Recessive and dominant mutations in COL12A1 cause a novel EDS/myopathy overlap syndrome in humans and mice

Abstract

Collagen VI-related myopathies are disorders of connective tissue presenting with an overlap phenotype combining clinical involvement from the muscle and from the connective tissue. Not all patients displaying related overlap phenotypes between muscle and connective tissue have mutations in collagen VI. Here, we report a homozygous recessive loss of function mutation and a de novo dominant mutation in collagen XII (COL12A1) as underlying a novel overlap syndrome involving muscle and connective tissue. Two siblings homozygous for a loss of function mutation showed widespread joint hyperlaxity combined with weakness precluding independent ambulation, while the patient with the de novo missense mutation was more mildly affected, showing improvement including the acquisition of walking. A mouse model with inactivation of the Col12a1 gene showed decreased grip strength, a delay in fiber-type transition and a deficiency in passive force generation while the muscle seems more resistant to eccentric contraction induced force drop, indicating a role for a matrix-based passive force-transducing elastic element in the generation of the weakness. This new muscle connective tissue overlap syndrome expands on the emerging importance of the muscle extracellular matrix in the pathogenesis of muscle disease.

Collagens XII and XIV: Two collagen types both associated with bovine muscle and intramuscular lipid metabolism

“…Collagen XII (from its correlations with some enzymes of oxidative metabolism) would be also associated with the oxidative muscle metabolism. This assumption is corroborated by the results of Zou et al (2014) which showed that the lack of collagen XII (in Col12a1-/-mice) is associated with a decrease in oxidative metabolism in two types of muscle. In m. soleus, there was a decrease in type I fiber number and an increase in type IIA fiber number.…”

“…Collagen XII could also play a role in oxidative metabolism of muscle fibres (Zou et al, 2014). From all these fragmented results, obtained in cell culture and in collagen XII knock-out mice, respectively, we can suppose that collagen XII and XIV would be involved in muscle metabolism as a whole (both IMF and muscle fibres).…”

Tendon development and musculoskeletal assembly: emerging roles for the extracellular matrix

“…Furthermore, mutations that disrupt genes encoding crosslinking collagens (e.g. COL12A1 in the case of Ehlers-Danlos syndrome), which bind Itga1/b1 or Itga2/b1, cause widespread defects in skin, bones and tendons (Mayer et al, 1997;Zou et al, 2014).…”

Tenascin-X: beyond the architectural function

“…Indeed, fibroblasts from TN-X -/-mice displayed a decreased expression of types I and VI collagens, as well as of several collagen fibril-associated molecules (types XII and XIV collagens, lumican and fibromodulin). 50,51 However, whether the down-regulation of those matrix protein-encoding genes reflects an adaptive process due to TN-X-deficiency or an active regulatory role exerted by TN-X remains an open question. While the overexpression of fulllength TN-X led to an increase of type VI collagen expression in immortalized BALB/3T3 fibroblasts, suggesting that the regulation of this gene by TN-X is a direct process, 50 some discrepancies have been observed between mouse and human tissues deficient in TN-X in terms of matrix gene regulation, instead implying an adaptive process.…”

“…This fact has been illustrated for the type XII collagen whose level is markedly reduced in TN-X -/-mice muscle samples (compared to wild-type mice), but remains unchanged in human biopsies deficient in TN-X (compared to healthy donors). 51 Secondly, the analysis of TN-X-deficient mice indicated a role for TN-X as a regulator of collagen deposition into the ECM. Indeed, dermal fibroblasts from TN-X -/-mice deposited fewer type I collagen molecules into the ECM compared to wild-type fibroblasts in vitro.…”