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1861 Person with muscular dystrophy depicted by Duchenne. Based on the muscles involved, this person could have had FSHD.
1884 Landouzy and Dejerine describe a form of childhood progressive muscle atrophy with a characteristic involvement of facial muscles and distinct from pseudohypertrophic (Duchenne's MD) and spinal muscle atrophy in adults.[1]
Two brothers with FSHD followed by Landouzy and Dejerine
Photograph of one brother at age 21. The right scapula is protracted, downwardly rotated, and laterally displaced.
Drawing of another brother at age 17. Visible is lumbar hyperlordosis. The upper arm and pectoral muscles appear atrophied.
1886 Landouzy and Dejerine describe progressive muscular atrophy of the scapulo-humeral type.[2]
1950 Tyler and Stephens study 1249 individuals from a single kindred with FSHD traced to a single ancestor and describe a typical Mendelian inheritance pattern with complete penetrance and highly variable expression. The term facioscapulohumeral dystrophy is introduced.[3]
1982 Padberg provides the first linkage studies to determine the genetic locus for FSHD in his seminal thesis "Facioscapulohumeral disease."[4]
1987 The complete sequence of the Dystrophin gene (Duchenne's MD) is determined.[5]
1991 The genetic defect in FSHD is linked to a region (4q35) near the tip of the long arm of chromosome 4.[6]
1992 FSHD, in both familial and de novo cases, is found to be linked to a recombination event that reduces the size of 4q EcoR1 fragment to < 28 kb (50–300 kb normally).[7]
1993 4q EcoR1 fragments are found to contain tandem arrangement of multiple 3.3-kb units (D4Z4), and FSHD is associated with the presence of < 11 D4Z4 units.[8]

A study of seven families with FSHD reveals evidence of genetic heterogeneity in FSHD.[9]

1994 The heterochromatic structure of 4q35 is recognized as a factor that may affect the expression of FSHD, possibly via position-effect variegation.[10]

DNA sequencing within D4Z4 units shows they contain an open reading frame corresponding to two homeobox domains, but investigators conclude that D4Z4 is unlikely to code for a functional transcript.[10][11]

1995 The terms FSHD1A and FSHD1B are introduced to describe 4q-linked and non-4q-linked forms of the disease.[12]
1996 FSHD Region Gene1 (FRG1) is discovered 100 kb proximal to D4Z4.[13]
1998 Monozygotic twins with vastly different clinical expression of FSHD are described.[14]
1999 Complete sequencing of 4q35 D4Z4 units reveals a promoter region located 149 bp 5' from the open reading frame for the two homeobox domains, indicating a gene that encodes a protein of 391 amino acid protein (later corrected to 424 aa[15]), given the name DUX4.[16]
2001 Investigators assessed the methylation state (heterochromatin is more highly methylated than euchromatin) of DNA in 4q35 D4Z4. An examination of SmaI, MluI, SacII, and EagI restriction fragments from multiple cell types, including skeletal muscle, revealed no evidence for hypomethylation in cells from FSHD1 patients relative to D4Z4 from unaffected control cells or relative to homologous D4Z4 sites on chromosome 10. However, in all instances, D4Z4 from sperm was hypomethylated relative to D4Z4 from somatic tissues.[17]
2002 A polymorphic segment of 10 kb directly distal to D4Z4 is found to exist in two allelic forms, designated 4qA and 4qB. FSHD1 is associated solely with the 4qA allele.[18]

Three genes (FRG1, FRG2, ANT1) located in the region just centromeric to D4Z4 on chromosome 4 are found in isolated muscle cells from individuals with FSHD at levels 10 to 60 times greater than normal, showing a linkage between D4Z4 contractions and altered expression of 4q35 genes.[19]

2003 A further examination of DNA methylation in different 4q35 D4Z4 restriction fragments (BsaAI and FseI) showed significant hypomethylation at both sites for individuals with FSHD1, non-FSHD-expressing gene carriers, and individuals with phenotypic FSHD relative to unaffected controls.[20]
2004 Contraction of the D4Z4 region on the 4qB allele to < 38 kb does not cause FSHD.[21]
2006 Transgenic mice overexpressing FRG1 are shown to develop severe myopathy.[22]
2007 The DUX4 open reading frame is found to have been conserved in the genome of primates for over 100 million years, supporting the likelihood that it encodes a required protein.[23]

Researchers identify DUX4 mRNA in primary FSHD myoblasts and identify in D4Z4-transfected cells a DUX4 protein, the overexpression of which induces cell death.[15]

DUX4 mRNA and protein expression are reported to increase in myoblasts from FSHD patients, compared to unaffected controls. Stable DUX4 mRNA is transcribed only from the most distal D4Z4 unit, which uses an intron and a polyadenylation signal provided by the flanking pLAM region. DUX4 protein is identified as a transcription factor, and evidence suggests overexpression of DUX4 is linked to an increase in the target paired-like homeodomain transcription factor 1 (PITX1).[24]

2009 The terms FSHD1 and FSHD2 are introduced to describe D4Z4-deletion-linked and non-D4Z4-deletion-linked genetic forms, respectively. In FSHD1, hypomethylation is restricted to the short 4q allele, whereas FSHD2 is characterized by hypomethylation of both 4q and both 10q alleles.[25]

Splicing and cleavage of the terminal (most telomeric) 4q D4Z4 DUX4 transcript in primary myoblasts and fibroblasts from FSHD patients is found to result in the generation of multiple RNAs, including small noncoding RNAs, antisense RNAs and capped mRNAs as new candidates for the pathophysiology of FSHD.[26]


Mechanism proposed of DBE-T (D4Z4 Regulatory Element transcript) leading to de-repression of 4q35 genes.[27]

2010 A unifying genetic model of FSHD is established: D4Z4 contractions only cause FSHD when in the context of a 4qA allele due to stabilization of DUX4 RNA transcript, allowing DUX4 expression.[28] Several organizations including The New York Times highlighted this research[29] (See FSHD Society).

Dr. Francis Collins, who oversaw the first sequencing of the Human Genome with the National Institutes of Health stated:[29]

"If we were thinking of a collection of the genome's greatest hits, this would go on the list,"

Daniel Perez, co-founder of the FSHD Society, hailed the new findings saying:[citation needed]

"This is a long-sought explanation of the exact biological workings of [FSHD]"

The MDA stated that:[citation needed]

"Now, the hunt is on for which proteins or genetic instructions (RNA) cause the problem for muscle tissue in FSHD."

One of the report's co-authors, Silvère van der Maarel of the University of Leiden, stated that[citation needed]

"It is amazing to realize that a long and frustrating journey of almost two decades now culminates in the identification of a single small DNA variant that differs between patients and people without the disease. We finally have a target that we can go after."

DUX4 is found actively transcribed in skeletal muscle biopsies and primary myoblasts. FSHD-affected cells produce a full-length transcript, DUX4-fl, whereas alternative splicing in unaffected individuals results in the production of a shorter, 3'-truncated transcript (DUX4-s). The low overall expression of both transcripts in muscle is attributed to relatively high expression in a small number of nuclei (~ 1 in 1000). Higher levels of DUX4 expression in human testis (~100 fold higher than skeletal muscle) suggest a developmental role for DUX4 in human development. Higher levels of DUX4-s (vs DUX4-fl) are shown to correlate with a greater degree of DUX-4 H3K9me3-methylation.[30]

2012 Some instances of FSHD2 are linked to mutations in the SMCHD1 gene on chromosome 18, and a genetic/mechanistic intersection of FSHD1 and FSHD2 is established.[31]

The prevalence of FSHD-like D4Z4 deletions on permissive alleles is significantly higher than the prevalence of FSHD in the general population, challenging the criteria for molecular diagnosis of FSHD.[32]

When expressed in primary myoblasts, DUX4-fl acted as a transcriptional activator, producing a > 3-fold change in the expression of 710 genes.[33] A subsequent study using a larger number of samples identified DUX4-fl expression in myogenic cells and muscle tissue from unaffected relatives of FSHD patients, per se, is not sufficient to cause pathology, and that additional modifiers are determinants of disease progression.[34]

2013 Mutations in SMCHD1 are shown to increase the severity of FSHD1.[35]

Transgenic mice carrying D4Z4 arrays from an FSHD1 allele (with 2.5 D4Z4 units), although lacking an obvious FSHD-like skeletal muscle phenotype, are found to recapitulate important genetic expression patterns and epigenetic features of FSHD.[36]

2014 DUX4-fl and downstream target genes are expressed in skeletal muscle biopsies and biopsy-derived cells of fetuses with FSHD-like D4Z4 arrays, indicating that molecular markers of FSHD are already expressed during fetal development.[37]

Researchers "review how the contributions from many labs over many years led to an understanding of a fundamentally new mechanism of human disease" and articulate how the unifying genetic model and subsequent research represent a "pivot-point in FSHD research, transitioning the field from discovery-oriented studies to translational studies aimed at developing therapies based on a sound model of disease pathophysiology." They describe the consensus mechanism of pathophysiology for FSHD as an "inefficient repeat-mediated epigenetic repression of the D4Z4 macrosatellite repeat array on chromosome 4, resulting in the variegated expression of the DUX4 retrogene, encoding a double-homeobox transcription factor, in skeletal muscle."[38]

2020 Voice of the Patient Report released documenting FSHD's impacts on daily life as conveyed by about 400 patients during an FDA externally led Patient-Focused Drug Development meeting, which was held on June 29, 2020.[39][40][41][42]

citations[edit]

  1. ^ Landouzy; Dejerine (1884). "De la myopathie atrophique progressive (myopathie héréditaire, débutant dans l'enfance par la face, sans altération du système nerveux)". Comptes Rendus de l'Académie des Sciences. 98: 53–55.
  2. ^ Landouzy; Dejerine (1886). "Contribution à l'étude de la myopathie atrophique progressive (myopathie atrophique progressive, à type scapulo-huméral)". Comptes Rendus des Séances de la Société de Biologie. 38: 478–481.
  3. ^ Tyler, Frank; Stephens, FE (April 1950). "Studies in disorders of muscle. II Clinical manifestations and inheritance of facioscapulohumeral dystrophy in a large family". Annals of Internal Medicine. 32 (4): 640–660. doi:10.7326/0003-4819-32-4-640. PMID 15411118.
  4. ^ Padberg, GW (1982-10-13). Facioscapulohumeral disease (Thesis). Leiden University.
  5. ^ Koenig, M; Hoffman, EP; Bertelson, CJ; Monaco, AP; Feener, C; Kunkel, LM (Jul 31, 1987). "Complete cloning of the Duchenne muscular dystrophy (DMD) cDNA and preliminary genomic organization of the DMD gene in normal and affected individuals". Cell. 50 (3): 509–517. doi:10.1016/0092-8674(87)90504-6. PMID 3607877. S2CID 35668717.
  6. ^ Wijmenga, C; Padberg, GW; Moerer, P; et al. (April 1991). "Mapping of facioscapulohumeral muscular dystrophy gene to chromosome 4q35-qter by multipoint linkage analysis and in situ hybridization". Genomics. 9 (4): 570–575. doi:10.1016/0888-7543(91)90348-I. PMID 2037288.
  7. ^ Wijmenga, C; Hewitt, JE; Sandkuijl, LA; et al. (Sep 1992). "Chromosome 4q DNA rearrangements associated with facioscapulohumeral muscular dystrophy". Nature Genetics. 2 (1): 26–30. doi:10.1038/ng0992-26. PMID 1363881. S2CID 21940164.
  8. ^ van Deutekom, JC; Wijmenga, C; van Tienhoven, EA; et al. (Dec 1993). "FSHD associated DNA rearrangements are due to deletions of integral copies of a 3.2 kb tandemly repeated unit". Human Molecular Genetics. 2 (12): 2037–2042. doi:10.1093/hmg/2.12.2037. PMID 8111371.
  9. ^ Gilbert, JR; Stajich, JM; Wall, S; et al. (Aug 1993). "Evidence for heterogeneity in facioscapulohumeral muscular dystrophy (FSHD)". American Journal of Human Genetics. 53 (2): 401–408. PMC 1682358. PMID 8328457.
  10. ^ a b Winokur, ST; Bengtsson, U; Feddersen, J; et al. (May 1994). "The DNA rearrangement associated with facioscapulohumeral muscular dystrophy involves a heterochromatin-associated repetitive element: implications for a role of chromatin structure in the pathogenesis of the disease". Chromosome Research. 2 (3): 225–234. doi:10.1007/bf01553323. PMID 8069466. S2CID 6933736.
  11. ^ Hewitt, JE; Lyle, R; Clark, LN; et al. (Aug 1994). "Analysis of the tandem repeat locus D4Z4 associated with facioscapulohumeral muscular dystrophy". Human Molecular Genetics. 3 (8): 1287–1295. doi:10.1093/hmg/3.8.1287. PMID 7987304.
  12. ^ Gilbert, JR; Speer, MC; Stajich, J; et al. (Oct 1995). "Exclusion mapping of chromosomal regions which cross hybridise to FSHD1A associated markers in FSHD1B". Journal of Medical Genetics. 32 (10): 770–773. doi:10.1136/jmg.32.10.770. PMC 1051697. PMID 8558552.
  13. ^ van Deutekom, JC; Lemmers, RJ; Grewal, PK; et al. (May 1996). "Identification of the first gene (FRG1) from the FSHD region on human chromosome 4q35". Human Molecular Genetics. 5 (5): 581–590. doi:10.1093/hmg/5.5.581. PMID 8733123.
  14. ^ Tupler, R; Barbierato, L; et al. (Sep 1998). "Identical de novo mutation at the D4F104S1 locus in monozygotic male twins affected by facioscapulohumeral muscular dystrophy (FSHD) with different clinical expression". Journal of Medical Genetics. 35 (9): 778–783. doi:10.1136/jmg.35.9.778. PMC 1051435. PMID 9733041.
  15. ^ a b Kowaljow, V; Marcowycz, A; Ansseau, E; et al. (Aug 2007). "The DUX4 gene at the FSHD1A locus encodes a pro-apoptotic protein". Neuromuscular Disorders. 17 (8): 611–623. doi:10.1016/j.nmd.2007.04.002. PMID 17588759. S2CID 25926418.
  16. ^ Gabriels, J; Beckers, MC; Ding, H; et al. (Aug 5, 1999). "Nucleotide sequence of the partially deleted D4Z4 locus in a patient with FSHD identifies a putative gene within each 3.3 kb element". Gene. 236 (1): 25–32. doi:10.1016/S0378-1119(99)00267-X. PMID 10433963.
  17. ^ Tsien, F; Sun, B; Hopkins, NE; et al. (Nov 2001). "Methylation of the FSHD syndrome-linked subtelomeric repeat in normal and FSHD cell cultures and tissues". Molecular Genetics and Metabolism. 74 (3): 322–331. doi:10.1006/mgme.2001.3219. PMID 11708861.
  18. ^ Lemmers, RJ; de Kievit, P; Sandkuijl, L; et al. (Oct 2002). "Facioscapulohumeral muscular dystrophy is uniquely associated with one of the two variants of the 4q subtelomere". Nature Genetics. 32 (2): 235–236. doi:10.1038/ng999. PMID 12355084. S2CID 28107557.
  19. ^ Gabellini, D; Green, MR; Tupler, R (Aug 9, 2002). "Inappropriate gene activation in FSHD: a repressor complex binds a chromosomal repeat deleted in dystrophic muscle". Cell. 110 (3): 339–348. doi:10.1016/S0092-8674(02)00826-7. hdl:11380/459475. PMID 12176321. S2CID 16396883.
  20. ^ van Overveld, PG; Lemmers, RJ; Sandkuijl, LA; et al. (Dec 2003). "Hypomethylation of D4Z4 in 4q-linked and non-4q-linked facioscapulohumeral muscular dystrophy". Nature Genetics. 35 (4): 315–317. doi:10.1038/ng1262. PMID 14634647. S2CID 28696708.
  21. ^ Lemmers, RJ; Wohlgemuth, M; Frants, RR; Padberg, GW; Morava, E; van der Maarel, SM (Dec 2004). "Contractions of D4Z4 on 4qB subtelomeres do not cause facioscapulohumeral muscular dystrophy". The American Journal of Human Genetics. 75 (6): 1124–1130. doi:10.1086/426035. PMC 1182148. PMID 15467981.
  22. ^ Gabellini, D; D'Antona, G; Moggio, M; et al. (Feb 23, 2006). "Facioscapulohumeral muscular dystrophy in mice overexpressing FRG1". Nature. 439 (7079): 973–977. Bibcode:2006Natur.439..973G. doi:10.1038/nature04422. PMID 16341202. S2CID 4427465.
  23. ^ Clapp, J; Mitchell, LM; Bolland, DJ; et al. (Aug 2007). "Evolutionary conservation of a coding function for D4Z4, the tandem DNA repeat mutated in facioscapulohumeral muscular dystrophy". The American Journal of Human Genetics. 81 (2): 264–279. doi:10.1086/519311. PMC 1950813. PMID 17668377.
  24. ^ Dixit, M; Ansseau, E; Tassin, A; et al. (Nov 13, 2007). "DUX4, a candidate gene of facioscapulohumeral muscular dystrophy, encodes a transcriptional activator of PITX1". Proceedings of the National Academy of Sciences of the USA. 104 (46): 18157–18162. Bibcode:2007PNAS..10418157D. doi:10.1073/pnas.0708659104. PMC 2084313. PMID 17984056.
  25. ^ de Greef, JC; Lemmers, RJ; van Engelen, BG; et al. (Oct 2009). "Common epigenetic changes of D4Z4 in contraction-dependent and contraction-independent FSHD". Human Mutation. 30 (10): 1449–1459. CiteSeerX 10.1.1.325.8388. doi:10.1002/humu.21091. PMID 19728363. S2CID 14517505.
  26. ^ Snider, L; Asawachaicharn, A; Tyler, AE; et al. (Jul 1, 2009). "RNA transcripts, miRNA-sized fragments and proteins produced from D4Z4 units: new candidates for the pathophysiology of facioscapulohumeral dystrophy". Human Molecular Genetics. 18 (13): 2414–2430. doi:10.1093/hmg/ddp180. PMC 2694690. PMID 19359275.
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  29. ^ a b Kolata, Gina (19 August 2010). "Reanimated 'Junk' DNA Is Found to Cause Disease". The New York Times. Retrieved 29 August 2010.
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  32. ^ Scionti, I; Greco, F; Ricci, G; et al. (Apr 6, 2012). "Large-scale population analysis challenges the current criteria for the molecular diagnosis of fascioscapulohumeral muscular dystrophy". The American Journal of Human Genetics. 90 (4): 628–635. doi:10.1016/j.ajhg.2012.02.019. PMC 3322229. PMID 22482803.
  33. ^ Geng, LN; Yao, Z; Snider, L; et al. (Jan 17, 2012). "DUX4 activates germline genes, retroelements, and immune mediators: implications for facioscapulohumeral dystrophy". Developmental Cell. 22 (1): 38–51. doi:10.1016/j.devcel.2011.11.013. PMC 3264808. PMID 22209328.
  34. ^ Jones, TI; Chen, JC; Rahimov, F; et al. (Oct 15, 2012). "Facioscapulohumeral muscular dystrophy family studies of DUX4 expression: evidence for disease modifiers and a quantitative model of pathogenesis". Human Molecular Genetics. 21 (20): 4419–4430. doi:10.1093/hmg/dds284. PMC 3459465. PMID 22798623.
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  36. ^ Krom, YD; Thijssen, PE; Young, JM; et al. (Apr 2013). "Intrinsic Epigenetic Regulation of the D4Z4 Macrosatellite Repeat in a Transgenic Mouse Model for FSHD". PLOS Genetics. 9 (4): e1003415. doi:10.1371/journal.pgen.1003415. PMC 3616921. PMID 23593020.
  37. ^ Ferreboeuf, M; Mariot, V; Bessieres, B; et al. (Jan 1, 2014). "DUX4 and DUX4 downstream target genes are expressed in fetal FSHD muscles". Human Molecular Genetics. 23 (1): 171–181. doi:10.1093/hmg/ddt409. PMID 23966205.
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