Universität zu Köln

Mohassel, Payam ORCID: 0000-0001-5313-9514, Liewluck, Teerin, Hu, Ying, Ezzo, Daniel, Ogata, Tracy, Saade, Dimah, Neuhaus, Sarah, Bolduc, Veronique, Zou, Yaqun, Donkervoort, Sandra, Medne, Livija, Sumner, Charlotte J., Dyck, P. James B., Wierenga, Klaas J., Tennekoon, Gihan, Finkel, Richard S., Chen, Jiani, Winder, Thomas L., Staff, Nathan P., Foley, A. Reghan, Koch, Manuel and Bonnemann, Carsten G. (2019). Dominant collagen XII mutations cause a distal myopathy. Ann. Clin. Transl. Neurol., 6 (10). S. 1980 - 1989. HOBOKEN: WILEY. ISSN 2328-9503

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Abstract

Objective To characterize the natural history and clinical features of myopathies caused by mono-allelic, dominantly acting pathogenic variants in COL12A1. Methods Patients with dominant COL12A1-related myopathies were characterized by history and clinical examination, muscle imaging, and genetic analysis. Pathogenicity of the variants was assessed by immunostaining patient-derived dermal fibroblast cultures for collagen XII. Results Four independent families with childhood-onset weakness due to novel, dominantly acting pathogenic variants in COL12A1 were identified. Adult patients exhibited distal-predominant weakness. Three families carried dominantly acting glycine missense variants, and one family had a heterozygous, intragenic, in-frame deletion of exon 52 of COL12A1. All pathogenic variants resulted in increased intracellular retention of collagen XII in patient-derived fibroblasts as well as loss of extracellular, fibrillar collagen XII deposition. Since haploinsufficiency for COL12A1 is largely clinically asymptomatic, we designed and evaluated small interfering RNAs (siRNAs) that specifically target the mutant allele containing the exon 52 deletion. Immunostaining of the patient fibroblasts treated with the siRNA showed a near complete correction of collagen XII staining patterns. Interpretation This study characterizes a distal myopathy phenotype in adults with dominant COL12A1 pathogenic variants, further defining the phenotypic spectrum and natural history of COL12A1-related myopathies. This work also provides proof of concept of a precision medicine treatment approach by proposing and validating allele-specific knockdown using siRNAs specifically designed to target a patient's dominant COL12A1 disease allele.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Mohassel, Payam UNSPECIFIED orcid.org/0000-0001-5313-9514 UNSPECIFIED Liewluck, Teerin UNSPECIFIED UNSPECIFIED UNSPECIFIED Hu, Ying UNSPECIFIED UNSPECIFIED UNSPECIFIED Ezzo, Daniel UNSPECIFIED UNSPECIFIED UNSPECIFIED Ogata, Tracy UNSPECIFIED UNSPECIFIED UNSPECIFIED Saade, Dimah UNSPECIFIED UNSPECIFIED UNSPECIFIED Neuhaus, Sarah UNSPECIFIED UNSPECIFIED UNSPECIFIED Bolduc, Veronique UNSPECIFIED UNSPECIFIED UNSPECIFIED Zou, Yaqun UNSPECIFIED UNSPECIFIED UNSPECIFIED Donkervoort, Sandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Medne, Livija UNSPECIFIED UNSPECIFIED UNSPECIFIED Sumner, Charlotte J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Dyck, P. James B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wierenga, Klaas J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Tennekoon, Gihan UNSPECIFIED UNSPECIFIED UNSPECIFIED Finkel, Richard S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Chen, Jiani UNSPECIFIED UNSPECIFIED UNSPECIFIED Winder, Thomas L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Staff, Nathan P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Foley, A. Reghan UNSPECIFIED UNSPECIFIED UNSPECIFIED Koch, Manuel UNSPECIFIED UNSPECIFIED UNSPECIFIED Bonnemann, Carsten G. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-141499
DOI:	10.1002/acn3.50882
Journal or Publication Title:	Ann. Clin. Transl. Neurol.
Volume:	6
Number:	10
Page Range:	S. 1980 - 1989
Date:	2019
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	2328-9503
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ULTRASOUND Multiple languages Clinical Neurology; Neurosciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/14149