## 3 Genetic NCPs  
### Small Heat Shock Proteins  
Diverse neurological and muscular disorders have been associated with mutations in sHsps. The sHsp \(\alpha\)-crystallin family includes 10 members and one related protein (HSP16.2/HSPB11) [66] that, in addition to the chaperoning function, participate in cytoskeleton stabilization and possess anti-aggregation and anti-apoptotic activities [67; 68; 69; 70; 71]. \begin{table}
\begin{tabular}{c c c c} \hline
**Mol. Chap.** & **Mutation** & **Disease** & **M. I.** & **Ref.** \\ \hline Homozygosity for a complex 2-bp deletion & & & \\ (c429\_430 del and c433\_43 del) in exon 2 & & & \\ resulting in a frameshift and a premature termination of the protein at amino acid 157 & & & \\ Nonsense mutation leading to premature & & & \\ termination (c.442C-T transition in exon 2 & & & \\ resulting in p.Gln148 Ter) & & & \\ c.792T-A transversion in exon 3 resulting in a premature termination (p.Tyr264 Ter) & & & \\ c.830C-T transition in exon 3 resulting in & & & \\ p.Leu277 Pro substitution & & & \\ c.1496G-C transversion in exon 3 resulting & & & \\ in p.Cys499 Ser substitution & & & \\ \hline c.32T-G transversion in exon 1 resulting in & & & \\ p.Val11 Gly substitution & & & \\ c.101G-C transversion in exon 1 resulting in & & & \\ p.Arg34 Pro substitution & & & \\
1-bp insertion in exon 2 (c.27 IdupT) leading & & & \\ to premature termination (p.Cys91 IsTer95) & & & \\ c.273C-G transversion in exon 2 resulting in & & & \\ p.Cys91 Trp substitution & & & \\ p.Cys303 fsTer305 & & & \\ c.931T-G transversion in exon 2 resulting in & & & \\ p.Ser311 Ala substitution & & & \\
2-bp deletion in exon 2 (c.1044\_1045 del) & & & \\ resulting in a frameshift and premature termination & & & \\  & termination (p.Pro350 fs) & & & \\ \hline Homozygous 3-bp deletion in exon 2 & & & \\ (c.337\_339 del) resulting in p.Val113 del & & & \\ Homozygous c.865G-C transversion in exon & & & \\ 3 resulting in p.Ala289 Pro substitution & & & \\ c.1063C-T transition in exon 3 resulting in a & & & \\ \hline BBS12 & & & \\ 2-bp deletion in exon 3 (c.1115\_1116 del) & & & \\ resulting in frameshift and premature & & & \\  & termination of the protein & & \\  & (p.Phe372 fsTer373) & & \\  & 2-bp deletion in exon 3 (c.1483\_1484 del) & & & \\ resulting in frameshift and premature & & & \\  & termination (p.Glu495 fsTer498) & & & \\ \hline \end{tabular} Abbreviations: Mol. Chap., molecular chaperones; M.I., mode of inheritance; Ref., reference; ADo, autosomal dominant; AR, autosomal recessive; dHHM2A/2B, distal Hereditary Motor Neuropathy type 2A/2B; CMT2L/2F, Charoct-Marie-Tooth type 2L/2F; DSMA5, Distal Spinal Muscular Atrophy-5, CLN4B, Ceroid Lipofectaminesonis Neuronal 4B; SPC13, Spastic Paraplega 13; HLD4, Hypomyelinating leukodystrophy-4; BBS, Bardet-Bied syndrome.  
\end{table} 
Table 1: \(Cont.\)Most of the mutations found in the sHsps are located in the highly conserved \(\alpha\)-crystallin domain, which is an 80-100 amino-acid-long domain responsible for the association/dissociation of sHsp dimers and for the formation and stabilization of large multisubunit homo- and hetero-oligomers [72]. These mutations lead to protein aggregation and cell death. Two hypotheses have been proposed to explain the pathologic findings: the mutated sHsp molecules may acquire an intrinsic toxicity (gain of toxic function), or they may suffer a loss of function with abolition of their protein quality control activity [73]. Two representative examples are the mutations occurring in the _HSPB8_ and _HSPB1_ genes that have been associated with the neuromuscular disorders Charcot-Marie-Tooth (CMT) disease and distal hereditary motor neuropathies (dHMN) (Table 1). The term CMT is used to indicate a clinically and genetically heterogeneous group of hereditary motor and sensory neuropathies, characterized by degeneration of peripheral nerves and subdivided in two subgroups: demyelinating (CMT1) and axonal (CMT2) [74].