Universität zu Köln

Pan, Te-Cheng, Zhang, Rui-Zhu, Arita, Machiko, Bogdanovich, Sasha, Adams, Sheila M., Gara, Sudheer Kumar, Wagener, Raimund, Khurana, Tejvior S., Birk, David E. and Chu, Mon-Li (2014). A Mouse Model for Dominant Collagen VI Disorders. J. Biol. Chem., 289 (15). S. 10293 - 10308. BETHESDA: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC. ISSN 1083-351X

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Abstract

Background: Dominant collagen VI gene mutations cause the severe Ullrich congenital muscular dystrophy (UCMD) and mild Bethlem myopathy. Results: A mutant mouse mimicking the most common molecular defect in dominant UCMD patients was generated and characterized. Conclusion: The mutant mouse displays muscle and connective tissue abnormalities. Significance: The mutant mouse provides an animal model for dominant collagen VI disorders. Dominant and recessive mutations in collagen VI genes, COL6A1, COL6A2, and COL6A3, cause a continuous spectrum of disorders characterized by muscle weakness and connective tissue abnormalities ranging from the severe Ullrich congenital muscular dystrophy to the mild Bethlem myopathy. Herein, we report the development of a mouse model for dominant collagen VI disorders by deleting exon 16 in the Col6a3 gene. The resulting heterozygous mouse, Col6a3(+/d16), produced comparable amounts of normal Col6a3 mRNA and a mutant transcript with an in-frame deletion of 54 bp of triple-helical coding sequences, thus mimicking the most common molecular defect found in dominant Ullrich congenital muscular dystrophy patients. Biosynthetic studies of mutant fibroblasts indicated that the mutant 3(VI) collagen protein was produced and exerted a dominant-negative effect on collagen VI microfibrillar assembly. The distribution of the 3(VI)-like chains of collagen VI was not altered in mutant mice during development. The Col6a3(+/d16) mice developed histopathologic signs of myopathy and showed ultrastructural alterations of mitochondria and sarcoplasmic reticulum in muscle and abnormal collagen fibrils in tendons. The Col6a3(+/d16) mice displayed compromised muscle contractile functions and thereby provide an essential preclinical platform for developing treatment strategies for dominant collagen VI disorders.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Pan, Te-Cheng UNSPECIFIED UNSPECIFIED UNSPECIFIED Zhang, Rui-Zhu UNSPECIFIED UNSPECIFIED UNSPECIFIED Arita, Machiko UNSPECIFIED UNSPECIFIED UNSPECIFIED Bogdanovich, Sasha UNSPECIFIED UNSPECIFIED UNSPECIFIED Adams, Sheila M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Gara, Sudheer Kumar UNSPECIFIED UNSPECIFIED UNSPECIFIED Wagener, Raimund UNSPECIFIED UNSPECIFIED UNSPECIFIED Khurana, Tejvior S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Birk, David E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Chu, Mon-Li UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-440735
DOI:	10.1074/jbc.M114.549311
Journal or Publication Title:	J. Biol. Chem.
Volume:	289
Number:	15
Page Range:	S. 10293 - 10308
Date:	2014
Publisher:	AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Place of Publication:	BETHESDA
ISSN:	1083-351X
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CONGENITAL MUSCULAR-DYSTROPHY; MITOCHONDRIAL DYSFUNCTION; BETHLEM MYOPATHY; TENASCIN-X; VONWILLEBRAND-FACTOR; ALPHA-2(VI) CHAINS; GLOBULAR DOMAINS; MUSCLE; MUTATIONS; DEFICIENCY Multiple languages Biochemistry & Molecular Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/44073