## 3 VCP and Genotype-Phenotype Correlations

Table 1: Neurological localizations and clinical phenotypes associated with VCP-MSP. \begin{table}
\begin{tabular}{c c c c c} \hline
**AA Substitution** & **Nucleotide Mutation** & **Domain** & **Phenotype or Disease** & **Inheritance** & **Reference** \\ \hline D6V & c.17A\(>\)T & & & Myalgia, myopathy, & AD & [54] \\ \hline I27V & c.79A\(>\)G & & IBM, PDB, FTD & AD & [55,56] \\ \hline K60R & c.179A\(>\)G & & ALS/FTD & SP & [57] \\ \hline D74V & c.221A\(>\)T & & Chorea; FTD & AD & [58] \\ \hline V87F & c.259C\(>\)T & & IBM & SP & [59] \\ \hline R89W & c.265C\(>\)T & & IBM, FTD & SP & [60] \\ \hline R89Q & c.266G\(>\)A & & ALS & SP & [61] \\ \hline N91Y & c.271A\(>\)T & & IBM, ALS, FTD & AD & [62] \\ \hline R93C & c.277C\(>\)T & & IBM, PDB, FTD & AD & [63] \\ \hline R93H & c.278G\(>\)A & & HSP & SP & [64] \\ \hline R95C & c.283C\(>\)T & & IBM & SP & [65] \\ \hline R95G & c.283C\(>\)G & & IBM, PDB, FTD, ALS & AD & [10,42] \\ \hline R95H & c.284G\(>\)A & & FTD & UN & [66] \\ \hline G97E & c.290G\(>\)A & & IBM, PDB, FTD & AD & [51,67] \\ \hline D98V & c.293A\(>\)T & & ALS, FTD & SP & [68] \\ \hline V99D & c.296T\(>\)A & & PDB, FTD & AD & [69] \\ \hline I114V & c.340A\(>\)G & & IBM (distal arm), ALS & SP & [70,71] \\ \hline P118L & c.353C\(>\)T & & FTD & AD & [69] \\ \hline G125D & c.374G\(>\)A & & IBM, PDB, FTD & AD & [69,72] \\ \hline I126F & c.376A\(>\)T & & IBM & AD & [73] \\ \hline I126V & c.376A\(>\)G & & IBM, FTD & SP & [59] \\ \hline I127A & c.379A\(>\)G & & FTD & SP & [74] \\ \hline G128A & c.383G\(>\)C & & IBM, PDB, FTD & AD & [42,75] \\ \hline G128C & c.382G\(>\)T & & N-Domain & IBM & SP & [75] \\ \hline G128V & c.383G\(>\)T & & Cofactor and & IBM, PDB, FTD & AD & [76] \\ \hline P137L & c.410C\(>\)T & & Substrate Binding & IBM (distal), PDB, FTD & AD & [77] \\ \hline I151V & c.451A\(>\)G & & ALS & SP & [78] \\ \hline V154F & c.460G\(>\)T & & FTD & AD & [79] \\ \hline R155H & c.464G\(>\)A & & IBM, PDB, FTD, ALS & AD & [10] \\ \hline R155C & c.463C\(>\)T & & IBM, PDB, FTD, ALS, & AD & [10,80] \\ \hline R155P & c.464G\(>\)C & & IBM, PDB, FTD & AD & [10] \\ \hline R155S & c.463C\(>\)A & & IBM, PDB, FTD & AD & [81] \\ \hline R155L & c.464G\(>\)T & & IBM, PDB, FTD, ALS, & AD & [82] \\ \hline G156S & c.466G\(>\)A & & IBM, PDB, FTD, ALS & AD & [83,84] \\ \hline G156C & c.466G\(>\)T & & ALS & AD & [85] \\ \hline G157R & c.469G\(>\)C & & IBM, PDB, FTD, SNH & AD & [86] \\ \hline M158V & c.472A\(>\)G & & PDB, ALS, FTD & AD & [87,88] \\ \hline M158I & c.474G\(>\)A & & IBM, PDB, ALS & AD & [42,75] \\ \hline R159H & c.476G\(>\)A & & IBM, PDB, FTD, ALS & AD & [70,72,89,90] \\ \hline R159C & c.475C\(>\)T & & IBM, PDB, FTD, ALS, & AD & [80,91,92,93] \\ \hline R159G & c.475C\(>\)G & & FTD, ALS & AD & [94] \\ \hline R159S & c.475C\(>\)A & & FTD & AD & [88] \\ \hline A160P & c.478G\(>\)C & & IBM, PDB, FTD, ALS & AD & [42,75] \\ \hline E185K & c.553G\(>\)A & & CMT2 & & [44] \\ \hline \end{tabular}
\end{table} 
Table 2: Mutations in _VCP_ organized by domain, and genotype-phenotype correlation. Reasons for the generally poor genotype-phenotype correlation could be related to various factors. For any late-onset genetic disorder, the interaction of environmental factors is certainly possible, and there is precedent from other late-onset neuromuscular conditions [111; 112; 113]. Host-microbiome interactions may be another way in which the onset and severity of disease can be modified, as is seen from early work in other neurodegenerative conditions [114]. However, it also bears mention that much of the variability may still be genetic: there is some evidence that modifier effects can alter the phenotype, such as APO\(\epsilon\)4 alleles associated with the FTD phenotype [115]. A recent publication also suggests a possible interaction with an intermediate-length repeat in _ATXN2_ and a complex neurodegenerative phenotype [116]. Future studies may also consider other possible modifiers that have been identified from studies of animal models or related disorders [24; 25; 117].