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Human Molecular Genetics, 2002, Vol. 11, No. 19 2297-2307
© 2002 Oxford University Press

Muscle-specific alternative splicing of myotubularin-related 1 gene is impaired in DM1 muscle cells

Anna Buj-Bello1, Denis Furling2, Hélène Tronchère3, Jocelyn Laporte1, Thierry Lerouge1, Gillian S. Butler-Browne2 and Jean-Louis Mandel1,*

1Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, 1 rue Laurent Fries, BP 163, 67404 Illkirch Cedex, CU de Strasbourg, France, 2Faculté de Médecine Pitié-Salpêtrière, CNRS UMR 7000, Université Paris 6, 75634 Paris Cedex, France and 3Institut Fédératif de Recherche en Immunologie Cellulaire et Moléculaire, INSERM, Unité 326, Hôpital Purpan, 31059 Toulouse Cedex, France

Received May 20, 2002; Accepted July 11, 2002

The myotubularin-related 1 (MTMR1) gene belongs to a highly conserved family of eucaryotic phosphatases, with at least 11 members in humans. The founder member of this gene family, MTM1, is mutated in X-linked myotubular myopathy, a severe congenital disorder that affects skeletal muscle, and codes for myotubularin, a specific phosphatidylinositol 3-phosphate [PI(3)P] phosphatase. MTM1 and MTMR1 are adjacent on the X chromosome, and the corresponding proteins share 59% sequence identity. In the present study, we investigated the putative role of MTMR1 in myogenesis by analysing its expression pattern in muscle cells during differentiation and in skeletal muscle throughout development. We have identified three novel coding exons in the MTMR1 intron 2 that are conserved between mouse and human, are alternatively spliced, and give rise to six mRNA isoforms. One of the transcripts is muscle-specific and is induced during myogenesis both in vitro and in vivo, and represents the major isoform in adult skeletal muscle. We show that the two main MTMR1 protein muscular isoforms, like myotubularin, efficiently dephosphorylate PI(3)P in vitro. We have also analysed whether MTMR1 alternative splicing is affected in skeletal muscle cells derived from patients with congenital myotonic dystrophy (cDM1), in which mRNA splicing disturbances of specific genes are thought to constitute an important pathogenic mechanism. We found a striking reduction in the level of the muscle-specific isoform and the appearance of an abnormal MTMR1 transcript in differentiated cDM1 muscle cells in culture and in skeletal muscle from cDM1 patients. Our results suggest that MTMR1 plays a role in muscle formation and represents a novel target for abnormal mRNA splicing in myotonic dystrophy.

* To whom correspondence should be addressed. Tel: +33 388653244; Fax: +33 388653246; Email: mtm{at}titus.u-strasbg.fr


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