**3. Genetic causes of FALS**

models to further study the disease and efficacy of therapeutic compounds.

**Autosomal Dominant Adult Onset Most common genetic causes** 

**Less frequent genetic causes** 

**Autosomal Dominant Juvenile Onset** 

**Genetic Loci Linked to Familial ALS** 

**ALS+FTD** 

Table 1. Summary of the Genetic Causes of Familial ALS

**Autosomal Recessive** 

518 Amyotrophic Lateral Sclerosis

pathological mutations in the Cu-Zn superoxide dismutase (*SOD1*) gene in ALS patients (Rosen et al 1993). Since then there has been an explosion of research into the mechanism(s) by which *SOD1* mutations cause ALS, however the answer remains elusive. There are now 16 genes associated with Mendelian forms of ALS (Table 1) which have mostly been identified using linkage analysis of rare families with large pedigrees affected by the disease (Lill et al 2011). More recently, studies to identify the proteins found in the ubiquitinated inclusions that are a common neuropathological feature of both ALS and FTD, have identified trans-activation response element (TAR) DNA binding protein of 43kDa (TDP-43) as the major component (Arai et al 2006; Neumann et al 2006). Mutations in the gene encoding TDP-43, *TARDBP*, were subsequently found as a genetic cause of ALS (Sreedharan et al 2008). The genetics of FALS has moved forward rapidly in recent years, providing invaluable insight into disease pathogenesis and allowing the development of animal

**Type Locus Reference** 

*SOD1* ALS1 21q22 (Rosen et al 1993) *TARDBP* ALS10 1p36.22 (Sreedharan et al 2008) *FUS* ALS6 16q12.1-2 (Abalkhail et al 2003)

*VAPB* ALS8 20q13.3 (Nishimura et al 2004) *ANG* ALS9 14q11.2 (Greenway et al 2004) *FIG4* ALS11 6q21 (Chow et al 2009) *OPTN* ALS12 10p15-14 (Maruyama et al 2010) *DAO* 12q22-23 (Mitchell et al 2010) *VCP* 9p13.3 (Johnson et al 2010b)

*SETX* ALS4 9q34 (Chen et al 2004)

*ALS2* ALS2 2q33-35 (Hentati et al 1994)

*SPG11* ALS5 15q15-22 (Orlacchio et al 2010) **Unknown** ALS7 20ptel-p13 (Sapp et al 2003) **Unknown** ALS3 18q21 (Hand et al 2002) *UBQLN2* ALSX Xp11-q12 (Deng et al 2011) *C9ORF72* ALS-FTD1 9p21-q22 (Hosler et al 2000) **Unknown** ALS-FTD2 9p13.2-p21.3 (Vance et al 2006)

*SIGMAR1* 9p13.3 (Luty et al 2010) *MAPT* 17q21 (Sundar et al 2007)
