. 2014 Dec;35(12):2882.e7-2882.e12.

doi: 10.1016/j.neurobiolaging.2014.07.012. Epub 2014 Jul 18.

Genetic architecture of ALS in Sardinia

Giuseppe Borghero¹, Maura Pugliatti², Francesco Marrosu¹, Maria Giovanna Marrosu³, Maria Rita Murru³, Gianluca Floris¹, Antonino Cannas¹, Leslie D Parish², Patrizia Occhineri², Tea B Cau⁴, Daniela Loi⁴, Anna Ticca⁵, Sebastiano Traccis⁶, Umberto Manera⁷, Antonio Canosa⁸, Cristina Moglia⁷, Andrea Calvo⁹, Marco Barberis¹⁰, Maura Brunetti¹⁰, Hannah A Pliner¹¹, Alan E Renton¹¹, Mike A Nalls¹², Bryan J Traynor¹³, Gabriella Restagno¹⁴, Adriano Chiò¹⁵; ITALSGEN and SARDINALS Consortia

Affiliations

¹ Department of Neurology, Azienda Universitario Ospedaliera di Cagliari and University of Cagliari, Cagliari, Italy.
² Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy.
³ Multiple Sclerosis Center Laboratory, University of Cagliari, Cagliari, Italy.
⁴ Azienda Sanitaria Locale n. 2, Olbia-Tempio, Italy.
⁵ Department of Neurology, Azienda Ospedaliera San Francesco, Nuoro, Italy.
⁶ Department of Neurology, Ospedale Antonio Segni, Ozieri, Italy.
⁷ Amyotrophic Lateral Sclerosis Center, "Rita Levi Montalcini" Department of Neuroscience, University of Turin, Turin, Italy.
⁸ Amyotrophic Lateral Sclerosis Center, "Rita Levi Montalcini" Department of Neuroscience, University of Turin, Turin, Italy; Department of Neurosciences, Ophthalmology, Genetics, Rehabilitation and Child Health, University of Genoa, Genoa, Italy; Azienda Ospedaliero Universitaria Città della Salute e della Scienza, Turin, Italy.
⁹ Amyotrophic Lateral Sclerosis Center, "Rita Levi Montalcini" Department of Neuroscience, University of Turin, Turin, Italy; Azienda Ospedaliero Universitaria Città della Salute e della Scienza, Turin, Italy.
¹⁰ Amyotrophic Lateral Sclerosis Center, "Rita Levi Montalcini" Department of Neuroscience, University of Turin, Turin, Italy; Laboratory of Molecular Genetics, Azienda Ospedaliero Universitaria Città della Salute e della Scienza, Torino, Italy.
¹¹ Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute of Aging, Bethesda, MD, USA.
¹² Molecular Genetics Section, Laboratory of Neurogenetics, National Institute of Aging, Bethesda, MD, USA.
¹³ Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute of Aging, Bethesda, MD, USA; Department of Neurology, Brain Science Institute, Johns Hopkins University, Baltimore, MD, USA.
¹⁴ Laboratory of Molecular Genetics, Azienda Ospedaliero Universitaria Città della Salute e della Scienza, Torino, Italy.
¹⁵ Amyotrophic Lateral Sclerosis Center, "Rita Levi Montalcini" Department of Neuroscience, University of Turin, Turin, Italy; Department of Neurosciences, Ophthalmology, Genetics, Rehabilitation and Child Health, University of Genoa, Genoa, Italy; Azienda Ospedaliero Universitaria Città della Salute e della Scienza, Turin, Italy; Neuroscience Institute of Torino (NIT), Turin, Italy. Electronic address: achio@usa.net.

PMID: 25123918
PMCID: PMC4252367
DOI: 10.1016/j.neurobiolaging.2014.07.012

Genetic architecture of ALS in Sardinia

Giuseppe Borghero et al. Neurobiol Aging. 2014 Dec.

. 2014 Dec;35(12):2882.e7-2882.e12.

doi: 10.1016/j.neurobiolaging.2014.07.012. Epub 2014 Jul 18.

Authors

Affiliations

¹ Department of Neurology, Azienda Universitario Ospedaliera di Cagliari and University of Cagliari, Cagliari, Italy.
² Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy.
³ Multiple Sclerosis Center Laboratory, University of Cagliari, Cagliari, Italy.
⁴ Azienda Sanitaria Locale n. 2, Olbia-Tempio, Italy.
⁵ Department of Neurology, Azienda Ospedaliera San Francesco, Nuoro, Italy.
⁶ Department of Neurology, Ospedale Antonio Segni, Ozieri, Italy.
⁷ Amyotrophic Lateral Sclerosis Center, "Rita Levi Montalcini" Department of Neuroscience, University of Turin, Turin, Italy.
⁸ Amyotrophic Lateral Sclerosis Center, "Rita Levi Montalcini" Department of Neuroscience, University of Turin, Turin, Italy; Department of Neurosciences, Ophthalmology, Genetics, Rehabilitation and Child Health, University of Genoa, Genoa, Italy; Azienda Ospedaliero Universitaria Città della Salute e della Scienza, Turin, Italy.
⁹ Amyotrophic Lateral Sclerosis Center, "Rita Levi Montalcini" Department of Neuroscience, University of Turin, Turin, Italy; Azienda Ospedaliero Universitaria Città della Salute e della Scienza, Turin, Italy.
¹⁰ Amyotrophic Lateral Sclerosis Center, "Rita Levi Montalcini" Department of Neuroscience, University of Turin, Turin, Italy; Laboratory of Molecular Genetics, Azienda Ospedaliero Universitaria Città della Salute e della Scienza, Torino, Italy.
¹¹ Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute of Aging, Bethesda, MD, USA.
¹² Molecular Genetics Section, Laboratory of Neurogenetics, National Institute of Aging, Bethesda, MD, USA.
¹³ Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute of Aging, Bethesda, MD, USA; Department of Neurology, Brain Science Institute, Johns Hopkins University, Baltimore, MD, USA.
¹⁴ Laboratory of Molecular Genetics, Azienda Ospedaliero Universitaria Città della Salute e della Scienza, Torino, Italy.
¹⁵ Amyotrophic Lateral Sclerosis Center, "Rita Levi Montalcini" Department of Neuroscience, University of Turin, Turin, Italy; Department of Neurosciences, Ophthalmology, Genetics, Rehabilitation and Child Health, University of Genoa, Genoa, Italy; Azienda Ospedaliero Universitaria Città della Salute e della Scienza, Turin, Italy; Neuroscience Institute of Torino (NIT), Turin, Italy. Electronic address: achio@usa.net.

PMID: 25123918
PMCID: PMC4252367
DOI: 10.1016/j.neurobiolaging.2014.07.012

Abstract

Conserved populations, such as Sardinians, displaying elevated rates of familial or sporadic amyotrophic lateral sclerosis (ALS) provide unique information on the genetics of the disease. Our aim was to describe the genetic profile of a consecutive series of ALS patients of Sardinian ancestry. All ALS patients of Sardinian ancestry, identified between 2008 and 2013 through the Italian ALS Genetic Consortium, were eligible to be included in the study. Patients and controls underwent the analysis of TARDBP, C9ORF72, SOD1, and FUS genes. Genetic mutations were identified in 155 out of 375 Sardinian ALS cases (41.3%), more commonly the p.A382T and p.G295S mutations of TARDBP and the GGGGCC hexanucleotide repeat expansion of C9ORF72. One patient had both p.G295S and p.A382T mutations of TARDBP and 8 carried both the heterozygous p.A382T mutation of TARDBP and a repeat expansion of C9ORF72. Patients carrying the p.A382T and the p.G295S mutations of TARDBP and the C9ORF72 repeat expansion shared distinct haplotypes across these loci. Patients with cooccurrence of C9ORF72 and TARDBP p.A382T missense mutation had a significantly lower age at onset and shorter survival. More than 40% of all cases on the island of Sardinia carry a mutation of an ALS-related gene, representing the highest percentage of ALS cases genetically explained outside of Scandinavia. Clinical phenotypes associated with different genetic mutations show some distinctive characteristics, but the heterogeneity between and among families carrying the same mutations implies that ALS manifestation is influenced by other genetic and nongenetic factors.

Keywords: Amyotrophic lateral sclerosis; Genetics; Penetrance; Phenotype; Prognosis; Sardinia.

PubMed Disclaimer

Conflict of interest statement

Conflict of interest: Adriano Chiò serves on a scientific advisory board for Biogen Idec, Cytokinetics, and Italfarmaco. Borghero, Pugliatti, F. Marrosu, M.G Marrosu, Murru, Floris, Cannas, Parish, Occhineri, Cau, Loi, Ticca, Manera, Canosa, Moglia, Calvo, Barberis, Brunetti, Pliner, Renton, Nalls, Traynor, Restagno report no conflicts of interest.

The sponsor organizations had no role in data collections and analysis and did not participate to writing and approving the manuscript. The information reported in the manuscript has never been reported elsewhere.

Figures

**Figure 1**
Geographic distribution of area of origin of parents of Sardinian ALS cases according to more common mutations. The two *TARDBP* p.A382T homozygous patients and the single patients with double p.A382T and p.G295S heterozygous mutations are included in the *TARDBP* figures. The 8 patients with double mutation (*C9ORF72* & p.A382T *TARDBP)* were included in both *C9ORF72* and *TARDBP* figures.

**Figure 2**
Cumulative probability of ALS onset according to genetic status of Sardinian patients. Brown, no detected mutations; violet, *TARDBP* p.A382T heterozygous mutations; green, C9ORF72 mutations; red, TARDBP p.G295S heterozygous mutations; yellow, double *C9ORF72* and *TARDBP* p.A382T heterozygous mutations.

**Figure 3**
Kaplan-Meier curves (tracheostomy-free survival) of ALS Sardinian patients with different genetic mutations. Brown, no detected mutations; violet, *TARDBP* p.A382T heterozygous mutations; green, C9ORF72 mutations; red, *TARDBP* p.G295S heterozygous mutations; yellow, double *C9ORF72* and *TARDBP* p.A382T heterozygous mutations.

See this image and copyright information in PMC

References

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Genetic architecture of ALS in Sardinia

Affiliations

Genetic architecture of ALS in Sardinia

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Miscellaneous