The distinct genetic pattern of ALS in Turkey and novel mutations

Aslıhan Özoğuz; Özgün Uyan; Güneş Birdal; Ceren Iskender; Ece Kartal; Suna Lahut; Özgür Ömür; Zeynep Sena Agim; Aslı Gündoğdu Eken; Nesli Ece Sen; Pınar Kavak; Ceren Saygı; Peter C Sapp; Pamela Keagle; Yeşim Parman; Ersin Tan; Filiz Koç; Feza Deymeer; Piraye Oflazer; Haşmet Hanağası; Hakan Gürvit; Başar Bilgiç; Hacer Durmuş; Mustafa Ertaş; Dilcan Kotan; Mehmet Ali Akalın; Halil Güllüoğlu; Mehmet Zarifoğlu; Fikret Aysal; Nilgün Döşoğlu; Kaya Bilguvar; Murat Günel; Özlem Keskin; Tahsin Akgün; Hilmi Özçelik; John E Landers; Robert H Brown; A Nazlı Başak

doi:10.1016/j.neurobiolaging.2014.12.032

The distinct genetic pattern of ALS in Turkey and novel mutations

Neurobiol Aging. 2015 Apr;36(4):1764.e9-1764.e18. doi: 10.1016/j.neurobiolaging.2014.12.032. Epub 2015 Jan 10.

Authors

Aslıhan Özoğuz¹, Özgün Uyan¹, Güneş Birdal¹, Ceren Iskender¹, Ece Kartal¹, Suna Lahut¹, Özgür Ömür¹, Zeynep Sena Agim¹, Aslı Gündoğdu Eken¹, Nesli Ece Sen¹, Pınar Kavak², Ceren Saygı¹, Peter C Sapp³, Pamela Keagle³, Yeşim Parman⁴, Ersin Tan⁵, Filiz Koç⁶, Feza Deymeer⁴, Piraye Oflazer⁴, Haşmet Hanağası⁴, Hakan Gürvit⁴, Başar Bilgiç⁴, Hacer Durmuş⁴, Mustafa Ertaş⁷, Dilcan Kotan⁸, Mehmet Ali Akalın⁹, Halil Güllüoğlu¹⁰, Mehmet Zarifoğlu¹¹, Fikret Aysal¹², Nilgün Döşoğlu¹³, Kaya Bilguvar¹⁴, Murat Günel¹⁴, Özlem Keskin¹⁵, Tahsin Akgün¹⁶, Hilmi Özçelik¹⁷, John E Landers³, Robert H Brown³, A Nazlı Başak¹⁸

Affiliations

¹ Suna and İnan Kıraç Foundation, Neurodegeneration Research Laboratory (NDAL), Molecular Biology and Genetics Department, Boğaziçi University, Istanbul, Turkey.
² Computer Engineering Department, Boğaziçi University, Istanbul, Turkey.
³ Neurology Department, Medical School, University of Massachusetts, Worcester, MA, USA.
⁴ Neurology Department, Istanbul Medical School, Istanbul University, Istanbul, Turkey.
⁵ Neurology Department, Medical School, Hacettepe University, Ankara, Turkey.
⁶ Neurology Department, Medical School, Çukurova University, Adana, Turkey.
⁷ Department of Neurology, Liv Hospital, Istanbul, Turkey.
⁸ Faculty of Medicine, Department of Neurology, Sakarya University, Sakarya, Turkey.
⁹ Neurology Department, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey.
¹⁰ Department of Neurology, Medical Park Izmir Hospital, Izmir, Turkey.
¹¹ Department of Neurology, School of Medicine, Uludağ University, Bursa, Turkey.
¹² Bakırköy Research and Training Hospital for Neurologic and Psychiatric Diseases, Istanbul, Turkey.
¹³ Department of Microbiology, Haydarpaşa Numune Education and Research Hospital, Istanbul, Turkey.
¹⁴ Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.
¹⁵ Chemical and Biological Engineering Department, Koç University, Istanbul, Turkey.
¹⁶ Department of Anesthesiology and Reanimation, American Hospital, Istanbul, Turkey.
¹⁷ Department of Pathology and Laboratory Medicine, Samuel Lunenfeld Research Institute, University of Toronto, Toronto, Ontario, Canada.
¹⁸ Suna and İnan Kıraç Foundation, Neurodegeneration Research Laboratory (NDAL), Molecular Biology and Genetics Department, Boğaziçi University, Istanbul, Turkey. Electronic address: basak@boun.edu.tr.

PMID: 25681989
PMCID: PMC6591733
DOI: 10.1016/j.neurobiolaging.2014.12.032

Abstract

The frequency of amyotrophic lateral sclerosis (ALS) mutations has been extensively investigated in several populations; however, a systematic analysis in Turkish cases has not been reported so far. In this study, we screened 477 ALS patients for mutations, including 116 familial ALS patients from 82 families and 361 sporadic ALS (sALS) cases. Patients were genotyped for C9orf72 (18.3%), SOD1 (12.2%), FUS (5%), TARDBP (3.7%), and UBQLN2 (2.4%) gene mutations, which together account for approximately 40% of familial ALS in Turkey. No SOD1 mutations were detected in sALS patients; however, C9orf72 (3.1%) and UBQLN2 (0.6%) explained 3.7% of sALS in the population. Exome sequencing revealed mutations in OPTN, SPG11, DJ1, PLEKHG5, SYNE1, TRPM7, and SQSTM1 genes, many of them novel. The spectrum of mutations reflect both the distinct genetic background and the heterogeneous nature of the Turkish ALS population.

Keywords: ALS; C9orf72; FUS; SOD1; TDP-43; Turkey.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / genetics
Adolescent
Adult
Aged
Amyotrophic Lateral Sclerosis / genetics*
Autophagy-Related Proteins
C9orf72 Protein
Cell Cycle Proteins / genetics
Cytoskeletal Proteins
DNA-Binding Proteins / genetics
Exome / genetics
Female
Genetic Association Studies*
Guanine Nucleotide Exchange Factors / genetics
Humans
Intracellular Signaling Peptides and Proteins / genetics
Male
Membrane Transport Proteins
Middle Aged
Mutation / genetics*
Nerve Tissue Proteins / genetics
Nuclear Proteins / genetics
Oncogene Proteins / genetics
Protein Deglycase DJ-1
Protein Serine-Threonine Kinases / genetics
Proteins / genetics*
RNA-Binding Protein FUS / genetics*
Sequestosome-1 Protein
Superoxide Dismutase / genetics*
Superoxide Dismutase-1
TRPM Cation Channels / genetics
Transcription Factor TFIIIA / genetics
Turkey
Ubiquitins / genetics
Young Adult

Substances

Adaptor Proteins, Signal Transducing
Autophagy-Related Proteins
C9orf72 Protein
C9orf72 protein, human
Cell Cycle Proteins
Cytoskeletal Proteins
DNA-Binding Proteins
FUS protein, human
Guanine Nucleotide Exchange Factors
Intracellular Signaling Peptides and Proteins
Membrane Transport Proteins
Nerve Tissue Proteins
Nuclear Proteins
OPTN protein, human
Oncogene Proteins
PLEKHG5 protein, human
Proteins
RNA-Binding Protein FUS
SOD1 protein, human
SPG11 protein, human
SQSTM1 protein, human
SYNE1 protein, human
Sequestosome-1 Protein
TARDBP protein, human
TRPM Cation Channels
Transcription Factor TFIIIA
UBQLN2 protein, human
Ubiquitins
Superoxide Dismutase
Superoxide Dismutase-1
Protein Serine-Threonine Kinases
TRPM7 protein, human
PARK7 protein, human
Protein Deglycase DJ-1

Grants and funding

R01 NS073873/NS/NINDS NIH HHS/United States