Mutations in HSPs themselves can lead to pathological conditions termed chaperonopathies that also are mostly associated with accumulation of protein aggregates. The first chaperonopathies found concerned mutations in members of the family of small HSPs (HSPBs). Later, members of the chaperonins and DNAJ families as well as some other chaperone cofactors (e.g, in BAG3, a  HSP70-NEF) have been implicated heritable chaperonopathies. No genetic chaperonopathies are associated with the Hsp70/HSPA or Hsp90/HSPC family members, either because of functional redundancy within these families or because they are crucial to the central chaperone machinery such that mutations leading to functional defects are incompatible with life.

Clinically, these genetic chaperonopathies can be categorized into neuropathies (hereditary spastic paraplegia, motor neuropathy, distal hereditary motor neuropathy, dHMN), myopathies (dilated cardiomyopathy, leukodystrophy, desmin-related myopathy, mitochondrial myopathy, muscular dystrophy) or retina- and eyelens- related diseases (congenital cataracts) (Macario et al., 2005)(Table I). A variety of these mutated chaperones have been or are studied in my research group to investigate how they lead to protein aggregation (loss of function, dominant-negative effects, self-aggregation and toxic gain-of-function) and whether and how these effects can be ameliorated.



Table I: Overview of chaperonopathies caused by mutations in HSPs. Mutations that lead to either recessive (R, green boxes) or dominant (D, red boxes) or both (R+D orange boxes) chaperonopathies are indicated and categorized as causative for a neuropathy, a myopathy or a retina-related disease (cataracts). h-SP = hereditary-spastic paraplegia; dHMN = distal hereditary motor neuropathy; MN = motor neuropathy; CMT2, = Charcot-Marie-Tooth disease 2; juPD = juvenile onset Parkinsonism; DCM = dilated cardiomyopathy; MFM = myofibrillar myopathy; LD = leukodystrophy; MD = muscular dystrophy; CC = congenital cataract; DT = dystrophy.
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