ullrich congenital muscular dystrophy
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2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Nana Takenaka-Ninagawa ◽  
Jinsol Kim ◽  
Mingming Zhao ◽  
Masae Sato ◽  
Tatsuya Jonouchi ◽  
...  

Abstract Background Mesenchymal stromal cells (MSCs) function as supportive cells on skeletal muscle homeostasis through several secretory factors including type 6 collagen (COL6). Several mutations of COL6A1, 2, and 3 genes cause Ullrich congenital muscular dystrophy (UCMD). Skeletal muscle regeneration deficiency has been reported as a characteristic phenotype in muscle biopsy samples of human UCMD patients and UCMD model mice. However, little is known about the COL6-dependent mechanism for the occurrence and progression of the deficiency. The purpose of this study was to clarify the pathological mechanism of UCMD by supplementing COL6 through cell transplantation. Methods To test whether COL6 supplementation has a therapeutic effect for UCMD, in vivo and in vitro experiments were conducted using four types of MSCs: (1) healthy donors derived-primary MSCs (pMSCs), (2) MSCs derived from healthy donor induced pluripotent stem cell (iMSCs), (3) COL6-knockout iMSCs (COL6KO-iMSCs), and (4) UCMD patient-derived iMSCs (UCMD-iMSCs). Results All four MSC types could engraft for at least 12 weeks when transplanted into the tibialis anterior muscles of immunodeficient UCMD model (Col6a1KO) mice. COL6 protein was restored by the MSC transplantation if the MSCs were not COL6-deficient (types 1 and 2). Moreover, muscle regeneration and maturation in Col6a1KO mice were promoted with the transplantation of the COL6-producing MSCs only in the region supplemented with COL6. Skeletal muscle satellite cells derived from UCMD model mice (Col6a1KO-MuSCs) co-cultured with type 1 or 2 MSCs showed improved proliferation, differentiation, and maturation, whereas those co-cultured with type 3 or 4 MSCs did not. Conclusions These findings indicate that COL6 supplementation improves muscle regeneration and maturation in UCMD model mice.


2021 ◽  
Vol 19 (2) ◽  
pp. 213-221
Author(s):  
Dinh Huong Thao ◽  
Nguyen Phuong Anh ◽  
Noriko Miyake ◽  
Nong Van Hai ◽  
Naomichi Matsumoto ◽  
...  

Collagen type VI-related disorders consist of Ullrich congenital muscular dystrophies (UCMD) and Bethlem myopathy, in which these entities are at two opposite extremes of the phenotype continuum. Clinical characteristics include proximal joint contracture, distal joint hyperlaxity, generalized muscle weakness, normal cognitive function, and pulmonary insufficiency. Affected individuals have trouble standing up and walking independently. Mutations in 3 genes (COL6A1, COL6A2, and COL6A3) are associated with decreasing collagen-VI production and disrupting the microfibrillar network between skeletal muscles. In the present study, using whole-exome sequencing (WES), a pathogenic variant in the COL6A1 gene (NM_001848, c.868G>C, p.G290R) was detected in a Vietnamese family with UCMD patients. Segregation analysis by Sanger sequencing confirmed that this mutation was inherited in an autosomal dominant pattern. This study expands the breadth of congenital muscular dystrophies research landcape and underscores the efficiency of WES in investigating the etiology of this group of heterogeneous diseases. Insight about the underlying genetic causes could contribute to develop a well-timed treatment regimen and help patients make an informed decision about reproductive health. 


BMC Neurology ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Nirmala Dushyanthi Sirisena ◽  
U. M. Jayami Eshana Samaranayake ◽  
Osorio Lopes Abath Neto ◽  
A. Reghan Foley ◽  
B. A. P. Sajeewani Pathirana ◽  
...  

Abstract Background Collagen VI-related dystrophies are a subtype of congenital muscular dystrophy caused by pathogenic variants in COL6A1, COL6A2 or COL6A3 genes affecting skeletal muscles and connective tissue. The clinical phenotype ranges from the milder Bethlem myopathy to the severe Ullrich congenital muscular dystrophy (UCMD). Herein, we report the first consanguineous Sri Lankan family with two children affected with UCMD due to a novel variant in the COL6A1 gene. Case presentation Two sisters, aged 10-years and 7-years, presented with progressive, bilateral proximal muscle weakness. Both probands had delayed motor milestones and demonstrated difficulty in standing from a squatting position, climbing stairs and raising arms above the shoulders. Cognitive, language and social development were age appropriate. Examination showed proximal muscle weakness of the upper and lower extremities and hyperlaxity of the wrist and fingers in both with some variability in clinical severity noted between the two siblings. Serum creatine kinase levels were elevated, and electromyography showed low polyphasic motor unit potentials in the 10-year-old and myopathic features with short duration motor unit potentials with no polyphasia in the 7-year-old. Whole exome sequencing (WES) was performed and a novel, homozygous missense, likely pathogenic variant in exon 25 of COL6A1 gene [NM_001848: c.1667G > T;NP_001839.2:p.Gly556Val] was identified in both probands. This variant was validated by Sanger sequencing in proband 1 as well as proband 2, and the parents and an unaffected sibling were found to be heterozygote carriers for the same variant. Conclusions The findings in this family add to the expanding number of COL6A1 variants identified and provides a better understanding of the genotype-phenotype correlations associated with UCMD.


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