O.9Dominant Collagen XII-related myopathy with a distal myopathy phenotype, amenable to treatment with allele-specific knockdown

Bi-allelic loss-of-function mutations in the collagen XII-encoding gene, COL12A1, are known to cause congenital hypotonia, respiratory insufficiency, joint hyperlaxity and joint contractures. Monoallelic, dominantly acting mutations in this gene cause a similar but milder phenotype and have been reported only in a handful of patients. We report detailed clinical characteristics of 6 patients (age 3-62 years) from 4 unrelated families with novel dominant mutations in COL12A1. All patients developed weakness at birth or during early childhood. Adult patients reported improvement of weakness and had little-to-no limitation of motor activities in young adulthood and mild weakness reemerged during 4th decade of life or later. Three pediatric patients had generalized weakness, while three adult patients had predominant distal upper and lower limb weakness. Joint contractures or hyperlaxity was observed in 5 patients. Three families carried dominant missense mutations affecting glycine residues, one in a laminin G-like domain and two in the Gly-X-Y repeats of the triple helix domain, while one family carried heterozygous in-frame deletion of exon 52. All of the mutations resulted in increased intracellular retention of collagen XII and loss of fibrillar pattern of staining in patients' fibroblasts. Since haploinsufficiency is not known to cause disease, we designed and screened small interfering RNAs (siRNAs) that specifically target the exon 52 mutant allele in patient-derived skin fibroblasts, thus converting the genetic abnormality to a haploinsufficient state. Immunostaining of the patient's fibroblasts treated with targeting siRNA corrected the intracellular retention and restored the fibrillar pattern of collagen XII staining. This study characterizes a distal myopathy phenotype in adults with dominant COL12A1 mutations, further defines the phenotypic spectrum and natural history of COL12A1-related myopathies, and 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 COL12A1 mutation.