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:
CreatorsEmailORCIDORCID Put Code
Mohassel, PayamUNSPECIFIEDorcid.org/0000-0001-5313-9514UNSPECIFIED
Liewluck, TeerinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hu, YingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ezzo, DanielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ogata, TracyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Saade, DimahUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Neuhaus, SarahUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bolduc, VeroniqueUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zou, YaqunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Donkervoort, SandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Medne, LivijaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sumner, Charlotte J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dyck, P. James B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wierenga, Klaas J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tennekoon, GihanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Finkel, Richard S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chen, JianiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Winder, Thomas L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Staff, Nathan P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Foley, A. ReghanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koch, ManuelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bonnemann, Carsten G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
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:
KeywordsLanguage
ULTRASOUNDMultiple languages
Clinical Neurology; NeurosciencesMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/14149

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