Evolutionary conservation of a coding function for D4Z4, the tandem DNA repeat mutated in facioscapulohumeral muscular dystrophy

Am J Hum Genet. 2007 Aug;81(2):264-79. doi: 10.1086/519311. Epub 2007 Jun 27.


Facioscapulohumeral muscular dystrophy (FSHD) is caused by deletions within the polymorphic DNA tandem array D4Z4. Each D4Z4 repeat unit has an open reading frame (ORF), termed "DUX4," containing two homeobox sequences. Because there has been no evidence of a transcript from the array, these deletions are thought to cause FSHD by a position effect on other genes. Here, we identify D4Z4 homologues in the genomes of rodents, Afrotheria (superorder of elephants and related species), and other species and show that the DUX4 ORF is conserved. Phylogenetic analysis suggests that primate and Afrotherian D4Z4 arrays are orthologous and originated from a retrotransposed copy of an intron-containing DUX gene, DUXC. Reverse-transcriptase polymerase chain reaction and RNA fluorescence and tissue in situ hybridization data indicate transcription of the mouse array. Together with the conservation of the DUX4 ORF for >100 million years, this strongly supports a coding function for D4Z4 and necessitates re-examination of current models of the FSHD disease mechanism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Conserved Sequence
  • Evolution, Molecular*
  • Homeodomain Proteins
  • Humans
  • In Situ Hybridization, Fluorescence
  • Mammals
  • Mice
  • Molecular Sequence Data
  • Muscular Dystrophy, Facioscapulohumeral / genetics*
  • Mutation
  • Phylogeny
  • Primates
  • Sequence Analysis, DNA
  • Sequence Homology, Amino Acid
  • Tandem Repeat Sequences*
  • Transcription, Genetic


  • DUX4L1 protein, human
  • Homeodomain Proteins

Associated data

  • GENBANK/AC135091
  • GENBANK/AF117653
  • GENBANK/AM398147
  • GENBANK/AM398148
  • GENBANK/AM398149
  • GENBANK/AM398150
  • GENBANK/AM398151
  • GENBANK/BN000980
  • GENBANK/BN000981
  • GENBANK/BN000982
  • GENBANK/BN000983
  • GENBANK/BN000984
  • GENBANK/BN000988
  • GENBANK/BN000989
  • GENBANK/BN000990
  • RefSeq/NM_027375