**A Major Genetic Factor at Chromosome 9p Implicated in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD)**

Ilse Gijselinck1,2, Kristel Sleegers1,2, Christine Van Broeckhoven1,2 and Marc Cruts1,2 *1Department of Molecular Genetics, VIB, Antwerpen 2University of Antwerp, Antwerpen Belgium* 

### **1. Introduction**

*Opinion in Neurology* 22:486-92 10.1097/WCO.0b013e32832ffbe3

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UV-CLIP are deregulated in ALS. *Mol Cell Neurosci* 47:167-80

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536 Amyotrophic Lateral Sclerosis

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Vance C, Rogelj B, Hortobagyi T, De Vos KJ, Nishimura AL, et al. 2009. Mutations in FUS, an

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sclerosis with frontotemporal dementia is linked to a locus on chromosome 9p13.2-

RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. *Science*

associated with Paget disease of bone and frontotemporal dementia is caused by

protein with three guanine-nucleotide exchange factor domains, is mutated in a

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are two fatal neurodegenerative diseases for which effective therapies aiming at delaying, halting or preventing the disease are lacking. ALS is the most common motor neuron disorder (Rowland & Shneider, 2001) and FTLD has a prevalence close to that of Alzheimer disease in the population below age 65 years (Rosso et al., 2003). They are considered as both extremes of a spectrum of clinically and pathologically overlapping disorders (Lillo & Hodges, 2009). In addition, there is emerging evidence that FTLD and ALS also share common genetic aetiologies, suggesting that overlapping disease mechanisms are involved in both diseases. Clinically, ALS patients show reduced control of voluntary muscle movement expressed in increased muscle weakness, disturbances of speech, swallowing or breathing, as a result of progressive upper and lower motor neuron degeneration in motor cortex, brainstem and spinal cord, and up to 50% of ALS patients shows mild disturbances in executive functions while a minority also develop overt FTLD (Lomen-Hoerth et al., 2003; Ringholz et al., 2005). FTLD symptoms include behavioural, personality and language disturbances, and also cognitive dysfunctions, due to affected frontal and temporal cortical neurons in the brain. FTLD patients may additionally present with typical clinical signs of ALS in a later stage of the disease (Neary et al., 1998). Pathologically, although in different neuronal cells, TAR DNA-binding protein-43 (TDP-43) is a major constituent of neuronal deposits in both ALS and TDP-43 positive FTLD (FTLD-TDP), the most common pathological FTLD subtype (Arai et al., 2006; Neumann et al., 2006). Five to 10% of ALS patients and up to 50% of FTLD patients has a positive familial history of disease with a Mendelian mode of inheritance indicating a significant contribution of genetic factors in disease aetiology. Although the exact biochemical pathways involved in ALS or FTLD are still unknown, several molecular components were identified in the last twenty years through molecular genetic studies in familial and sporadic patients, which are most likely part of a complex network of cellular mechanisms. Since these genes explain only a minority of patients, further unraveling the

A Major Genetic Factor at Chromosome 9p Implicated in

**LOD score at 9p21** 

**Family Origin Max** 

Que1 French-

F2 North-

F476 North-

Canadian

American

American

families, not linked separately)

Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD) 539

The minimal candidate region was previously defined by D9S169 (Luty et al., 2008) and D9S1805 (Valdmanis et al., 2007) spanning 7 Mb and was recently reduced to 3.6 Mb between D9S169 (Luty et al., 2008) and D9S251 by Boxer and colleagues (2010) (figure 1).

> **Mean disease duration in years (range)**

Luty Australian 3.41 53 (43-68) 9 (1-16) + 2 2 7 (Luty et al.,

DR14 Belgian 3.38 58.1 (51-65) 6.4 (1-17) + 1 0 10 (Gijselinck

F2 Dutch 3.02 60.3 (39-72) 3.0 (1-8) ND 7 3 2 (Vance et

Que23 Canadian 3.01 55.8 (46-58) 2.4 (1.5-3) ND 5 0 3 (Valdmanis

VSM20 Irish 3.01 45.7 (35-57) 5.4 (3-10) + 2 3 5 (Boxer et al.,

F438 Scandinavian 3.00 55.3 (45-64) 4.3 (1-9) ND 5 0 9 (Morita et

6 families French 8.01 57.9 (40-84) 3.6 (1-8) + 9 12 10 (Le Ber et

Fr104 Spanish 1.55 ND ND ND 4 1 0 (Valdmanis

Gwent Brittish ND 42.2 (31-52) 3.6 (1-13) + 3 6 0 (Pearson et

ALS\_A American ND ? (35-73) ? (0.5-5) ND 6 0 0 (Krueger et

Table 1. Genetic, clinical and pathological characteristics of ALS-FTLD families linked or associated with chromosome 9p21 (ND: not determined; 1summed LODscore in 6 small

**TDP-43+**

2.51 54.3 (45-63) 4.8 (2-9) ND 5 3 0 (Valdmanis

1.5 ND ND ND 0 7 0 (Momeni et

ND ND ND ND 2 3 0 (Momeni et

**# ALS # ALS + FTLD** 

**# FTLD References** 

2008)

et al., 2010)

et al., 2007)

al., 2006)

2010)

al., 2006)

al., 2009)

et al., 2007)

et al., 2007)

al., 2006)

al., 2011)

al., 2006)

al., 2009)

Therefore, several parts of this study were still investigated in the 7 Mb region.

**Mean onset age in years (range)** 

genetic heterogeneity is necessary to identify new therapeutic targets. Mutations causing ALS were observed in genes encoding Cu/Zn superoxide dismutase 1 (*SOD1*) (Rosen et al., 1993), TDP-43 (*TARDBP*) (Gitcho et al., 2008; Kabashi et al., 2008; Sreedharan et al., 2008; Van Deerlin et al., 2008; Yokoseki et al., 2008), fused in sarcoma (*FUS*) (Kwiatkowski, Jr. et al., 2009; Vance et al., 2009) and angiogenin (*ANG*) (Greenway et al., 2006), among other genes, while in familial FTLD patients mutations in the genes encoding granulin (*GRN*) (Baker et al., 2006; Cruts et al., 2006), the microtubule-associated protein tau (*MAPT*) (Hutton et al., 1998), the valosin-containing protein (*VCP*) (Watts et al., 2004) and the charged multivesicular body protein 2B (*CHMP2B*) (Skibinski et al., 2005) were found. Recent family-based linkage and population-based association studies identified genetic factors overlapping between ALS and FTLD. For example, mutations in the ALS genes *TARDBP* and *FUS* are occasionally found in FTLD patients (Kovacs et al., 2009; Van Langenhove et al., 2010) and mutations in the FTLD gene *VCP* were also detected in ALS (Johnson et al., 2010). However, most convincing evidence for the genetic overlap comes from the observation that both ALS and FTLD can occur within the same family or within a single patient of a family. More than 15 autosomal dominant families with ALS and FTLD worldwide are causally linked with a major disease locus at chromosome 9p13-p21 (ALSFTD2 locus) (Boxer et al., 2010; Gijselinck et al., 2010; Le Ber et al., 2009; Luty et al., 2008; Momeni et al., 2006; Morita et al., 2006; Pearson et al., 2011; Valdmanis et al., 2007; Vance et al., 2006). The minimally linked region in all these families is about 3.6 Mb in size containing five known protein-coding genes. Moreover, several recent genome-wide association studies (GWAS) in ALS populations from different European origins showed the presence of a major genetic risk factor for ALS at the same chromosome 9p region (Laaksovirta et al., 2010; Shatunov et al., 2010; van Es et al., 2009). The Finnish study narrowed the associated region to a 232 kb linkage disequilibrium (LD) block containing three known genes (*MOBKL2B*, *IFNK*, *C9orf72*) and suggested the presence of a major risk gene with high penetrance (Laaksovirta et al., 2010). Likewise, a GWAS in FTLD has implicated the same region (Van Deerlin et al., 2010). This finding was further confirmed in other FTLD and ALS-FTLD cohorts (Rollinson et al., 2011). Together, these data demonstrate that ALS and FTLD share a major common genetic factor on chromosome 9p, most likely showing high mutation frequencies. Despite all attempts of several research groups, the genetic defect(s) underlying both genetic linkage and association to this region have not been identified yet.

In this book chapter we will report and discuss the latest findings in the studies aiming at identifying the chromosome 9 gene defect.
