title: 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.
authors: Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA.
authors: Yaqun
authors: Y
authors: Zou
authors: Daniela
authors: D
authors: Zwolanek
authors: Yayoi
authors: Y
authors: Izu
authors: Shreya
authors: S
authors: Gandhy
authors: Gudrun
authors: G
authors: Schreiber
authors: Knut
authors: K
authors: Brockmann
authors: Marcella
authors: M
authors: Devoto
authors: Zuozhen
authors: Z
authors: Tian
authors: Ying
authors: Y
authors: Hu
authors: Guido
authors: G
authors: Veit
authors: Markus
authors: M
authors: Meier
authors: Jörg
authors: J
authors: Stetefeld
authors: Debbie
authors: D
authors: Hicks
authors: Volker
authors: V
authors: Straub
authors: Nicol C
authors: NC
authors: Voermans
authors: David E
authors: DE
authors: Birk
authors: Elisabeth R
authors: ER
authors: Barton
authors: Manuel
authors: M
authors: Koch
authors: Carsten G
authors: CG
authors: Bönnemann
mesh_terms: D000818:Animals; D002675:Child, Preschool; D024142:Collagen Type VI / Q000235:genetics / Q000378:metabolism; D024082:Collagen Type XII / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D007223:Infant; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000473:pathology; D009135:Muscular Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009154:Mutation / Q000235:genetics*
chemical_list: C547160:COL12A1 protein, human; D024142:Collagen Type VI; D024082:Collagen Type XII