Aberrant Mitochondria in a Bethlem Myopathy Patient with a Homozygous Amino Acid Substitution That Destabilizes the Collagen VI α2(VI) Chain

Abstract

Background: Collagen VI amino acid substitutions are common, and it is difficult to determine if they are pathogenic. Results: COL6A2 p.D871N chains are abnormal and cannot assemble. Alternatively spliced chains lacking the mutation cannot functionally substitute. Conclusion: COL6A2 p.D871N is a recessive mutation. Significance: Protein studies reveal the consequences of amino acid substitutions in the globular domains of collagen VI.

The extracellular matrix and insulin resistance

“…ECM remodeling is also reflected by alterations in mechano-signal transduction to the nucleus and mitochondria [37, 38]. This may be a consequence of disturbances in actin and intermediate filament organization and/or the sarcoglycan complex, a junction whereby the myofiber interacts with the ECM.…”

“…It is plausible that these alterations may impair the ability of the muscle to adapt to exercise via compromised mechano-signal transduction to the nucleus or mitochondria that, under normal conditions, would induce gene transcription in response to exercise. In support of the ECM modulating mitochondrial function in the skeletal muscle, there is evidence that alterations in the collagen VI composition of the matrix affect mitochondrial function [37, 38]. Insulin resistant muscle is characterized by alterations in exercise tolerance and mitochondrial function, thus this provides another route whereby the ECM may regulate muscle insulin action.…”

Genetic Disorders of the Extracellular Matrix

“…Mutations outside the collagen VI triple helix can be dominant or recessive. If the chains cannot be incorporated into monomers they can undergo proteasomal degradation (Zamurs et al, ), but if incorporated into monomers, dimers, and tetramers, the mutant chains can prevent microfibril formation (Tooley et al, ) or form abundant disorganized microfibrils (Zhang et al, ).…”

Reply to Sabatelli et al.: Detecting Collagen VI in Bethlem Myopathy

“…Unfortunately we used the term "absent collagen VI" in the subheading, and this has resulted in the inadvertent apparent inconsistency. The collagen VI staining was actually done on sections of paraffinembedded muscle, not frozen sections as suggested under "Experimental Procedures," and this is why we used an antigen retrieval protocol, which resulted in strong staining in the control muscle (2). We apologize for omitting this important detail under "Experimental Procedures.…”