Dominant collagen XII mutations cause a distal myopathy

Payam Mohassel, Teerin Liewluck, Ying Hu, Daniel Ezzo, Tracy Ogata, Dimah Saade, Sarah Neuhaus, Véronique Bolduc, Yaqun Zou, Sandra Donkervoort, Livija Medne, Charlotte J. Sumner, Peter J Dyck, Klaas J. Wierenga, Gihan Tennekoon, Richard S. Finkel, Jiani Chen, Thomas L. Winder, Nathan P Staff, A. Reghan FoleyManuel Koch, Carsten G. Bönnemann

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalAnnals of Clinical and Translational Neurology
DOIs
StateAccepted/In press - Jan 1 2019

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Distal Myopathies
Collagen
Mutation
Muscular Diseases
Small Interfering RNA
Fibroblasts
Alleles
Natural History
Exons
Fibrillar Collagens
Haploinsufficiency
Precision Medicine
Glycine
Virulence
History
Staining and Labeling
Phenotype
Muscles
Skin

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology

Cite this

Mohassel, P., Liewluck, T., Hu, Y., Ezzo, D., Ogata, T., Saade, D., ... Bönnemann, C. G. (Accepted/In press). Dominant collagen XII mutations cause a distal myopathy. Annals of Clinical and Translational Neurology. https://doi.org/10.1002/acn3.50882

Dominant collagen XII mutations cause a distal myopathy. / Mohassel, Payam; Liewluck, Teerin; Hu, Ying; Ezzo, Daniel; Ogata, Tracy; Saade, Dimah; Neuhaus, Sarah; Bolduc, Véronique; Zou, Yaqun; Donkervoort, Sandra; Medne, Livija; Sumner, Charlotte J.; Dyck, Peter J; Wierenga, Klaas J.; Tennekoon, Gihan; Finkel, Richard S.; Chen, Jiani; Winder, Thomas L.; Staff, Nathan P; Foley, A. Reghan; Koch, Manuel; Bönnemann, Carsten G.

In: Annals of Clinical and Translational Neurology, 01.01.2019.

Research output: Contribution to journalArticle

Mohassel, P, Liewluck, T, Hu, Y, Ezzo, D, Ogata, T, Saade, D, Neuhaus, S, Bolduc, V, Zou, Y, Donkervoort, S, Medne, L, Sumner, CJ, Dyck, PJ, Wierenga, KJ, Tennekoon, G, Finkel, RS, Chen, J, Winder, TL, Staff, NP, Foley, AR, Koch, M & Bönnemann, CG 2019, 'Dominant collagen XII mutations cause a distal myopathy', Annals of Clinical and Translational Neurology. https://doi.org/10.1002/acn3.50882
Mohassel, Payam ; Liewluck, Teerin ; Hu, Ying ; Ezzo, Daniel ; Ogata, Tracy ; Saade, Dimah ; Neuhaus, Sarah ; Bolduc, Véronique ; Zou, Yaqun ; Donkervoort, Sandra ; Medne, Livija ; Sumner, Charlotte J. ; Dyck, Peter J ; Wierenga, Klaas J. ; Tennekoon, Gihan ; Finkel, Richard S. ; Chen, Jiani ; Winder, Thomas L. ; Staff, Nathan P ; Foley, A. Reghan ; Koch, Manuel ; Bönnemann, Carsten G. / Dominant collagen XII mutations cause a distal myopathy. In: Annals of Clinical and Translational Neurology. 2019.
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AU - Mohassel, Payam

AU - Liewluck, Teerin

AU - Hu, Ying

AU - Ezzo, Daniel

AU - Ogata, Tracy

AU - Saade, Dimah

AU - Neuhaus, Sarah

AU - Bolduc, Véronique

AU - Zou, Yaqun

AU - Donkervoort, Sandra

AU - Medne, Livija

AU - Sumner, Charlotte J.

AU - Dyck, Peter J

AU - Wierenga, Klaas J.

AU - Tennekoon, Gihan

AU - Finkel, Richard S.

AU - Chen, Jiani

AU - Winder, Thomas L.

AU - Staff, Nathan P

AU - Foley, A. Reghan

AU - Koch, Manuel

AU - Bönnemann, Carsten G.

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N2 - 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.

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