International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


POSTER 4 - IDENTIFICATION OF MURINE HOMOLOGUES OF THE HUMAN REPEAT D4Z4, DELETIONS OF WHICH ARE CAUSALLY ASSOCIATED WITH FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY

Clapp J 1, Fantes J 2, Hewitt JE 1

1 Institute of Genetics, University of Nottingham, Nottingham, United Kingdom, 2 MRC Human Genetics Unit, Western General Hospital, Edinburgh, United Kingdom

Facioscapulohumeral muscular dystrophy (FSHD) is a dominant human neuromuscular disorder caused by a deletion within the tandem repeat array D4Z4 on human chromosome 4q35: affected individuals carry <12 repeat units on one D4Z4 allele. The mechanism whereby this mutation causes FSHD is still debated, but current models favour epigenetic effects such as de-repression of 4q35 genes and altered methylation. D4Z4 contains an open reading frame (ORF) potentially encoding a homeodomain protein. However, by DNA hybridization techniques, homologues have only been identified in higher primates supporting the hypothesis of a non-coding function of D4Z4. Here we show that bioinformatics analysis of the draft mouse genome sequence enabled us to identify a potential mouse homologue (mD4Z4). The sequence and organisation of mD4Z4 has been confirmed by a combination of PCR, pulsed field gel electrophoresis and FISH. The repeat unit size in mouse is 4.9kb, compared to 3.3kb in human. The repeat contains an ORF of 2025bp, potentially encoding two homeodomains with 55% aa similarity to those encoded by human D4Z4. There is no significant sequence conservation outside the coding region. The mD4Z4 repeat units are arranged in large tandem arrays, with FISH analysis suggesting a single chromosome locus. A rat homologue of D4Z4 has also been identified, potentially encoding a homeodomain protein with 66% aa similarity to the mouse. The conservation of the ORF between human, mouse and rat, and the identification of several mouse ESTs suggest a coding function for D4Z4. Our findings also provide potential for the development of a mouse model of FSHD.

[an error occurred while processing this directive]