Self‐regulated alternative splicing at the AHNAK locus

• Published in: The FASEB journal 2012-01, Vol.26 (1), p.93-103
• Main Authors: Morrée, Antoine, Droog, Marjolein, Moursel, Laure Grand, Bisschop, Ilona J. M., Impagliazzo, Antonietta, Frants, Rune R., Klooster, Rinse, Maarel, Silve're M. van der
• Format: Article
• Language: English
• Subjects: Alternative Splicing - physiology; Amino Acid Sequence; Animals; Calcium Signaling - physiology; Cell Differentiation - physiology; Cells, Cultured; Evolution, Molecular; Feedback, Physiological - physiology; Gene Expression Regulation - genetics; Humans; Key Words; LGMD; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Molecular Sequence Data; muscle differentiation; Myoblasts, Skeletal - cytology; Myoblasts, Skeletal - physiology; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Phylogeny; RNA expression; RNA Processing, Post-Transcriptional - physiology; RNA, Messenger - genetics
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.11-187971

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.—De Morrée, A., Droog, M., Grand Moursel, L., Bisschop, I.J. M., Impagliazzo, A., Frants, R., Klooster, R., van der Maarel, S. M. Self‐regulated alternative splicing at the AHNAK locus. FASEB J. 26, 93–103 (2012). www.fasebj.org