title: Self-regulated alternative splicing at the AHNAK locus.
abstract: AHNAK is a 700-kDa protein involved in cytoarchitecture and calcium signaling. It is secondarily reduced in muscle of dysferlinopathy patients and accumulates in muscle of calpainopathy patients, both affected by a muscular dystrophy. AHNAK directly interacts with dysferlin. This interaction is lost on cleavage of AHNAK by the protease calpain 3, explaining the molecular observations in patients. Currently, little is known of AHNAK regulation. We describe the self-regulation of multiple mRNA transcripts emanating from the AHNAK locus in muscle cells. We show that the AHNAK gene consists of a 17-kb exon flanked by multiple small exons. This genetic structure is shared by AHNAK2 and Periaxin, which share a common ancestor. Two major AHNAK transcripts are differentially expressed during muscle differentiation that encode for a small (17-kDa) and a large (700-kDa) protein isoform. These proteins interact in the cytoplasm, but the small AHNAK is also present in the nucleus. During muscle differentiation the small AHNAK is strongly increased, thereby establishing a positive feedback loop to regulate mRNA splicing of its own locus. A small 17-kDa isoform of Periaxin similarly traffics between the cytoplasm and the nucleus to regulate mRNA splicing. Thus, AHNAK constitutes a novel mechanism in post-transcriptional control of gene expression.
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Antoine
authors.initials: A
authors.lastname: de Morrée
authors.forename: Marjolein
authors.initials: M
authors.lastname: Droog
authors.forename: Laure
authors.initials: L
authors.lastname: Grand Moursel
authors.forename: Ilona J M
authors.initials: IJ
authors.lastname: Bisschop
authors.forename: Antonietta
authors.initials: A
authors.lastname: Impagliazzo
authors.forename: Rune R
authors.initials: RR
authors.lastname: Frants
authors.forename: Rinse
authors.initials: R
authors.lastname: Klooster
authors.forename: Silvère M
authors.initials: SM
authors.lastname: van der Maarel
mesh_terms: D017398:Alternative Splicing / Q000502:physiology*; D000595:Amino Acid Sequence; D000818:Animals; D020013:Calcium Signaling / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D019143:Evolution, Molecular; D025461:Feedback, Physiological / Q000502:physiology; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D032448:Myoblasts, Skeletal / Q000166:cytology / Q000502:physiology*; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D010802:Phylogeny; D012323:RNA Processing, Post-Transcriptional / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics
chemical_list: C075176:AHNAK protein, human; C489572:Ahnak protein, mouse; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger