title: Identification of variants in the 4q35 gene FAT1 in patients with a facioscapulohumeral dystrophy-like phenotype.
abstract: Facioscapulohumeralmuscular dystrophy (FSHD) is linked to copy-number reduction (N < 10) of the 4q D4Z4 subtelomeric array, in association with DUX4-permissive haplotypes. This main form is indicated as FSHD1. FSHD-like phenotypes may also appear in the absence of D4Z4 copy-number reduction. Variants of the SMCHD1 gene have been reported to associate with D4Z4 hypomethylation in DUX4-compatible haplotypes, thus defining FSHD2. Recently, mice carrying a muscle-specific knock-out of the protocadherin gene Fat1 or its constitutive hypomorphic allele were shown to develop muscular and nonmuscular defects mimicking human FSHD. Here, we report FAT1 variants in a group of patients presenting with neuromuscular symptoms reminiscent of FSHD. The patients do not carry D4Z4 copy-number reduction, 4q hypomethylation, or SMCHD1 variants. However, abnormal splicing of the FAT1 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. AONs confirmed these effects. Altered transcripts may affect FAT1 protein interactions or stability. Altogether, our data suggest that defective FAT1 is associated with an FSHD-like phenotype.
authors.affiliation: Aix Marseille Université, GMGF, Marseille, France; Inserm, UMR, S 910, Marseille, France.
authors.forename: Francesca
authors.initials: F
authors.lastname: Puppo
authors.forename: Eugenie
authors.initials: E
authors.lastname: Dionnet
authors.forename: Marie-Cécile
authors.initials: MC
authors.lastname: Gaillard
authors.forename: Pascaline
authors.initials: P
authors.lastname: Gaildrat
authors.forename: Christel
authors.initials: C
authors.lastname: Castro
authors.forename: Catherine
authors.initials: C
authors.lastname: Vovan
authors.forename: Karine
authors.initials: K
authors.lastname: Bertaux
authors.forename: Rafaelle
authors.initials: R
authors.lastname: Bernard
authors.forename: Shahram
authors.initials: S
authors.lastname: Attarian
authors.forename: Kanako
authors.initials: K
authors.lastname: Goto
authors.forename: Ichizo
authors.initials: I
authors.lastname: Nishino
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Frédérique
authors.initials: F
authors.lastname: Magdinier
authors.forename: Martin
authors.initials: M
authors.lastname: Krahn
authors.forename: Françoise
authors.initials: F
authors.lastname: Helmbacher
authors.forename: Marc
authors.initials: M
authors.lastname: Bartoli
authors.forename: Nicolas
authors.initials: N
authors.lastname: Lévy
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D017398:Alternative Splicing; D015820:Cadherins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002894:Chromosomes, Human, Pair 4; D019175:DNA Methylation; D005091:Exons; D015870:Gene Expression; D017930:Genes, Reporter; D014644:Genetic Variation; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008875:Middle Aged; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000175:diagnosis* / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: D015820:Cadherins; C502403:FAT1 protein, human
keywords: FAT1-protocadherin; facioscapulohumeral dystrophy; neuromuscular pathology