Myopathic Ehlers-Danlos syndrome (RmEDS) is an emerging hybrid phenotype that combines connective and muscle tissue abnormalities. It has been associated with variants of the COL12A1 gene, which are known as Ullrich congenital muscular dystrophy-2 (UCMD2; 616470) and Bethlem myopathy-2 (BTHLM2; 616471). Here, we report two splicing mutations of COL12A1 identified in three patients from two unrelated families who present a combination of joint hypermobility and axial, distal, and proximal weakness. The muscular strength of their neck and limb muscles was assessed at 4/5 (MRC); however, when measured with a myometer, the expected percentage by age and sex ranged from 35% to 40% for elbow flexion, 37% to 75% for knee extension, and was 50% for neck flexion. In addition to confirming the characteristic atrophy of the rectus femoris, we presented evidence of involvement of the neck and lumbar muscles through MRI and CT imaging. In vitro studies revealed filamentous disorganization and an altered pattern of collagen XII alpha 1 chain migration due to the skipping of exons 55 and 56 of collagen XII. Additionally, we review the myopathic involvement of COL12-RM in 30 patients across 18 families with dominant mutations and 15 patients from 13 families with recessive mutations.

While there have been several reports of patients with dominantly acting COL12A1 variants, few cases of the more severe recessive Collagen XII-related disorders have previously been documented. We present detailed clinical, immunocytochemical, and imaging data on eight additional patients from seven families with biallelic pathogenic variants in COL12A1. All patients presented with a consistent constellation of congenital onset clinical features: hypotonia, dysmorphic features, most notably gingival hypertrophy, prominent distal joint hyperlaxity, with co-occurring contractures of large joints, and variable muscle involvement, evident both clinically and on muscle imaging. Five patients presented with a severe congenital phenotype manifesting with profound weakness, significantly delayed or minimal attainment of motor milestones, respiratory insufficiency, and feeding difficulties. Three patients presented with mild-to-moderate muscle weakness and delayed milestones but were able to achieve independent ambulation. Patients were found to have biallelic loss-of-function COL12A1 variants, except for one family (p.I1393Ffs*11/p.A1110D). Consistent with the variable clinical spectrum, in vitro immunocytochemistry analysis in fibroblasts ranged from complete absence of Collagen XII expression in a patient with severe disease, to a mild reduction in a patient with milder disease. Here we characterize the clinical presentation, muscle imaging, and dermal fibroblast immunostaining findings associated with biallelic variants in COL12A1, further establishing COL12A1 as a recessive myopathic Ehlers-Danlos syndrome (mEDS) gene, and expanding the clinical spectrum to include a milder EDS phenotype.

Collagen XII is highly expressed in skeletal tissues, and mutations in collagen XII cause myopathic Ehlers-Danlos syndrome, manifesting as early onset myopathy and joint disorder. Besides skeletal tissues and muscles, collagen XII has been detected in blood and matrix vesicles, and its expression in correlation with LDL is increased in patients with obesity. However, the roles of collagen XII in fat metabolism have not been elucidated. In this study, we aimed to explore the potential role of collagen XII in fat tissue using a Col12a1 null mouse model. Collagen XII deficiency reduced the volume of subcutaneous (ScAT), visceral (VAT), and brown adipose tissue (BAT). Adipocytes were smaller in Col12a1 null ScAT and VAT but not in BAT compared with those in wild-type controls. Real-time PCR analysis revealed that Col12a1 mRNA was expressed in VAT and ScAT. Microarray analysis of ScAT from Col12a1 null mice revealed 1243 genes with upregulated expression, 167 of which were implicated in cytoskeletal muscle structure and 153 of which were associated with muscle development. Among these genes, myostatin positive cells were clearly detected in Col12a1 null but not in wild-type ScAT, as revealed by immunohistochemistry. These results suggest that collagen XII is involved in ScAT homeostasis, and impairment of its expression may contribute to the development of myopathy by inducing ectopic activation of muscle-related genes and emergence of myostatin-positive cells in adipose tissue.

Collagen VI and collagen XII are structurally complex collagens of the extracellular matrix (ECM). Like all collagens, type VI and XII both possess triple-helical components that facilitate participation in the ECM network, but collagen VI and XII are distinct from the more abundant fibrillar collagens in that they also possess arrays of structurally globular modules with the capacity to propagate signaling to attached cells. Cell attachment to collagen VI and XII is known to regulate protective, proliferative or developmental processes through a variety of mechanisms, but a growing body of genetic and biochemical evidence suggests that at least some of these phenomena may be potentiated through mechanisms that require coordinated interaction between the two collagens. For example, genetic studies in humans have identified forms of myopathic Ehlers-Danlos syndrome with overlapping phenotypes that result from mutations in either collagen VI or XII, and biochemical and cell-based studies have identified accessory molecules that could form bridging interactions between the two collagens. However, the demonstration of a direct or ternary structural interaction between collagen VI or XII has not yet been reported. This Hypothesis and Theory review article examines the evidence that supports the existence of a functional complex between type VI and XII collagen in the ECM and discusses potential biological implications.

Mutations in collagen type IV-associated genes lead to Ullrich congenital muscular dystrophy (UCMD) and Bethlem myopathy (BM). COL12A1 gene mutations have rarely been reported in patients with UCMD- and BM-like disorders not involving COL6 mutations. UCMD-2 results from homozygous mutations in the COL12A1 gene on the long arm of chromosome 6. Pathogenic variants in COL12A1 result in a rare congenital connective tissue/myopathy overlap syndrome under the heading of myopathic Ehlers-Danlos syndrome. COL12A1 dominant pathogenic variants have been rarely reported, and the phenotypic spectrum has not yet been identified. We describe a female patient aged 2 years and 10 months exhibiting a milder phenotype who presented due to pronounced joint hyperlaxity, frequent falls, and skin lesions. Genetic analysis revealed a homozygous c.8903C>T (p.Pro2968Leu) missense variant that had previously been described but concerning which there had been no clinical report, in the COL12A1 gene. This report is presented in order to raise awareness of rare mutations in the COL12A1 gene that affect muscle and connective tissue and to add to the literature in defining the phenotypic spectrum.