3 months of treatment he had not only revealed the truth to his family but also had decided to launch a similar psychoanalysis approach in his home town. In his last visit he declared: “For the first time in my life I took off my shirt and enjoyed swimming in the ocean”.
J., aged 31, was examined for the first time at the HGC when she was 20 years old. She referred that since she was 12 years-old she had difficulty raising her arms and she was never able to whistle. Currently, she has signif-icant hypotonia, upper limbs proximal asymmetrical muscle weakness and atrophy, facial weakness (inability to whistle, smile and close the eyes), severe lumbar hyperlordosis, scapular winging and proximal lower limbs weakness. Her mother and other maternal relatives are also affected but less severely. After psychoanalysis treatment she abandoned her resignation “feeling” and rejected others compassion “feeling” towards her. Despite her severe body deformity she decided to pursue her dream to be a teacher and went back to college. Similarly to the first patient she is now not ashamed of her body and they found another way to cope with their own sexuality. http://dx.doi:10.1016/j.nmd.2013.06.641
P.16.5
Anxiety is responsible for altered sleep quality in Facio-Scapulo-Humeral Muscular Dystrophy (FSHD)
L. Leclair-Visonneau1, A. Magot2, A. Tremblay3, X. Bruneau3, Y. Pereon2
