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Abstract
Mutations in the DNAJB6 gene have been associated with the autosomal dominant limb girdle muscular dystrophy type 1D (LGMD1D), a disorder characterized by abnormal protein aggregates and rimmed vacuoles in muscle fibers. DNAJB6 is a ubiquitously expressed Hsp40 co-chaperone characterized by a J domain that specifies Hsp70 functions in the cellular environment. DNAJB6 is also a potent inhibitor of expanded polyglutamine (polyQ) aggregation preventing aggregate toxicity in cells. In DNAJB6-mutated patients this anti-aggregation property is significantly reduced, albeit not completely lost. To elucidate the pathogenetic mechanisms underlying the DNAJB6-related myopathy, animal models have been created showing that, indeed, conditional muscular expression of a DNAJB6 mutant in the mouse causes a LGMD1D myofibrillary muscle tissue phenotype. Both mutations and phenotypes reported until recently were rather homogeneous, being exclusively missense mutations of a few amino acids of the protein G/F domain, and with a phenotype characterized by adult-onset slowly progressive muscular dystrophy predominantly affecting proximal muscles. Lately, several novel mutations and new phenotypes of DNAJB6 have been described. These mutations once more affect the G/F domain of DNAJB6 with missense changes and a splice site mutation; and the phenotypes include childhood onset and distal involvement of muscles, or childhood-onset LGMD1D with loss of ambulation in early adulthood and respiratory involvement. Thus, the spectrum of DNAJB6-related phenotypes is widening. Although our knowledge about the role of DNAJB6 in the pathogenesis of muscle diseases has made great progression, several questions remain unsolved, including why a ubiquitous protein affects only, or predominantly, skeletal muscle; why only the G/F domain is involved; and what is the possible role of the DNAJB6a isoform. Clarification of these issues will provide clues to implement possible therapeutic strategies for DNAJB6-related myopathies.
Highlights
The first description of what it was, at that time, defined as “an unusual form of muscular dystrophy” dates back to 1969, when Schneiderman et al (1969) described a four generation family affected by a late onset dominant muscular dystrophy form, predominantly affecting proximal limb muscles
Why do DNAJB6 mutations affect mainly skeletal muscle and rarely the central nervous system, and why has no cardiac involvement been reported in these patients? Possible explanations include the selective expression of a DNAJB6 client protein in skeletal muscle, the interaction of DNAJB6 with the chaperoneassisted selective autophagy (CASA) system with BAG3, or a functional redundancy of DNAJ family members in all tissues except skeletal muscle
(2) Why are only mutations of the G/F domain implicated? Are any other regions of the protein more flexible and more adaptable to variations, or are mutations in other regions lethal? In this context, the animal models could be useful in preclinical studies addressed to better understand the physio-pathological mechanisms involved in DNAJB6related myopathies
Summary
The first description of what it was, at that time, defined as “an unusual form of muscular dystrophy” dates back to 1969, when Schneiderman et al (1969) described a four generation family affected by a late onset dominant muscular dystrophy form, predominantly affecting proximal limb muscles. In the present review we will focus our attention on the pathological effects of mutations affecting the DNAJB6 chaperone protein, and on the clinical and histopathological features of the DNAJB6-related myopathies.
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