Actin Isoforms in Neuronal Development and Function - International Review of Cell and Molecular Biology - page 196

regeneration in vivo. It is likely that γ-actin or another actin isoform may
compensate for the loss of β-actin function, or that the role of actin in general
may be limited during peripheral nerve regeneration, where the activity of
microtubules, for example, may be sufficient for successful regeneration.
While the studies described above indicate that β-actin is not required
for motor neuron function or axonal regeneration, it is important to note
that they do not conclusively rule out a role for β-actin in SMA. It is pos-
sible that the mislocalization of β-actin RNA and protein in SMA motor
neurons leads to a gain-of-function rather than a loss-of-function mecha-
nism, perhaps leading to the ectopic sequestering of accessory proteins or
factors leading to motor neuron dysfunction and disease. Alternatively, some
compensatory mechanism occurring in MNs- Actb KO mice may not also
occur in SMA motor neurons, which would be an interesting and poten-
tially therapeutically relevant discovery in itself. Although recent studies
have continued to define axonal transport and mRNA localization roles
for SMN in motor neurons ( Fallini et al., 2011 ), it is important to note that
evidence is also mounting in support of alternative pathogenic mechanisms
in SMA involving tissue-specific disruptions in snRNP assembly and RNA
splicing more aligned with the classical roles described for SMN ( Gabanella
et al., 2007 ; Workman et al., 2009 ; Zhang et al., 2008 ).
6.3.2. Neurological Effects of Mutations in Human β - and γ -Actin
Perhaps the most direct evidence for cytoplasmic actin functions in neuro-
nal development and function in vivo comes directly from human patients.
Seventeen distinct dominant missense mutations (five in Actb and 12 in
Actg1 ) in the cytoplasmic actins have been identified as causative in vari-
ous human diseases ( Nunoi et al., 1999 ; Procaccio et al., 2006 ; Rendtorff
et al., 2006 ; Riviere et al., 2012 ; van Wijk et al., 2003 ; Zhu et al., 2003 ).
This includes one patient with an E364K mutation in Actb that resulted in
mental retardation and significant immunodeficiency ( Nunoi et al., 1999 ),
while a set of monozygotic twins with an R183W mutation in the Actb
gene exhibited multiple phenotypes including moderate cognition deficits,
generalized dystonia, and cofilin-actin aggregates within the brain ( Gear-
ing et al., 2002 ; Procaccio et al., 2006 ). Western blotting of tissue or cells
derived from these patients did not reveal any substantial decrease in β-actin
expression, however, suggesting that these mutations cause disease either by
a gain-of-function or dominant negative mechanism.
Six mutations in Actg1 have been identified as the cause of the inher-
ited genetic disorder DFNA20, which results in late onset hearing loss