SLITRK2 , an X-linked modifier of the age at onset in C9orf72 frontotemporal lobar degeneration
Mathieu Barbier
(1)
,
Agnès Camuzat
(1)
,
Khalid El Hachimi
(1)
,
Justine Guegan
(1)
,
Daisy Rinaldi
(1, 2)
,
Serena Lattante
(3, 4)
,
Marion Houot
(1, 2, 2)
,
Raquel Sánchez-Valle
(5)
,
Mario Sabatelli
(4, 3)
,
Anna Antonell
(5)
,
Laura Molina-Porcel
(5)
,
Fabienne Clot
(6)
,
Philippe Couratier
(7)
,
Emma van Der Ende
(8)
,
Julie van Der Zee
(9, 10)
,
Claudia Manzoni
(11)
,
William Camu
(12)
,
Cécile Cazeneuve
(6)
,
François Sellal
(13, 14)
,
Mira Didic
(15, 16)
,
Véronique Golfier
(17)
,
Florence Pasquier
(18)
,
Charles Duyckaerts
(1, 2)
,
Giacomina Rossi
(19)
,
Amalia Bruni
(20)
,
Victoria Alvarez
(21, 22)
,
Estrella Gómez-Tortosa
(23)
,
Alexandre de Mendonça
(24)
,
Caroline Graff
(25)
,
Mario Masellis
(26)
,
Benedetta Nacmias
(27, 28)
,
Badreddine Mohand Oumoussa
(29)
,
Ludmila Jornea
(1)
,
Sylvie Forlani
(1)
,
Viviana van Deerlin
(30)
,
Jonathan Rohrer
(11)
,
Ellen Gelpi
(5, 11)
,
Rosa Rademakers
(31)
,
John van Swieten
(8)
,
Eric Le Guern
(6)
,
Christine van Broeckhoven
(31, 10)
,
Raffaele Ferrari
(11)
,
Emmanuelle Génin
(32)
,
Alexis Brice
(1)
,
Isabelle Le Ber
(1, 2)
1
ICM -
Institut du Cerveau = Paris Brain Institute
2 CHU Pitié-Salpêtrière [AP-HP]
3 Unicatt - Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma]
4 Fondazione Policlinico Universitario Agostino Gemelli IRCCS
5 IDIBAPS - Institut d'Investigacions Biomèdiques August Pi i Sunyer
6 CIC Paris-Est - Centre d'investigation clinique Paris Est [CHU Pitié Salpêtrière]
7 Hôpital Dupuytren [CHU Limoges]
8 Erasmus MC - Erasmus University Medical Center [Rotterdam]
9 VIB-UAntwerp - Center for Molecular Neurology
10 UA - University of Antwerp
11 UCL - University College of London [London]
12 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
13 Service de Neurologie [Hôpitaux Civils de Colmar]
14 MCPN - Mécanismes Centraux et Périphériques de la Neurodégénérescence
15 Neurologie, maladies neuro-musculaires [Hôpital de la Timone - APHM]
16 INS - Institut de Neurosciences des Systèmes
17 Hôpital de Saint-Brieuc [Hôpital Yves Le Foll]
18 LilNCog - Lille Neurosciences & Cognition - U 1172
19 Fondazione IRCCS Istituto Neurologico "Carlo Besta"
20 CRN - ASP Catanzaro - Regional Neurogenetic Centre [Lamezia Terme, Italy]
21 Hospital Central de Asturias
22 ISPA - Institute of Health Research of Principado de Asturias
23 FJD - Hospital Universitario Fundación Jiménez Díaz [Madrid]
24 Faculdade de Medicina [Lisboa]
25 Karolinska University Hospital [Stockholm]
26 SRI - Sunnybrook Research Institute [Toronto]
27 UniFI - Università degli Studi di Firenze = University of Florence = Université de Florence
28 Fondazione Don Carlo Gnocchi
29 PASS-P3S - Plateforme Post-génomique de la Pitié-Salpêtrière
30 HUP - Hospital of the University of Pennsylvania
31 Neurodegenerative Brain Diseases group, Department of Molecular Genetics, VIB, Antwerpen, Belgium
32 GGB - Génétique, génomique fonctionnelle et biotechnologies (UMR 1078)
2 CHU Pitié-Salpêtrière [AP-HP]
3 Unicatt - Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma]
4 Fondazione Policlinico Universitario Agostino Gemelli IRCCS
5 IDIBAPS - Institut d'Investigacions Biomèdiques August Pi i Sunyer
6 CIC Paris-Est - Centre d'investigation clinique Paris Est [CHU Pitié Salpêtrière]
7 Hôpital Dupuytren [CHU Limoges]
8 Erasmus MC - Erasmus University Medical Center [Rotterdam]
9 VIB-UAntwerp - Center for Molecular Neurology
10 UA - University of Antwerp
11 UCL - University College of London [London]
12 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
13 Service de Neurologie [Hôpitaux Civils de Colmar]
14 MCPN - Mécanismes Centraux et Périphériques de la Neurodégénérescence
15 Neurologie, maladies neuro-musculaires [Hôpital de la Timone - APHM]
16 INS - Institut de Neurosciences des Systèmes
17 Hôpital de Saint-Brieuc [Hôpital Yves Le Foll]
18 LilNCog - Lille Neurosciences & Cognition - U 1172
19 Fondazione IRCCS Istituto Neurologico "Carlo Besta"
20 CRN - ASP Catanzaro - Regional Neurogenetic Centre [Lamezia Terme, Italy]
21 Hospital Central de Asturias
22 ISPA - Institute of Health Research of Principado de Asturias
23 FJD - Hospital Universitario Fundación Jiménez Díaz [Madrid]
24 Faculdade de Medicina [Lisboa]
25 Karolinska University Hospital [Stockholm]
26 SRI - Sunnybrook Research Institute [Toronto]
27 UniFI - Università degli Studi di Firenze = University of Florence = Université de Florence
28 Fondazione Don Carlo Gnocchi
29 PASS-P3S - Plateforme Post-génomique de la Pitié-Salpêtrière
30 HUP - Hospital of the University of Pennsylvania
31 Neurodegenerative Brain Diseases group, Department of Molecular Genetics, VIB, Antwerpen, Belgium
32 GGB - Génétique, génomique fonctionnelle et biotechnologies (UMR 1078)
Cécile Cazeneuve
- Function : Author
- PersonId : 763171
- ORCID : 0000-0002-5195-9348
- IdRef : 273757075
Mira Didic
- Function : Author
- PersonId : 757436
- ORCID : 0000-0001-7067-536X
Badreddine Mohand Oumoussa
- Function : Author
- PersonId : 183910
- IdHAL : badreddine-mohand-oumoussa
- ORCID : 0000-0001-5837-9672
- IdRef : 253127076
Emmanuelle Génin
- Function : Author
- PersonId : 181372
- IdHAL : emmanuelle-genin
- ORCID : 0000-0003-4117-2813
- IdRef : 114211302
Alexis Brice
- Function : Author
- PersonId : 1104774
- ORCID : 0000-0002-0941-3990
- IdRef : 050512935
Abstract
The G4C2-repeat expansion in C9orf72 is the most common cause of frontotemporal dementia and of amyotrophic lateral sclerosis. The variability of age at onset and phenotypic presentations is a hallmark of C9orf72 disease. In this study, we aimed to identify modifying factors of disease onset in C9orf72 carriers using a family-based approach, in pairs of C9orf72 carrier relatives with concordant or discordant age at onset. Linkage and association analyses provided converging evidence for a locus on chromosome Xq27.3. The minor allele A of rs1009776 was associated with an earlier onset (P = 1 × 10−5). The association with onset of dementia was replicated in an independent cohort of unrelated C9orf72 patients (P = 0.009). The protective major allele delayed the onset of dementia from 5 to 13 years on average depending on the cohort considered. The same trend was observed in an independent cohort of C9orf72 patients with extreme deviation of the age at onset (P = 0.055). No association of rs1009776 was detected in GRN patients, suggesting that the effect of rs1009776 was restricted to the onset of dementia due to C9orf72. The minor allele A is associated with a higher SLITRK2 expression based on both expression quantitative trait loci (eQTL) databases and in-house expression studies performed on C9orf72 brain tissues. SLITRK2 encodes for a post-synaptic adhesion protein. We further show that synaptic vesicle glycoprotein 2 and synaptophysin, two synaptic vesicle proteins, were decreased in frontal cortex of C9orf72 patients carrying the minor allele. Upregulation of SLITRK2 might be associated with synaptic dysfunctions and drives adverse effects in C9orf72 patients that could be modulated in those carrying the protective allele. How the modulation of SLITRK2 expression affects synaptic functions and influences the disease onset of dementia in C9orf72 carriers will require further investigations. In summary, this study describes an original approach to detect modifier genes in rare diseases and reinforces rising links between C9orf72 and synaptic dysfunctions that might directly influence the occurrence of first symptoms.