Scientific Projects

Current Fields Center projects are focused on the following areas of FSHD (FSH dystrophy) research:

 

CLINICAL RESEARCH:

  • Clinical Care: Develop clinical practice guidelines for the care of individuals with FSHD. These practice guidelines will deal with issues such as genetic testing, physical therapy, exercise, bracing, scapular surgery and potential retinal and respiratory complications of FSHD. The guidelines will help standardize the care of patients with FSHD across the world.
  • Clincal Trials Readiness: Develop consensus on the best outcome measures for future FSHD clinical trials. As part of this effort, we are developing a disease-specific, patient-determined outcome measure.

BASIC AND TRANSLATIONAL RESEARCH:

  • Development of Biological Resources: Collect DNA, muscle and skin biopsy samples from individuals with FSHD who are carefully characterised to allow for accurate correlation of the clinical manifestations with changes observed in the DNA and tissue samples. Tissue resources generated include muscle biopsy samples, myoblasts cell lines, fibroblast cell lines as well as the creation of immortalized myoblasts..
  • Detailed genotyping of patients with FSHD: This allows the identification of rare kindreds with unsual large deletions extending outside of the known D4Z4 repeat area allowing a better understanding of the minimal region of 4q35 necessary to cause FSHD. Additionally, detailed genotyping will allow the identification of unique DNA sequences within the distal part of of 4q35 necessary for the development of FSHD.
  • Indentification of the underlying pathophysiology of FSHD: In 2010, Fields Center investigators discovered that contraction of the repeat DNA elements on chromosome 4 which occurs in 95% of individuals with FSHD leads to the inappropriate expression of the toxic gene DUX4. In 2012, the same investigators identified another gene, a mutation in which also cause the inappropriate expression of DUX4. This second mechanism for triggering the epxression of DUX4 occurs in the remaining 5% of patients with FSHD, also known now as FSHD type 2.
  • Identification of therapeutic targets for FSHD: Finding effective treatments for patients with FSHD is the ultimate target of the Fields Center. Discovering the underlying cause of FSHD, namely the inappropriate expression of a toxic gene, investigators across the globe now have a target for treatment. The efforts of the FIelds Center investigators have now shifter towards the development of therapeutic interventions for FSHD.

Scientific Publications

 

The following is a list of Scientific publications of studies performed by the Fields Center investigators.

 

    1. Scully MA, Eichinger KJ, Donlin-Smith CM, Tawil R, Statland JM. Restrictive Lung Involvement in Facioscapulohumeral Muscular Dystrophy. Muscle Nerve. 2014 Feb 23. doi: 10.1002/mus.24218. [Epub ahead of print]PMID: 24639337
    2. Tawil R, Shaw DW, van der Maarel SM, Tapscott SJ.. Clinical trial preparedness in facioscapulohumeral dystrophy: Outcome measures and patient access: 8-9 April 2013, Leiden, The Netherlands.Neuromuscul Disord. 2013 Aug 2. doi:pii: S0960-8966(13)00929-2. 10.1016/j.nmd.2013.07.009.

    3. Sacconi S, Lemmers RJ, Balog J, van der Vliet PJ, Lahaut P, van Nieuwenhuizen MP, Straasheijm KR, Debipersad RD, Vos-Versteeg M, Salviati L, Casarin A, Pegoraro E, Tawil R, Bakker E, Tapscott SJ, Desnuelle C, van der Maarel SM. The FSHD2 Gene SMCHD1 Is a Modifier of Disease Severity in Families Affected by FSHD1. Am J Hum Genet. 2013 Sep 25. doi:pii: S0002-9297(13)00379-0. 10.1016/j.ajhg.2013.08.004. PMID: 24075187
    4. Darras BT, Tawil R. Predicting hearing loss in facioscapulohumeral muscular dystrophy.  Neurology. 2013 Sep 16. [Epub ahead of print]. PMID: 24042094.
    5. Statland JM, Tawil R. Risk of functional impairment in facioscapulohumeral muscular dystrophy. Muscle Nerve. 2013 Jul 19. doi: 10.1002/mus.23949. [Epub ahead of print] PMID: 23873337 [PubMed - as supplied by publisher]
    6. Block GJ, Narayanan D, Amell AM, Petek LM, Davidson KC, Bird TD, Tawil R, Moon RT, Miller DG. Wnt/β-catenin signaling suppresses DUX4 expression and prevents apoptosis of FSHD muscle cells. Hum Mol Genet. 2013 Jul 12. [Epub ahead of print] PMID: 23821646 [PubMed - as supplied by publisher]
    7. Krom YD, Thijssen PE, Young JM, den Hamer B, Balog J, Yao Z, Maves L, Snider L, Knopp P, Zammit PS, Rijkers T, van Engelen BG, Padberg GW, Frants RR, Tawil R, Tapscott SJ, van der Maarel SM. Intrinsic Epigenetic Regulation of the D4Z4 Macrosatellite Repeat in a Transgenic Mouse Model for FSHD. PLoS Genet. 2013 Apr;9(4):e1003415. doi: 10.1371/journal.pgen.1003415. Epub 2013 Apr 4. PMID: 23593020 [PubMed - in process] Free PMC Article
    8. Lassche S, Stienen GJ, Irving TC, van der Maarel SM, Voermans NC, Padberg GW, Granzier H, van Engelen BG, Ottenheijm CA. Sarcomeric dysfunction contributes to muscle weakness in facioscapulohumeral muscular dystrophy. Neurology. 2013 Feb 19;80(8):733-7. doi: 10.1212/WNL.0b013e318282513b. Epub 2013 Jan 30.PMID: 23365058
    9. Hartweck LM, Anderson LJ, Lemmers RJ, Dandapat A, Toso EA, Dalton JC, Tawil R, Day JW, van der Maarel SM, Kyba M. A focal domain of extreme demethylation within D4Z4 in FSHD2 . Neurology. 2013 Jan 22;80(4):392-9. doi: 0.1212/WNL.0b013e31827f075c. Epub 2013 Jan 2. PMID: 23284062

    10. Statland JM, Sacconi S, Farmakidis C, Donlin-Smith CM, Chung M, Tawil R. Coats syndrome in facioscapulohumeral dystrophy type 1: Frequency and D4Z4 contraction size. Neurology. 2013 Feb 27. Neurology. 2013 Feb 27. [Epub ahead of print] PMID: 23446679 [PubMed - as supplied by publisher]
    11. Statland JM, McDermott MP, Heatwole C, Martens WB, Pandya S, van der Kooi EL, Kissel JT, Wagner KR, Tawil R. Reevaluating measures of disease progression in facioscapulohumeral muscular dystrophy. Neuromuscul Disord. 2013 Feb 11. doi:pii: S0960-8966(13)00033-3. 10.1016/j.nmd.2013.01.008. [Epub ahead of print] PMID: 23406877 [PubMed - as supplied by publisher]
    12. Johnson NE, Quinn C, Eastwood E, Tawil R, Heatwole CR. Patient-identified disease burden in facioscapulohumeral muscular dystrophy. Muscle Nerve. 2012 Dec;46(6):948-50.
    13. Lemmers RJ, Tawil R, Petek LM, Balog J, Block GJ, Santen GW, Amell AM, van der Vliet PJ, Almomani R, Straasheijm KR, Krom YD, Klooster R, Sun Y, den Dunnen JT, Helmer Q, Donlin-Smith CM, Padberg GW, van Engelen BG, de Greef JC, Aartsma-Rus AM, Frants RR, de Visser M, Desnuelle C, Sacconi S, Filippova GN, Bakker B, Bamshad MJ, Tapscott SJ, Miller DG, van der Maarel SM. Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2. Nat Genet. 2012 Dec;44(12):1370-4. doi: 10.1038/ng.2454
    14. Hartweck LM, Anderson LJ, Lemmers RJ, Dandapat A, Toso EA, Dalton JC, Tawil R, Day JW, van der Maarel SM, Kyba M. A focal domain of extreme demethylation within D4Z4 in FSHD2. Neurology. 2013 Jan 2. [Epub ahead of print]
    15. Krom YD, Dumonceaux J, Mamchaoui K, den Hamer B, Mariot V, Negroni E, Geng LN, Martin N, Tawil R, Tapscott SJ, van Engelen BG, Mouly V, Butler-Browne GS, van der Maarel SM. Generation of isogenic D4Z4 contracted and noncontracted immortal muscle cell clones from a mosaic patient: a cellular model for FSHD.Am J Pathol. 2012 Oct;181(4):1387-401.
    16. van der Maarel SM, Miller DG, Tawil R, Filippova GN, Tapscott SJ. Facioscapulohumeral muscular dystrophy: consequences of chromatin relaxation. Curr Opin Neurol. 2012 Oct;25(5):614-20.
    17. Block GJ, Petek LM, Narayanan D, Amell AM, Moore JM, Rabaia NA, Tyler A, van der Maarel SM, Tawil R, Filippova GN, Miller DG. Asymmetric Bidirectional Transcription from the FSHD-Causing D4Z4 Array Modulates DUX4 Production. PLoS One. 2012;7(4):e35532. Epub 2012 Apr 20.
    18. Balog J, Thijssen PE, de Greef JC, Shah B, van Engelen BG, Yokomori K, Tapscott SJ, Tawil R, van der Maarel SM. Correlation analysis of clinical parameters with epigenetic modifications in the DUX4 promoter in FSHD. Epigenetics. 2012 Jun 1;7(6). [Epub ahead of print]
    19. Geng LN, Yao Z, Snider L, Fong AP, Cech JN, Young JM, van der Maarel SM, Ruzzo WL, Gentleman RC, Tawil R, Tapscott SJ. DUX4 activates germline genes, retroelements, and immune mediators: implications for facioscapulohumeral dystrophy. Dev Cell. 2012 Jan 17;22(1):38-51.
    20. Hilbert JE, Kissel JT, Luebbe EA, Martens WB, McDermott MP, Sanders DB, Tawil R, Thornton CA, Moxley RT 3rd; Registry Scientific Advisory Committee. If you build a rare disease registry, will they enroll and will they use it? Methods and data from the National Registry of Myotonic Dystrophy (DM) and Facioscapulohumeral Muscular Dystrophy (FSHD). Contemp Clin Trials. 2012 Mar;33(2):302-11.
    21. Balog J, Thijssen P, de Greef JC, Shah B, van Engelen BG, Yokomori K, Tapscott SJ, Tawil R, van der Maarel SM. Correlation analysis of clinical parameters with epigenetic modifications in the DUX4 promoter in FSHD. Epigenetics. 2012 Jun 1;7(6).
    22. van der Maarel SM, Tawil R, Tapscott SJ. Facioscapulohumeral muscular dystrophy and DUX4: breaking the silence. Trends Mol Med. 2011 Jan 31. [Epub ahead of print] PMID: 21288772 [PubMed - as supplied by publisher]
    23. Snider L, Geng LN, Lemmers RJ, Kyba M, Ware CB, Nelson AM, Tawil R, Filippova GN, van der Maarel SM, Tapscott SJ, Miller DG. Facioscapulohumeral dystrophy: incomplete suppression of a retrotransposed gene. PLoS Genet. 2010 Oct 28;6(10):e1001181.
    24. van der Maarel SM, Tawil R, Tapscott SJ. Facioscapulohumeral muscular dystrophy and DUX4: breaking the silence. Trends Mol Med. 2011 May;17(5):252-8. Epub 2011 Feb 1.
    25. Statland JM, Tawil R. Facioscapulohumeral muscular dystrophy: molecular pathological advances and future directions.Curr Opin Neurol. 2011 Oct;24(5):423-8.
    26. Tsumagari K, Chang SC, Lacey M, Baribault C, Chittur SV, Sowden J, Tawil R, Crawford GE, Ehrlich M. Gene expression during normal and FSHD myogenesis. BMC Med Genomics. 2011 Sep 27;4:67.
    27. de Greef JC, Lemmers RJ, Camaño P, Day JW, Sacconi S, Dunand M, van Engelen BG, Kiuru-Enari S, Padberg GW, Rosa AL, Desnuelle C, Spuler S, Tarnopolsky M, Venance SL, Frants RR, van der Maarel SM, Tawil R. Clinical features of facioscapulohumeral muscular dystrophy 2. Neurology. 2010 Oct 26;75(17):1548-54. PMID: 20975055 [PubMed - in process]
    28. Lemmers RJ, van der Vliet PJ, Klooster R, Sacconi S, Camaño P, Dauwerse JG, Snider L, Straasheijm KR, Jan van Ommen G, Padberg GW, Miller DG, Tapscott SJ, Tawil R, Frants RR, van der Maarel SM. A Unifying Genetic Model for Facioscapulohumeral Muscular Dystrophy. Science. 2010 Aug 19. [Epub ahead of print] PMID: 20724583 [PubMed - as supplied by publisher]
    29. Tsumagari K, Chen D, Hackman JR, Bossler AD, Ehrlich M.FSH dystrophy and a subtelomeric 4q haplotype: a new assay and associations with disease. J Med Genet. 2010 Aug 15. [Epub ahead of print] PMID: 20710047 [PubMed - as supplied by publisher]
    30. Tawil R, van der Maarel S, Padberg GW, van Engelen BG. 171st ENMC international workshop: Standards of care and management of facioscapulohumeral muscular dystrophy. Neuromuscul Disord. 2010 Jul;20(7):471-5. No abstract available. PMID: 20554202 [PubMed - indexed for MEDLINE
    31. Lemmers RJ, van der Vliet PJ, van der Gaag KJ, Zuniga S, Frants RR, de Knijff P, van der Maarel SM. Worldwide population analysis of the 4q and 10q subtelomeres identifies only four discrete interchromosomal sequence transfers in human evolution. Am J Hum Genet. 2010 Mar 12;86(3):364-77. Epub 2010 Mar 4. PMID: 20206332 [PubMed - in process] 
    32. Xu X, Tsumagari K, Sowden J, Tawil R, Boyle AP, Song L, Furey TS, Crawford GE, Ehrlich M. DNaseI hypersensitivity at gene-poor, FSH dystrophy-linked 4q35.2. Nucleic Acids Res. 2009 Dec;37(22):7381-93. [Epub ahead of print] PMID: 19820107 [PubMed - as supplied by publisher]
    33. Masny PS, Chan OY, de Greef JC, Bengtsson U, Ehrlich M, Tawil R, Lock LF, Hewitt JE, Stocksdale J, Martin JH, van der Maarel SM, Winokur ST. Analysis of allele-specific RNA transcription in FSHD by RNA-DNA FISH in single myonuclei. Eur J Hum Genet. 2009 Nov 4. [Epub ahead of print] PMID: 19888305.
    34. Zeng W, de Greef JC, Chen YY, Chien R, Kong X, Gregson HC, Winokur ST, Pyle A, Robertson KD, Schmiesing JA, Kimonis VE, Balog J, Frants RR, Ball AR Jr, Lock LF, Donovan PJ, van der Maarel SM, Yokomori K. Specific loss of histone H3 lysine 9 trimethylation and HP1gamma/cohesin binding at D4Z4 repeats is associated with facioscapulohumeral dystrophy (FSHD). PLoS Genet. 2009 Jul;5(7):e1000559. Epub 2009 Jul 10. PMID: 19593370
    35. de Greef JC, Lemmers RJ, van Engelen BG, Sacconi S, Venance SL, Frants RR, Tawil R, van der Maarel SM. Common epigenetic changes of D4Z4 in contraction-dependent and contraction-independent FSHD. Hum Mutat. 2009 Jul 14. [Epub ahead of print] PMID: 19728363 [PubMed - as supplied by publisher]
    36. Snider L, Asawachaicharn A, Tyler AE, Geng LN, Petek LM, Maves L, Miller DG, Lemmers RJ, Winokur ST, Tawil R, van der Maarel SM, Filippova GN, Tapscott SJ. RNA Transcripts, miRNA-sized Fragments, and Proteins Produced from D4Z4 Units: New Candidates for the Pathophysiology of Facioscapulohumeral Dystrophy. Hum Mol Genet. 2009 Apr 9. [Epub ahead of print] PMID: 19359275.
    37. Klooster R, Straasheijm K, Shah B, Sowden J, Frants R, Thornton C, Tawil R, van der Maarel S.Comprehensive expression analysis of FSHD candidate genes at the mRNA and protein level. Eur J Hum Genet. 2009 Oct 7. [Epub ahead of print] PMID: 19809486 [PubMed - as supplied by publisher]
    38. Tawil R. Facioscapulohumeral muscular dystrophy. Neurotherapeutics. 2008; 5(4):601-6. PMID: 19019312.
    39. de Greef JC, Frants RR, van der Maarel SM. Epigenetic mechanisms of facioscapulohumeral muscular dystrophy. Mutat Res. 2008 Aug 3. [Epub ahead of print] PMID: 18723032.
    40. van der Maarel SM. Epigenetic mechanisms in health and disease. Ann Rhem Dis. 2008. PMID: 19022824.
    41. Pandya S, King WM, Tawil R. Facioscapulohumeral dystrophy. Phys Ther. 2008 Jan;88(1):105-13.

For more information, please contact the Fields Center FieldsCenter@urmc.rochester.edu