In a multigeneration French family with autosomal dominant alpha-B crystallin-related myofibrillar myopathy (608810) and cataracts reported by Fardeau et al. (1978), Vicart et al. (1998) identified a heterozygous 3787A-G transition in the CRYAB gene, resulting in an arg120-to-gly (R120G) substitution. Functional expression studies in muscle cells showed that the R120G mutation resulted in the presence of cytoplasmic or perinuclear alpha-beta-crystallin-labeled aggregates in 80 to 90% of the cells. Desmin-labeled aggregates were also detected. Ultrastructural analysis showed that each aggregate had an inner dense core surrounded by 10-nm intermediate filaments that appeared to engulf the dense deposit.
Fu and Liang (2003) observed that alpha-B-crystallin carrying the R120G mutation had decreased interactions with wildtype alpha-A- (123580) and alpha-B-crystallins, but slightly increased interactions with wildtype beta-B2- (123620) and gamma-C- (123680) crystallins.
Chavez Zobel et al. (2003) reported that the R120G mutant protein has impaired in vivo function and structure, as reflected by a highly reduced capacity to protect cells against heat shock and by an abnormal supramolecular organization even in cells not expressing desmin. In many cells, the mutant protein accumulated in inclusion bodies that had characteristics of aggresomes concentrating around the centrosome. Three distinct chaperone mechanisms could reduce or even prevent the formation of these aggresomes: wildtype alpha-B crystallin and HSP27 (602195) prevented aggresome formation by co-oligomerizing with the R120G mutant; HSP70 (see 140550) with its cochaperone HDJ1 or CHIP (607207) reduced the frequency of aggresome formation, likely by targeting the mutant protein for degradation; and HSPB8 (608014) interacted only transiently with alpha-B but nonetheless rescued the R120G protein oligomeric organization. Chavez Zobel et al. (2003) concluded that the formation of inclusion bodies in alpha-B crystallin R120G-mediated desmin-related myopathy may be due to the misfolding of the mutant protein per se and may be delayed or prevented by expression of the wildtype alpha-B allele or other molecular chaperones, which would explain the adult onset of the disease.
In transfected rat primary cardiomyocytes, Inagaki et al. (2006) observed intracellular aggregates of the R120G mutant protein. In mammalian-2-hybrid assays, the mutant showed decreased binding to the heart-specific N2B domain and the adjacent striated muscle-specific I26/I27 domains of titin (TTN; 188840) compared to wildtype.
