Dominant collagen XII mutations cause a distal myopathy

Abstract

ObjectiveTo characterize the natural history and clinical features of myopathies caused by mono‐allelic, dominantly acting pathogenic variants in COL12A1. MethodsPatients 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.ResultsFour 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.InterpretationThis 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.

GGPS1 Mutations Cause Muscular Dystrophy/Hearing Loss/Ovarian Insufficiency Syndrome

“…Muscle biopsies and skin biopsies were processed following standard procedures. Dermal fibroblasts derived from skin biopsies were cultured as described previously 14 . Some of the dermal fibroblasts were converted to myoblasts with the Lenti‐MyoD lentiviral system (Clontech Laboratories, Mountain View, CA).…”

Ehlers‐Danlos/myopathy overlap syndrome caused by a large de novo deletion in COL12A1

“…Recessive inheritance is associated with biallelic loss‐of‐function variants and severe congenital weakness precluding the acquisition of walking (Zou et al, 2013). Dominant inheritance is described for variants with a dominant negative effect on the collagen XII homotrimer assembly and leads to a milder phenotype (Delbaere et al, 2020; Hicks et al, 2014; Jezela‐Stanek et al, 2019; Mohassel et al, 2019; Witting et al, 2018; Zou et al, 2013).…”

Ablation of the FACIT collagen XII disturbs musculoskeletal ECM organization and causes patella dislocation and myopathy

“…Collagen XII has been identified as a key organizer of the extracellular matrix in tendon, bone, cornea, and muscle (1). Mutations in the COL12A1 gene were identified as the cause of myopathic Ehlers-Danlos (mEDS) overlap syndrome (5,6). Depending on the nature of the mutation, dominant or recessive, the phenotype varies in severity (7).…”

“…Interestingly, the muscle weakness is not progressive and patients with de novo missense mutations are more mildly affected. Surprisingly, the muscle weakness improves over time, including the ability to walk (5,6).…”