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Identification of Variants in the 4q35 Gene FAT 1 in Patients with a Facioscapulohumeral Dystrophy‐Like Phenotype
Author(s) -
Puppo Francesca,
Dionnet Eugenie,
Gaillard MarieCécile,
Gaildrat Pascaline,
Castro Christel,
Vovan Catherine,
Bertaux Karine,
Bernard Rafaelle,
Attarian Shahram,
Goto Kanako,
Nishino Ichizo,
Hayashi Yukiko,
Magdinier Frédérique,
Krahn Martin,
Helmbacher Françoise,
Bartoli Marc,
Lévy Nicolas
Publication year - 2015
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22760
Subject(s) - biology , facioscapulohumeral muscular dystrophy , genetics , haploinsufficiency , rna splicing , phenotype , gene , subtelomere , exon , muscular dystrophy , copy number variation , protocadherin , haplotype , allele , chromosome , cadherin , genome , rna , cell
ABSTRACT Facioscapulohumeralmuscular dystrophy ( FSHD ) is linked to copy‐number reduction ( N < 10) of the 4q D 4 Z 4 subtelomeric array, in association with DUX 4‐permissive haplotypes. This main form is indicated as FSHD 1. FSHD ‐like phenotypes may also appear in the absence of D 4 Z 4 copy‐number reduction. Variants of the SMCHD 1 gene have been reported to associate with D 4 Z 4 hypomethylation in DUX 4‐compatible haplotypes, thus defining FSHD 2. Recently, mice carrying a muscle‐specific knock‐out of the protocadherin gene F at1 or its constitutive hypomorphic allele were shown to develop muscular and nonmuscular defects mimicking human FSHD . Here, we report FAT 1 variants in a group of patients presenting with neuromuscular symptoms reminiscent of FSHD . The patients do not carry D 4 Z 4 copy‐number reduction, 4q hypomethylation, or SMCHD 1 variants. However, abnormal splicing of the FAT 1 transcript is predicted for all identified variants. To determine their pathogenicity, we elaborated a minigene approach coupled to an antisense oligonucleotide ( AON ) assay. In vitro, four out of five selected variants induced partial or complete alteration of splicing by creating new splice sites or modifying splicing regulators. AON s confirmed these effects. Altered transcripts may affect FAT 1 protein interactions or stability. Altogether, our data suggest that defective FAT 1 is associated with an FSHD ‐like phenotype.