Correlation between low FAT1 expression and early affected muscle in facioscapulohumeral muscular dystrophy. Issue 3 (3rd July 2015)

• Record Type: Journal Article
• Authors: Mariot, Virginie; Roche, Stephane; Hourdé, Christophe; Portilho, Debora; Sacconi, Sabrina; Puppo, Francesca; Duguez, Stephanie; Rameau, Philippe; Caruso, Nathalie; Delezoide, Anne‐Lise; Desnuelle, Claude; Bessières, Bettina; Collardeau, Sophie; Feasson, Leonard; Maisonobe, Thierry; Magdinier, Frederique; Helmbacher, Françoise; Butler‐Browne, Gillian; Mouly, Vincent; Dumonceaux, Julie
• Is Part Of: Annals of neurology. Volume 78:Issue 3(2015:Sep.)
• Page Start: 387
• Page End: 400
• Publication Date: 2015-07-03
• Subjects: Neurology -- Periodicals; Pediatric neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; 616.8
• DOI: 10.1002/ana.24446
• Languages: English
• ISSNs: 0364-5134

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="ana24446-sec-0001" sec-type="section"> <title>Objective</title> <p>Facioscapulohumeral muscular dystrophy (FSHD) is linked to either contraction of D4Z4 repeats on chromosome 4 or to mutations in the <italic>SMCHD1</italic> 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 <italic>Fat1</italic> functions exhibit FSHD‐like phenotypes, we have investigated the expression of the human <italic>FAT1</italic> gene in FSHD.</p> </sec> <sec id="ana24446-sec-0002" sec-type="section"> <title>Methods</title> <p>We first analyzed <italic>FAT1</italic> expression in FSHD adult muscles and determined whether <italic>FAT1</italic> expression was driven by DUX4. We next determined <italic>FAT1</italic> expression levels in 64 muscles isolated from 16 control fetuses. These data were further complemented with analysis of <italic>Fat1</italic> expression in developing mouse embryos.</p> </sec> <sec id="ana24446-sec-0003" sec-type="section"> <title>Results</title> <p>We demonstrated that <italic>FAT1</italic> expression is independent of DUX4. Moreover, we observed that (1) in control fetal human biopsies or in developing mouse embryos, <italic>FAT1</italic> 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, <italic>FAT1</italic> expression is lower in FSHD muscles compared to control muscles.</p> </sec> <sec id="ana24446-sec-0004" sec-type="section"> <title>Interpretation</title> <p>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. Ann Neurol 2015;78:387–400</p> </sec> </abstract>