**2.11 ALS11 (FIG4)**

Mutations in the PI(3,5)P(2)5-phosphatase (*FIG4*) gene on chromosome 6q21 are known to cause a severe form of Charcot-Marie-Tooth (CMT) disease with early onset and loss of sensory and motor neurons, CMT4J (Chow et al., 2007). In a screen for *FIG4* mutations in a large cohort of sALS and fALS patients, several variants were detected that were unique to fALS and sALS patients (Chow et al., 2009). Two mutations were identified in patients diagnosed with primary lateral sclerosis. To date, no other studies have replicated the finding of ALS-associated FIG4 mutations in other cohorts and it is unclear whether *FIG4* mutations are pathogenic in ALS patients.

FIG4 is a phosphoinositide 5-phosphatase that regulates PI(3,5)P2 abundance. PI(3,5)P2 is a signalling lipid that mediates endosomal trafficking to the trans-Golgi network (Rutherford et al., 2006). Pale tremor mice, which are homozygous for null mutations in *FIG4*, show neurodegeneration in sensory and autonomic ganglia, motor cortex, striatum, and cerebellum. Motor neurons in the ventral spinal cord contain vacuoles (Chow et al., 2007). Mutant mice lacking *Vac14*, a gene encoding for a FIG4 interactor, show a similar neurodegeneration (Zhang et al., 2007).

### **2.12 ALS12 (OPTN)**

Using homozygosity mapping in six ALS patients from consanguineous marriages, an overlapping region on chromosome 10 was identified as the candidate region. Screening of

RNA which results in inhibition of protein translation (Yamasaki et al., 2009). ANG is also expressed in spinal motor neurons (Sebastià et al., 2009). It is thought that *ANG* mutations cause ALS due to a loss of function and it has been shown that wild-type but not mutant angiogenin is neuroprotective and that mutant angiogenin impairs neurite outgrowth *in* 

TDP-43 was identified as one of the main components of ubiquitinated cytoplasmic inclusions in ALS and FTD (Neumann et al., 2006). Sequencing of the gene encoding this protein (*TARDBP*) identified mutations in ALS patients (Kabashi et al., 2008; Shreedharan et al., 2008). To date over 40 mutations in *TARDBP* have been identified in several different populations with a frequency of ~5% of fALS cases and up to 2% of sALS cases (Corrado et al., 2009; Iida et al., 2010; Millecamps et al., 2010; Ticozzi et al., 2009; Van Deerlin et al., 2008). *TARDBP* mutations have also been observed in ALS-FTD and FTD patients (Benajiba et al., 2009; Gitcho et al., 2009b). Despite the presence of *TARDBP* mutations in only a portion of ALS and FTD patients, TDP-43-positive cytoplasmic inclusions are found in almost all ALS patients but they are also seen in other neurodegenerative diseases such as FTD,

Huntington's, Alzheimer's, and Parkinson's disease (Da Cruz and Cleveland, 2011).

TDP-43, like FUS, is a DNA/RNA binding protein that is part of the heterogeneous ribonucleoprotein family. It has a role in gene transcription, regulation of splicing, and mRNA transport and stabilization (Buratti and Baralle, 2010). Except for one truncation mutation, all *TARDBP* mutations identified in ALS patients are missense mutations clustered in the glycine-rich C-terminal region which is involved in protein-protein interactions (Lagier-Tourenne et al., 2010). *TARDBP* mutations lead to an abnormal

Mutations in the PI(3,5)P(2)5-phosphatase (*FIG4*) gene on chromosome 6q21 are known to cause a severe form of Charcot-Marie-Tooth (CMT) disease with early onset and loss of sensory and motor neurons, CMT4J (Chow et al., 2007). In a screen for *FIG4* mutations in a large cohort of sALS and fALS patients, several variants were detected that were unique to fALS and sALS patients (Chow et al., 2009). Two mutations were identified in patients diagnosed with primary lateral sclerosis. To date, no other studies have replicated the finding of ALS-associated FIG4 mutations in other cohorts and it is unclear whether *FIG4*

FIG4 is a phosphoinositide 5-phosphatase that regulates PI(3,5)P2 abundance. PI(3,5)P2 is a signalling lipid that mediates endosomal trafficking to the trans-Golgi network (Rutherford et al., 2006). Pale tremor mice, which are homozygous for null mutations in *FIG4*, show neurodegeneration in sensory and autonomic ganglia, motor cortex, striatum, and cerebellum. Motor neurons in the ventral spinal cord contain vacuoles (Chow et al., 2007). Mutant mice lacking *Vac14*, a gene encoding for a FIG4 interactor, show a similar

Using homozygosity mapping in six ALS patients from consanguineous marriages, an overlapping region on chromosome 10 was identified as the candidate region. Screening of

*vitro* (Sebastià et al., 2009; Subramanian et al., 2008; Wu et al., 2007).

**2.10 ALS10 (TARDBP)** 

distribution of the protein to the cytoplasm.

mutations are pathogenic in ALS patients.

neurodegeneration (Zhang et al., 2007).

**2.12 ALS12 (OPTN)** 

**2.11 ALS11 (FIG4)** 

17 genes in this region revealed a homozygous deletion in the gene for optineurin (*OPTN*), a gene known to cause primary open-angle glaucoma, in two siblings and an individual from a different family (Murayama et al., 2010; Rezaie et al., 2002). In addition, a homozygous nonsense (Q398X) mutation was identified in one fALS case (Murayama et al., 2010). Subsequent screening in a larger cohort of fALS and sALS patients identified a heterozygous missense mutation (E478G) in a four individuals with ALS from two families (Murayama et al., 2010). A homozygous E478G mutation was identified in a Japanese fALS case in a different study (Iida et al., 2011). One additional nonsense mutation and one missense mutation in *OPTN* were identified in fALS cases from Italy (Del Bo et al., 2011). Two separate studies identified novel variants in fALS patients but the authors state that these variants may be a genetic predisposition to glaucoma instead of causing ALS (Belzil et al., 2011; Millecamps et al., 2011). One study also detected mutations in sALS patients with a rapid disease progression (van Blitterswijk et al., 2011). Another study could not identify *OPTN* mutations in fALS and sALS patients (Sugihara et al., 2011).

OPTN is a multifunctional protein involved in membrane trafficking, maintainance of the Golgi complex, and exocytosis (Sahlender et al., 2005). OPTN can inhibit the activation of NFκB and it has been proposed that mutations in *OPTN* causing ALS may relieve this inhibition and cause neuronal death (Murayama et al., 2010).
