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Detection of common and private mutations in the COL6A1 gene of patients with Bethlem myopathy

From the Department of Medical and Surgical Critical Care and Center of Research, Transfer and High Education (Drs. Lucioli, Giusti, Vanegas, and Pepe, L. Lucarini, V. Pietroni) "MCIDNENT," University of Florence, Florence, Italy; Unit of Molecular Medicine, Department of Laboratory Medicine (Drs. Lucioli and Bertini), Bambin Gesù Children’s Hospital, Rome, Italy; Department of Pediatrics, Neuromuscular Unit (Drs. Mercuri and Muntoni), Imperial College, Hammersmith Hospital, London, UK; Child Neurology Unit (Dr. Mercuri), Catholic University, Rome, Italy; Institut de Myologie (Drs. Urtizberea and Ben Yaou), Groupe Hôpitalier Pitié-Salpêtrière, Paris, France; Department of Neurology (Drs. de Visser and van der Kooi), Academic Medical Center, Amsterdam, The Netherlands; Division of Neurology (Dr. Bönnemann), The Children’s Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, PA; Department of Pediatric Neurology (Dr. Iannaccone), Scottish Rite Hospital for Children, Dallas, TX; Neuromuscular Unit (Dr. Merlini), Istituto Ortopedico Rizzoli, Bologna, Italy; Institute of Human Genetics (Dr. Busby), University of Newcastle upon Tyne, Newcastle upon Tyne, UK; and Departments of Dermatology and Cutaneous Biology and Biochemistry and Molecular Pharmacology (Dr. Chu), Thomas Jefferson University, Philadelphia, PA.

Address correspondence and reprint requests to Dr. Guglielmina Pepe, Viale Morgagni, 85 50134 Florence, Italy; e-mail: g.pepe{at}dac.unifi.it

Background: Dominant mutations in COL6A1, COL6A2, and COL6A3, the three genes encoding collagen type VI, a ubiquitous extracellular matrix protein, are associated with Bethlem myopathy (BM) and Ullrich scleroatonic muscular dystrophy.

Methods: The authors devised a method to screen the entire coding sequence of the three genes by reverse transcriptase–PCR amplification of total RNA from skin fibroblasts and direct sequencing of the resulting 25 overlapping cDNA fragments covering 107 exons.

Results: Four splicing and four missense mutations were identified in 16 patients with BM, six of which are novel mutations in COL6A1. Both common and private mutations are localized in the 1 (VI) chain between the regions corresponding to the 3' end of the NH2-globular domain and the 5' end of the triple helix, encoded by exons 3 through 14.

Conclusions: The clustering of the mutations in a relatively narrow area of the three collagen type VI chains in patients with Bethlem myopathy (BM) suggests that mutations in different regions could result in different phenotypes or in no phenotype at all. Moreover, the detection of mutations in only 60% of the patients suggests the existence of at least another gene associated with BM. The authors propose the direct sequencing of COL6 cDNAs as the first mutation screening analysis in BM, given the high number of exon-skipping events.

*These authors contributed equally to this work.

Supported by Ministero dell’Università e della Ricerca Scientifica e Tecnologica, FIRB Prot.N. RBNE01JJ45_005, Italy; by the European Community (grant QLG1-CT-1999-00870), NIH grant AR38912, and logistic support of the European Neuromuscular Centre.

Received November 25, 2004. Accepted in final form March 4, 2005.

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