Correlation between low FAT1 expression and early affected muscle in facioscapulohumeral muscular dystrophy

Virginie Mariot, Stephane Roche, Christophe Hourdé, Debora Portilho, Sabrina Sacconi, Francesca Puppo, Stephanie Duguez, Philippe Rameau, Nathalie Caruso, Anne-Lise Delezoide, Claude Desnuelle, Bettina Bessières, Sophie Collardeau, Leonard Feasson, Thierry Maisonobe, Frederique Magdinier, Françoise Helmbacher, Gillian Butler-Browne, Vincent Mouly, Julie Dumonceaux

Research output: Contribution to journalArticlepeer-review

34 Citations (Scopus)

Abstract

OBJECTIVE
Facioscapulohumeral muscular dystrophy (FSHD) is linked to either contraction of D4Z4 repeats on chromosome 4 or to mutations in the SMCHD1 gene, both of which result in the aberrant expression of the transcription factor DUX4. However, it is still difficult to correlate these genotypes with the phenotypes observed in patients. Because we have recently shown that mice with disrupted Fat1 functions exhibit FSHD-like phenotypes, we have investigated the expression of the human FAT1 gene in FSHD.
METHODS
We first analyzed FAT1 expression in FSHD adult muscles and determined whether FAT1 expression was driven by DUX4. We next determined FAT1 expression levels in 64 muscles isolated from 16 control fetuses. These data were further complemented with analysis of Fat1 expression in developing mouse embryos.
RESULTS
We demonstrated that FAT1 expression is independent of DUX4. Moreover, we observed that (1) in control fetal human biopsies or in developing mouse embryos, FAT1 is expressed at lower levels in muscles that are affected at early stages of FSHD progression than in muscles that are affected later or are nonaffected; and (2) in adult muscle biopsies, FAT1 expression is lower in FSHD muscles compared to control muscles.
INTERPRETATION
We propose a revised model for FSHD in which FAT1 levels might play a role in determining which muscles will exhibit early and late disease onset, whereas DUX4 may worsen the muscle phenotype.
Original languageEnglish
Pages (from-to)387-400
Number of pages4
JournalAnnals of Neurology
Volume78
Issue number3
Early online date3 Jul 2015
DOIs
Publication statusPublished (in print/issue) - 21 Aug 2015

Keywords

  • FSHD
  • FAT1

Fingerprint

Dive into the research topics of 'Correlation between low FAT1 expression and early affected muscle in facioscapulohumeral muscular dystrophy'. Together they form a unique fingerprint.

Cite this