DUX4, a Candidate Gene of Facioscapulohumeral Muscular Dystrophy, Encodes a Transcriptional Activator of PITX1

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2007 Nov 7

PMID 17984056

Citations 221

Authors

Manjusha Dixit

Eugenie Ansseau

Alexandra Tassin

Sara Winokur

Rongye Shi

Hong Qian

Sebastien Sauvage

Christel Matteotti

Anne M van Acker

Oberdan Leo

Denise Figlewicz

Marietta Barro

Dalila Laoudj-Chenivesse

Alexandra Belayew

Frederique Coppee

Yi-Wen Chen

Affiliations

Soon will be listed here.

Abstract

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disorder linked to contractions of the D4Z4 repeat array in the subtelomeric region of chromosome 4q. By comparing genome-wide gene expression data from muscle biopsies of patients with FSHD to those of 11 other neuromuscular disorders, paired-like homeodomain transcription factor 1 (PITX1) was found specifically up-regulated in patients with FSHD. In addition, we showed that the double homeobox 4 gene (DUX4) that maps within the D4Z4 repeat unit was up-regulated in patient myoblasts at both mRNA and protein level. We further showed that the DUX4 protein could activate transient expression of a luciferase reporter gene fused to the Pitx1 promoter as well as the endogenous Pitx1 gene in transfected C2C12 cells. In EMSAs, DUX4 specifically interacted with a 30-bp sequence 5'-CGGATGCTGTCTTCTAATTAGTTTGGACCC-3' in the Pitx1 promoter. Mutations of the TAAT core affected Pitx1-LUC activation in C2C12 cells and DUX4 binding in vitro. Our results suggest that up-regulation of both DUX4 and PITX1 in FSHD muscles may play critical roles in the molecular mechanisms of the disease.

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