D4Z4

The D4Z4 repeat is very polymorphic in length. D4Z4 rearrangements occur almost exclusively via intrachromosomal gene conversions.

Pathology

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.

Autosomal dominant facioscapulohumeral muscular dystrophy (FSHD) is associated with contractions of the D4Z4 repeat in the subtelomere of chromosome 4q (15467981, 15674778).

Autosomal dominant facioscapulohumeral muscular dystrophy (FSHD) is mainly characterized by progressive wasting and weakness of the facial, shoulder, and upper-arm muscles.

Almost-identical D4Z4-repeat arrays have been identified on chromosome 10q26 and on two equally common chromosome 4 variants, 4qA and 4qB. Yet only repeat contractions of D4Z4 on chromosome 4qA cause FSHD; contractions on the other chromosomes are nonpathogenic.

Repeat contractions in two of the nine haplotypes, one of which is a 4qA haplotype, are not associated with FSHD. Each of these haplotypes has its unique sequence signature.

References

 Clapp J, Mitchell LM, Bolland DJ, Fantes J, Corcoran AE, Scotting PJ, Armour JA, Hewitt JE. 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. PMID: 17668377

 Lemmers RJ, Wohlgemuth M, van der Gaag KJ, van der Vliet PJ, van Teijlingen CM, de Knijff P, Padberg GW, Frants RR, van der Maarel SM. Specific Sequence Variations within the 4q35 Region Are Associated with Facioscapulohumeral Muscular Dystrophy. Am J Hum Genet. 2007 Nov;81(5):884-94. PMID: 17924332