Table 1.
Gene mutations that cause ALS
| Gene | Fraction fALS (%) | Locus | Encoded protein | Functionality | Clinical phenotype | Neuropathology | Reference(s) |
|---|---|---|---|---|---|---|---|
| C9ORF72 | 40–50 | 9p21.3 | C9ORF72 | Transcription and pre-mRNA splicing regulation; membrane traffic via Rab GTPase family | ALS; ALS+ FTLD; FTLD | NCI; DN; GCI; intranuclear RNA foci (sense, antisense); cytoplasmic RNA peptide aggregates | DeJesus-Hernandez et al. 2011; Renton et al. 2011; Cooper-Knock et al. 2012; Diekstra et al. 2014 |
| SOD1 | 20–25 | 21q22 | SOD1 | Major cytosolic antioxidant | ALS; PMA | NCI; NII; DN; GCI; aggregates—p62, C9ORF72, ubiquilin 2, others; impaired axonal transport, mitochondrial function; disturbed dendritic arborization of neurons; oxidative stress-related neuronal toxicity | Rosen et al. 1993; Watanabe et al. 2001; Forsberg et al. 2011 |
| TARDBP | 4–5 | 1p36.2 | TDP-43 | Transcription and pre-mRNA splicing regulation; micRNA biogenesis; RNA transport and stabilization; translational regulation of ApoE-II and CFTR | ALS; ALS+ FTLD; FTLD | NCI; NII; DN; GCI | Rutherford et al. 2008; Sreedharan et al. 2008; Neumann 2009 |
| FUS | 4–5 | 16p11.2 | FUS (or TLS) | Transcription and pre-mRNA splicing regulation; micRNA processing; mRNA transport and stabilization; maintenance of genomic integrity; regulating protein synthesis at synapse | ALS; ALS+ FTLD; FTLD | NCI; DN; GCI | Kwiatkowski et al. 2009; Vance et al. 2009; Huang et al. 2010 |
| OPTN | 2–3 | 10p13 | Optineurin | Golgi maintenance; exocytosis; vesicular trafficking; regulator of NF-kB signaling pathway; autophagy process | ALS; ALS+ FTLD | NCI; ↑ TDP-43, FUS, and SOD1 aggregates | Maruyama et al. 2010 |
| PFN1 | 1–2 | 17p13 | Profilin 1 | Regulates ATP-mediated actin polymerization | ALS | NCI; ↓ axonal distension and growth cone elongation; co-aggregation with TDP-43 | Wu et al. 2012 |
| VCP | 1–2 | 9p13 | VCP or p97 | Protein degradation via UPS, autophagy, and the ER; membrane fusion | ALS; ALS+ FTLD; FTLD | NCI; NII; DN; ↑ TDP-43 aggregates; ↓ stress-granule clearance | Forman et al. 2006; Kimonis et al. 2008; Johnson et al. 2010 |
| ANG | 1–2 | 14q11.2 | Angiogenin | RNA processing and tRNA modification; vascularization; RNAase activity and assembly of stress granules; neurite outgrowth and pathfinding | ALS; ALS+ FTLD | ↓ Stress-granule formation in motor neurons | Greenway et al. 2006; Thiyagarajan et al. 2012 |
| TUBA4A | 1 | 2q35 | Tubulin α4A | Major component of microtubules; neuronal cell skeleton | ALS; ALS+ FTLD | NCI; destabilized microtubule network; ↓ microtubules repolymerization capability | Smith et al. 2014 |
| UBQLN2 | <1 | Xp11 | Ubiquilin 2 | Protein degradation via UPS | ALS; ALS+ FTLD; FTLD (Rare) | NCI; ↑ TDP-43, p62, FUS, and OPTN inclusions | Deng et al. 2011; Ugwu et al. 2014 |
| TAF15 | <1 | 17q11 | TAF15 | Transcription initiation; RNA polymerase II gene component | ALS | NCI | Couthouis et al. 2011 |
| EWSR1 | <1 | 22q12.2 | EWSR1 | Transcriptional repressor | ALS | NCI; DN | Couthouis et al. 2012 |
| hnRNPA1 | <1 | 12q13 | hnRNPA1 | Packing and transport of mRNA; micRNA biogenesis | Rare ALS; ALS+ FTLDa; FTLD (rare) | NCI | Bekenstein and Soreq 2013; Kim et al. 2013; Le Ber et al. 2014 |
| hnRNPA2B1 | <1 | 7p15 | hnRNPA2/B1 | Packing and transport of mRNA; micRNA biogenesis | ALS+ FTLD (rare)a; FTLD (rare) | NCI | Kim et al. 2013; Le Ber et al. 2014 |
| SETX | <1 | 9q34.13 | Senataxin | DNA/RNA helicase activity; DNA/RNA metabolism | ALSb | ↓ neuronal differentiation; ↓ neurite growth | Chen et al. 2004 |
| CREST | <1 | 20q13.3 | SS18L1 | Ca2+-dependent transcriptional activator | ALS | DN; ↓ dendrite outgrowth; ↑ interaction with FUS | Chesi et al. 2013; Teyssou et al. 2014 |
| MATR3 | <1 | 5q31.2 | Matrin 3 | RNA processing; stabilizing mRNAs; gene silencing; chromatin organization | ALS; ALS+ FTLD (Rare) | NCI; NII; ↑ interaction with TDP-43 | Johnson et al. 2014b; Millecamps et al. 2014 |
| ATXN2 | 1-2 | 12q24 | Ataxin 2 | RNA processing; regulation of receptor tyrosine kinase endocytosis | ALS; ALS+ FTLD; PMA | NCI; ↑ interaction with TDP-43 | Elden et al. 2010; Baumer et al. 2014 |
| ELP3 | <1 | 8p21.1 | ELP3 | RNA processing; transcript elongation; histone acetylation; modification of tRNA wobble nucleosides | ALS | NCI; abnormal branching in motor axons; co-localization with TDP-43 and FUS aggregates | Simpson et al. 2009; Fujita et al. 2014 |
| SQSTM1 | <1 | 5q35 | p62 or SQSTM1 | Autophagy and UPS degradation; regulator of NF-kB signaling pathway; immune response | ALS; ALS+ FTLD; FTLD | NCI; NII; GCI; ↓ mutSOD1 autophagic degradation | Gal et al. 2009; Fecto et al. 2011; Rubino et al. 2012 |
| CHMP2B | <1 | 3p11 | CHMP2B | MVBs formation; protein trafficking between plasma membrane, trans-Golgi network, and lysosome | ALSc; PMAd; FTLD | NCI; DN; GCI; disrupted endosomal structure; aggregates of autophagosomes and multilamellar structures; ↑ TDP-43, p62, and ubiquitin inclusions | Cannon et al. 2006; Parkinson et al. 2006 |
| ALS2 | <1 | 2q33.1 | Alsin | Activation of the small GTPase Rac1 macropinocytosis-associated endosome fusion and trafficking; neurite outgrowth | ALSe; PLS | ↓ axonal growth; ↓ lysosome-dependent clearance of p62 and LC3-II | Hadano et al. 2001; Yang et al. 2001; Otomo et al. 2008 |
| VAPB | <1 | 20q13 | VAPB | Regulation of ER–Golgi transport and secretion | ALS; PLS; PMA | NCI; ↑ TDP-43 toxicity and inclusions; aberrant synaptic microtubule cytoskeleton; nuclei mispositioning and aberrant architecture | Nishimura et al. 2004; Sanhueza et al. 2014 |
| SIGMAR1 | <1 | 9p13.3 | SIGMAR1 | Lipid transport through ER; BDNF and EGF signaling | ALS; ALS+ FTLD; FTLD | NCI; ↑ apoptosis induced by ER stress; ↑ interaction with VAPB | Al-Saif et al. 2011; Belzil et al. 2013; Prause et al. 2013 |
| DCTN1 | <1 | 2p13 | Dynactin | ER–Golgi transport; centripetal movement of lysosomes and endosomes; spindle formation, chromosome movement; nuclear positioning; axonogenesis | ALS | NCI; p150glued aggregation; ↑ SOD1 aggregates | Munch et al., 2004 |
| FIG4 | <1 | 6q21 | PI3,5P2 | Phosphoinositide phosphatase activity; endosomal vesicle trafficking to the trans-Golgi network; regulation of autophagy | ALS; PLS | NCI; ↑ swollen intracellular vacuoles; ↑ LC3-II, p62, and LAMP-2 aggregates in neurons and astrocytes | Zhang et al. 2007; Chow et al. 2009 |
| SPG11 | 1 | 15q21.1 | Spatascin | Neuronal cell skeleton; axonal transport; involved in synaptic vesicles | ALS; HSP | NCI; DN; ↓ acetylated stabilized tubulin; ↓ synaptic vesicles in neurites; disrupted anterograde axonal transport | Stevanin et al. 2007; Orlacchio et al. 2010; Manole et al. 2016 |
| NEFH | <1 | 22q12.2 | NEFH | Maintaining axon diameter | ALS | NCI; ↑ neurofilament aggregates | Figlewicz et al. 1994 |
| PRPH | <1 | 12q13 | Peripherin | Regulating neurite elongation during development and axonal regeneration after injury | ALS | NCI; DN; ↓ ability of the neurofilament network to assemble; ↑ ubiquitinated inclusions; coaggregation with mutSOD1 | Beaulieu et al. 1999; Julien and Beaulieu 2000; Gros-Louis et al. 2004 |
| NTE | <1 | 19p13 | Neuropathy target esterase | Regulating the neuronal membrane composition | ALS; HSP | Disruption of ER; ↑ reticular aggregates; ↑ vacuolization of nerve cell bodies | Akassoglou et al. 2004; Rainier et al. 2008; Song et al. 2013 |
| PON1-3 | <1 | 7q21 | Paraoxonase 1-3 | Enzymatic breakdown of nerve toxins | ALS | Oxidative stress-related neuronal toxicity | Saeed et al. 2006; Slowik et al. 2006; Wills et al. 2009 |
| DAO | <1 | 12q22 | DAO | Regulating levels of D-serine, NMDAR function | ALS | NCI; NII; ↑ D-serine levels in motor neurons and glia; ↑ ubiquitinated inclusions | Mitchell et al. 2010 |
| CHRNA3, CHRNA4, CHRNB4 | <1 | 15q24, 20q13, 15q24 | nAChR | Cholinergic neurotransmission | ALS§ | Cationic overloading, Ca+2 toxicity in MNs | Sabatelli et al. 2009, 2012; Moriconi et al. 2011) |
| ERBB4 | <1 | 2q34 | Receptor tyrosine-protein kinase ErbB-4 | Neuronal cell mitogenesis and differentiation | ALS | Takahashi et al. 2013 | |
| CHCHD10 | <1 | 22q11 | Mitochondrial protein | Mitochondrial genome stability; cristae integrity and mitochondrial fusion | ALS+ FTLD | Mitochondrial fragmentation and DNA instability; mitochondrial crystalloid inclusions | Bannwarth et al. 2014; Chaussenot et al. 2014; Johnson et al. 2014a |
| C19orf12 | <1 | 9q12 | Mitochondrial protein | Unknown | ALS | Deschauer et al. 2012 | |
| ALS3 | <1 | 18q21 | Disulfide redox protein | Unknown | ALS | Hand et al. 2002 | |
| ALS7 | <1 | 20p13 | Unknown | Unknown | ALS | Hand et al. 2002 | |
| ALS6-21 | <1 | 6p25, 21q22 | Unknown | Unknown | ALS§ | Butterfield et al. 2009 | |
| ALS-FTD | <1 | 16p12 | Unknown | Unknown | ALS+ FTLD | NCI; DN; Type B TDP pathology; phosphorylated tau pathology | Dobson-Stone et al. 2013 |
| Gene variants that influence ALS phenotype | |||||||
| UNC13A | 19p13 | Unc-13 homolog A | Regulating neurite outgrowth and synaptic neurotransmission | ALS; ALS+ FTLD | ↓ synaptogenesis at neuromuscular junction; possible glutamate excitotoxicity | Varoqueaux et al. 2005; van Es et al. 2009; Diekstra et al. 2014 | |
| EPHA4 | 2q36.1 | Ephrin receptor A4 | Receptor tyrosine kinase activity Modulation of cell morphology and integrin-dependent cell adhesion; regulation of synaptic plasticity and CNS development | ALS | NII; neurite outgrowth deficits in mutant TDP-43 expressed neurons | Van Hoecke et al. 2012; Uyan et al. 2013 | |
| CHGB | 20p12.3 | CHGB | Involved in the ER–Golgi system | ALS | NCI; ↓ density of synaptophysin-like immunoreactivity; ↑ interaction with mutSOD1 | Gros-Louis et al. 2009; Schrott-Fischer et al. 2009 | |
| KIFAP3 | 1q24.2 | Kinesin-associated protein 3 | Tethering chromosomes to spindle pole; chromosome movement; axonal transport of choline acetyl-transferase | ALS§ | NCI; KIFAP3-SOD1 coaggregation in Lewy-body-like hyaline inclusions | Landers et al. 2009; Tateno et al. 2009; Orsetti et al. 2011 | |
| SMN | 5q13 | Germin 1 | Regulating biogenesis of snRNPs | ALS; LMN | NCI; NII; DN; coaggregation with mutFUS, mutSOD1; axonal defects | Jackson et al. 1996; Moulard et al. 1998; Gertz et al. 2012; Groen et al. 2013 | |
ALS, amyotrophic lateral sclerosis; BDNF, brain derived neurotrophic factor; C9ORF72, chromosome 9 open reading frame 72; CHGB, chromogranin B (secretogranin 1); CHMP2B, charged multivesicular body protein 2B; DAO, D-amino acid oxidase; DN, dystrophic neurites; EGF, epidermal growth factor; ELP3, elongator acetyltransferase complex subunit 3; ER, endoplasmic reticulum; EWSR1, Ewing sarcoma breakpoint region 1; FTLD, frontotemporal lobe dementia; FUS, fused in sarcoma; GCIs, glial cell inclusions; hnRNPA1, heterogeneous nuclear ribonucleoprotein A1; hnRNPA2B1, heterogeneous nuclear ribonucleoproteins A2/B1; HSP, hereditary spastic paraplegia; LAMP-2, lysosomal-associated membrane protein 2; LC3-II, microtubule-associated protein 1A/1B-light chain 3-II; LMN, lower motor neuron disease; micRNA, micro RNA; mRNA, messenger RNA; mutSOD1, mutant superoxide dismutase 1; MVBs, multivesicular bodies; nAChR, nicotinic acetylcholine receptor; NCI, neuronal cytoplasmic inclusions; NEFH, neurofilament heavy chain; NII, neuronal intranuclear inclusions; NMDAR, N-methyl-D-aspartate receptor; PI3,5P2, phosphatidylinositol 3,5-bisphosphate 5-phosphatase; PLS, primary lateral sclerosis; PMA, progressive muscular atrophy; SIGMAR1, σ non-opioid intracellular receptor 1; SQSTM1, sequestosome 1; SS18L1, synovial sarcoma translocation gene on chromosome 18-Like 1; TAF15, TATA box binding protein-associated factor 15; TDP-43, TAR DNA-binding protein; TLS, translocated in liposarcoma; UMN, upper motor neuron; UPS, ubiquitin-proteasome system; VAPB, vesicle-associated membrane protein B; VCP, valosin-containing protein.
aAs part of multisystem proteinopathy.
bPhenotype more similar to Silver syndrome than to ALS.
cPredominant LMN phenotype.
dAs part of ALS.
ePredominant UMN phenotype.