DNAJB6 Myopathies: Focused Review on an Emerging and Expanding Group of Myopathies

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.

Keywords: DNAJB6; LGMD1D; autophagy; chaperone; distal myopathy; protein aggregation; vacuolar myopathy.

Figure 1

The Hsp40-Hsp70 cycle. Hsp40 co-chaperone forms complexes with unfolded or non- native proteins delivering them to Hsp70. The interaction between Hsp40 and the ATP-bound Hsp70 takes place through the J-domain. The client protein transiently interacts with the Hsp70 and the interaction is stabilized by a conformational change in Hsp70 caused by the hydrolysis of ATP which, in turn, is stimulated by both Hsp40 and client protein. Hsp40 is then released. A nucleotide exchange factor (NEF) then binds Hsp70 (having more affinity for the ADP-bound form compared to the ATP form), stimulating the dissociation of ADP through a conformational change in Hsp70. An ATP molecule is bound again to Hsp70 because of its higher cellular concentration, causing the release of the client protein. The system is then ready for a new cycle (Kampinga and Craig, 2010).

Figure 2

The DNAJ protein family. Based on their structure, DNAJs are divided into three subtypes. Type I, or A, has an N-terminal J domain (with a conserved histidine, proline, and aspartic acid tripeptide), followed by a glycine/phenylalanine-rich domain (G/F), by a zinc finger region rich in cysteine, and by a C-terminal domain, responsible for client binding and presenting two barrel domains, CTDI and CDTII. Type II, or B, is similar to type I, but lacks the zinc finger region. Type III, or C, has only the conserved J domain which is variably located in the protein (Fan et al., 2003).

Figure 3

The DNAJB6 protein. The J, G/F and C-terminal domains, and position of the amino acid and splicing mutations are represented (Fan et al., ; Sato et al., ; Ruggieri et al., 2015).

Figure 4

Histopathological features of muscle biopsies from DNAJB6-mutated patients. H&E (A,B) and Gomori trichrome stains (C,D) reveal several autophagic vacuoles, visible either in subsarcolemmal regions or centrally located, internalized myonuclei as well as variability in fiber sizes (Ruggieri et al., 2015).