Genetics of amyotrophic lateral sclerosis

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There are more than 25 genes known to be associated with

first-degree relatives of an individual with ALS have a 1% risk of developing ALS.[4][5] ALS has an oligogenic mode of inheritance, meaning that mutations in two or more genes are required to cause disease.[6]

C9orf72 is the most common gene associated with ALS, causing 40% of familial cases of ALS, as well as a small percentage of sporadic cases;[7] it also causes about 25% of familial cases of frontotemporal dementia.[6] The pathogenic mutation is a hexanucleotide repeat expansion (a series of six nucleotides repeated over and over); the more repeats in C9orf72, the more pathogenic the mutation. People without ALS tend to have fewer than 25 repeat units, while people with ALS due to a mutation in C9orf72 tend to have hundreds or thousands of repeat units. It is not clear exactly how many repeat units are needed to cause disease.[1]

superoxide dismutase 1, is the second most common gene associated with ALS and causes about 12% of familial cases and about 2% of sporadic cases.[6] More than 150 mutations in SOD1 have been described, almost all of which have an autosomal dominant mode of inheritance.[8]

TDP-43 is involved in the repair of DNA double-strand breaks. It is recruited to DNA damage sites and interacts with proteins involved in the repair process of non-homologous end joining.[9]

FUS, which codes for "Fused in sarcoma" protein, is associated with 1–5% of familial ALS and less than 1% of sporadic ALS. FUS is an RNA-binding protein with a similar function to TDP-43.[6]

Some people have both ALS and frontotemporal dementia (FTD–ALS). The four main genes associated with FTD–ALS are C9orf72,

SQSTM1, and TBK1.[8] C9orf72 repeat expansions explain about 40% of familial ALS and 25% of familial FTD; thus, C9orf72 provides a genetic explanation for most of the overlap between the two diseases.[6] While about half of the people with ALS have some degree of cognitive impairment, only 10-15% have cognitive impairment severe enough to meet the criteria for frontotemporal dementia (FTD). Additionally, about 15% of people with FTD have symptoms of motor neuron dysfunction that resemble ALS.[10] Mutations in TARDBP, FUS, C9orf72, and other genes can cause ALS as well as related forms of frontotemporal dementia (FTD–ALS). Proteins made by these genes appear to have prion-like activity and form inclusion bodies in some instances of ALS.[11][12]

Genes

As of May 2017 more than 20 genes have been associated with various types of ALS.[8] As of 2016 these genes explained about 70% of familial ALS (fALS) and 15% of sporadic ALS (sALS).[2][13] These associations include:

Type[8]
OMIM
(see references at OMIM link) 		Gene[8] Locus[8] Inheritance[8] Year Identified[2] Remarks
ALS1 105400 SOD1 21q22.1
autosomal recessive
 1993 The first gene associated with ALS, SOD1 accounts for about 12% of fALS and 1-2% of sALS.[2]
ALS2 205100 ALS2 2q33.1 autosomal recessive 2001 Juvenile-onset
ALS3 606640 Un­known 18q21 autosomal dominant —
ALS4 602433 SETX 9q34.13 autosomal dominant 1998
ALS5 602099 SPG11 15q21.1 autosomal recessive 2010 Juvenile onset
ALS6 608030
FUS
 		16p11.2 autosomal dominant/recessive 2009 Impaired DNA damage response.[14] Occurs in about 5% of familial and 1% of sporadic ALS cases.
ALS7 608031 Un­known 20p13 autosomal dominant —
ALS8 608627 VAPB 20q13.3 autosomal dominant 2004
ALS9 611895 ANG 14q11.2 autosomal dominant 2006
ALS10 612069
TARDBP
 		1p36.2 autosomal dominant 2008 ALS with or without frontotemporal dementia. Impaired repair of DNA damage.[9]
ALS11 612577
FIG4
 		6q21 autosomal dominant 2009
ALS12 613435 OPTN 10p13 autosomal dominant/recessive 2010
ALS13 183090
ATXN2
 		12q24.12 autosomal dominant 2010 Preliminary research indicates that intermediate-length CAG trinucleotide repeats in the ATXN2 gene may be associated with increased risk of ALS, whereas longer repeats cause spinocerebellar ataxia type 2[15][16]
ALS14 613954 VCP 9p13.3 autosomal dominant 2010 Preliminary research indicates a possible link in ALS mechanism[17][18]
ALS15 300857 UBQLN2 Xp11.21
X-linked dominant
 2011 Described in one family[19]
ALS16 614373
SIGMAR1
 		9p13.3 autosomal recessive 2011 Juvenile onset, very rare, described only in one family[20]
ALS17 614696 CHMP2B 3p11.2 autosomal dominant 2006 Very rare, reported only in a handful of people
ALS18 614808
PFN1
 		17p13.2 autosomal dominant 2012 Very rare, described only in a handful of Chinese families[21]
ALS19 615515 ERBB4 2q34 autosomal dominant 2013 Very rare, as of late 2013 described only in four people[22]
ALS20 615426
HNRNPA1
 		12q13.13 autosomal dominant 2013 Very rare, as of late 2013 described only in two people[23]
ALS21 606070 MATR3 5q31.2 autosomal dominant 2014 Associated with 0.5-2.0% of ALS cases.[1]
ALS22 616208 TUBA4A 2q35 autosomal dominant 2014 Associated with 1% of fALS cases and 0.4% of sALS cases; not enough evidence to conclude it causes ALS or FTD as of 2018.[1]
ALS23[24] 617839
ANXA11
 		10q22.3 autosomal dominant 2017 Associated with 1% of fALS and 1.7% sALS cases; considered a causal gene.[1]
ALS24[25] 617892
NEK1
 		4q33 Un­known[1] 2016 Associated with 3-5% of ALS cases; considered an ALS risk gene rather than a causative gene as of 2018.[1]
ALS25[26] 617921 KIF5A 12q13.3 autosomal dominant 2018
FTD-ALS1 105550 C9orf72 9p21.2 autosomal dominant 2011 The gene most commonly associated with ALS, C9orf72 accounts for 40% of fALS cases and 7% of sALS cases.[2]
FTD-ALS2 615911 CHCHD10 22q11.23 autosomal dominant 2014 Associated with less than 1% of ALS-FTD cases and about 2% of fALS cases.[1]
FTD-ALS3 616437
SQSTM1
 		5q35.3 autosomal dominant 2011
FTD-ALS4 616439 TBK1 12q14.2 autosomal dominant 2015 Associated with 1.3% of ALS cases and 3-4% of ALS-FTD cases.[1]
IBMPFD2 615422 HNRNPA2B1 7p15.2 autosomal dominant 2013 Proposed names: Inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 2 (IBMPFD2); multisystem proteinopathy 2 (MSP2). Very rare, as of late 2013 described only in two people[23]

Other genes

The following genes associated with ALS have been discussed in a June 2018 literature review,[1] but have not yet been added to the Online Mendelian Inheritance in Man database.

Type
OMIM
 Gene Locus Inheritance Year Identified Remarks
— — C21orf2 21q22.3 Un­known 2016 Associated with less than 1% of ALS cases.[1]
— — CCNF 16p13.3 autosomal dominant 2016 Associated with 0.6%-3.3% of fALS-FTD cases.[1]
— — TIA1 2p13.3 autosomal dominant 2017 Associated with 2% of fALS cases and less than 0.5% of sALS cases.[1]

SOD1

In 1993, scientists discovered that mutations in the gene (SOD1) that produces the

H46R) have a very long clinical course, while others, such as A4V, are exceptionally aggressive. When the defenses against oxidative stress fail, programmed cell death (apoptosis
) is upregulated. To date, 180 different mutations in SOD1 gene are known to cause familial ALS.[27]

A defect in SOD1 could be a loss or gain of function. A loss of SOD1 function could lead to an accumulation of DNA damage. A gain of SOD1 function could be toxic in other ways.[28][29]

Aggregate accumulation of mutant SOD1 is suspected to play a role in disrupting cellular functions by damaging

proteasomes, protein folding chaperones, or other proteins.[30] Hypotheses proposed in explaining structural instability causing the misfold in the mutant SOD1 include, (1) glutamate excitotoxicity caused by reduced astroglial glutamate transporter EAAT2; (2) abnormalities of mitochondria in which increased misfolded SOD1 are deposited in the spinal cord mitochondria leading to defects in mitochondrial transport causing energy depletion, disruption in Ca2+ buffering, activating synaptic dysfunction, and loss of neurons; (3) impaired axonal structure or transport defects, in which neurotrophic signaling is lost, with defective anterograde and retrograde axonal transport observed in early pathogenesis, and (4) free radical-mediated oxidative stress causing cytotoxicity.[31]

A 2016 paper proposed that SOD1 maturation and proteins regulating intracellular copper levels are potential therapeutic targets of SOD1-ALS.[27]

The DNA oxidation product 8-oxoG is a well-established marker of oxidative DNA damage. 8-oxoG accumulates in the mitochondria of spinal motor neurons of persons with ALS.[32] In transgenic ALS mice harboring a mutant SOD1 gene, 8-oxoG accumulates in mitochondrial DNA of spinal motor neurons.[33] Thus oxidative damage to mitochondrial DNA of motor neurons due to altered SOD1 may be a significant factor in the etiology of ALS.[citation needed]

UBQLN2, TARDBP

The UBQLN2 gene encodes production of the protein ubiquilin 2 in the cell, which is a member of the ubiquilin family and controls the degradation of ubiquitinated proteins. Mutations in UBQLN2 interfere with protein degradation, leading to neurodegeneration and causing dominantly inherited, chromosome X-linked ALS and ALS/dementia.[19]

The TDP-43 protein, coded for by the TARDBP gene, is responsible for regulation of RNA expression.[34] The discovery of mutations in the TARDBP gene, in relation to ALS, was the first proof that RNA processing defects lead to protein inclusions typical in RNA, and contribute to the pathogenesis of the disease.[34] Other mutations that have been shown to be associated with ALS from GWAS include ATXN2,[35] Nek1 and TBK1.[34]

TBK1, SQSTM1, OPTN

The

p62 and optineurin proteins. As a result, motor neurons can no longer produce a functional autophagosome leading to the inhibition of autophagy.[citation needed
]

C9orf72

vesicular transport during autophagy.[36]
Mutations in the C9orf72 gene lead to inhibition of the formation of the C9orf72 protein preventing the active transport of the autophagsome leading to inhibition of autophagy.

Mitochondria

Mitochondrial abnormalities, such as increased free radical production and impaired ATP production, have been observed but these mechanisms are unproven causes of ALS.[40] SOD1 and TDP-43 mutations may play a role in causing mitochondria dysfunction.[41]

Increased markers of oxidative stress have been observed in sporadic cases of ALS, including 8-Oxo-2'-deoxyguanosine and 4-Hydroxynonenal. This hypothesis is further supported by various risk factors observed for ALS, such as trauma and exposure to certain chemicals that may play a role in increasing oxidative stress. However, failed trials with anti-oxidants and methodological limitation limit the hypothesis.[42] One proposed mechanism of ALS incorporating both the genetic mutations of RNA binding proteins and oxidative stress, suggests that with age cells lose their ability to buffer against the genetic changes due to increasing oxidative stress resulting in the death of sensitive cells.[43] A possible mechanism for dysregulation of glutaminergic neurotransmission may be through excessive oxidative stress of astrocytes.[42]

Given the co-occurrence and symptomatic overlap with frontotemporal dementia, they may share an underlying pathophysiology, such as dysregulated microRNA activity (possibly originating in a TDP-43 mutation.) However authors cautioned against assuming a causal role of microRNA dysregulation.[44]

History

The first gene to be associated with ALS was

ATXN2, OPTN, and UBQLN2 were associated with ALS that same year.[2]

Another major milestone was the discovery of

NEK1 were associated with ALS in 2016.[2]

The first

statistical power to confidently identify a gene's association with ALS.[6]

References

  1. ^
    PMID 29154141
    .
  2. S2CID 14354178
    .
  3. PMID 22132186
    .
  4. ISBN 978-0-12-800403-6. Archived
    from the original on 8 September 2017. Retrieved 2 May 2015.
  5. ^
    PMID 24369373
    .
  6. ^ "Amyotrophic Lateral Sclerosis (ALS) Fact Sheet | National Institute of Neurological Disorders and Stroke". www.ninds.nih.gov. Retrieved 2018-06-02.
  7. ^
    PMID 28449881
    .
  8. ^
    PMID 31331820
    .
  9. PMID 28449882
    .
  10. S2CID 3895544
    .
  11. PMID 29491392
    .
  12. PMID 26889480
    .
  13. PMID 29362359
    .
  14. PMID 20740007
    .
  15. PMID 28017481
    .
  16. PMID 21145000
    .
  17. PMID 23791177
    .
  18. ^
    PMID 21857683
    .
  19. S2CID 1583824
    .
  20. PMID 22801503
    .
  21. PMID 24119685
    .
  22. ^
    PMID 23455423
    .
  23. ^ Kniffin, Cassandra L. (January 2018). "AMYOTROPHIC LATERAL SCLEROSIS 23; ALS23". Online Mendelian Inheritance in Man. Johns Hopkins School of Medicine. Retrieved July 7, 2018.
  24. ^ Hamosh, Ada (February 2018). "AMYOTROPHIC LATERAL SCLEROSIS, SUSCEPTIBILITY TO, 24; ALS24". Online Mendelian Inheritance in Man. Johns Hopkins School of Medicine. Retrieved July 7, 2018.
  25. ^ Kniffin, Cassandra L. (March 2018). "AMYOTROPHIC LATERAL SCLEROSIS, SUSCEPTIBILITY TO, 25; ALS25". Online Mendelian Inheritance in Man. Johns Hopkins School of Medicine. Retrieved July 7, 2018.
  26. ^
    PMID 27136532
    .
  27. PMID 9743498
    .
  28. S2CID 13070253
    .
  29. PMID 17015226
    .
  30. PMID 26629397
    .
  31. S2CID 2102463
    .
  32. PMID 11311985
    .
  33. ^
    PMID 28408982
    .
  34. PMID 25285812
    .
  35. ^
    PMID 27498188
    .
  36. PMID 22084127
    .
  37. S2CID 4361171
    .
  38. PMID 27211305
    .
  39. PMID 24148000
    .
  40. PMID 23678877
    .
  41. ^
    PMID 23797033
    .
  42. PMID 24010870
    .
  43. PMID 24506814
    .


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