Abstract
Several single-gene disorders with clinical and radiological characteristics similar to those observed in multiple sclerosis (MS) patients have been described. To evaluate whether this phenotypic overlap can be ascribed to a common genetic etiology, 28 genes known to present pathogenic mutations for 24 of these disorders were sequenced in 270 MS patients. All identified variants were genotyped in 2131 MS cases and 830 healthy controls, and those exclusively observed in patients were assessed for segregation within families. This analysis identified 9 rare variants in 6 genes segregating with disease in 13 families. Four different mutations were identified in CYP27A1, including a reported pathogenic mutation for cerebrotendinous xanthomatosis (p.R405W), which was observed in six patients from a multi-incident family, three diagnosed with MS, two with an undefined neurological disease and one seemingly healthy. A LYST p.V1678A and a PDHA1 p.K387Q mutation were both observed in five MS patients from three separate multi-incident families. In addition, CLCN2 p.V174G, GALC p.D162E and POLG p.R361G were each identified in two MS patients from one family. This study suggests a shared genetic etiology between MS and the characterized single-gene disorders, and highlights cholesterol metabolism and the synthesis of oxysterols as important biological mechanisms for familial MS.
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Barrat FJ, Le Deist F, Benkerrou M, Bousso P, Feldmann J, Fischer A, de Saint Basile G (1999) Defective CTLA-4 cycling pathway in Chediak–Higashi syndrome: a possible mechanism for deregulation of T lymphocyte activation. Proc Natl Acad Sci USA 96:8645–8650
Bashinskaya VV, Kulakova OG, Boyko AN, Favorov AV, Favorova OO (2015) A review of genome-wide association studies for multiple sclerosis: classical and hypothesis-driven approaches. Hum Genet 134:1143–1162
Castiglioni C, Verrigni D, Okuma C, Diaz A, Alvarez K, Rizza T, Carrozzo R, Bertini E, Miranda M (2015) Pyruvate dehydrogenase deficiency presenting as isolated paroxysmal exercise induced dystonia successfully reversed with thiamine supplementation. Case report and mini-review. Eur J Paediatr Neurol 19:497–503
Chalmin F, Rochemont V, Lippens C, Clottu A, Sailer AW, Merkler D, Hugues S, Pot C (2015) Oxysterols regulate encephalitogenic CD4(+) T cell trafficking during central nervous system autoimmunity. J Autoimmun 56:45–55
Cyster JG, Dang EV, Reboldi A, Yi T (2014) 25-Hydroxycholesterols in innate and adaptive immunity. Nat Rev Immunol 14:731–743
Davydov EV, Goode DL, Sirota M, Cooper GM, Sidow A, Batzoglou S (2010) Identifying a high fraction of the human genome to be under selective constraint using GERP ++. PLoS Comput Biol 6:e1001025
Ebers GC (2008) Environmental factors and multiple sclerosis. Lancet Neurol 7:268–277
Exome Aggregation Consortium, Lek M, Karczewski K, Minikel E, Samocha K (2015) Analysis of protein-coding genetic variation in 60,706 humans. BioRxiv. doi:10.1101/030338
Fagnani C, Neale MC, Nistico L, Stazi MA, Ricigliano VA, Buscarinu MC, Salvetti M, Ristori G (2015) Twin studies in multiple sclerosis: a meta-estimation of heritability and environmentality. Mult Scler 21:1404–1413
Fong JS, Rae-Grant A, Huang D (2008) Neurodegeneration and neuroprotective agents in multiple sclerosis. Recent Pat CNS Drug Discov 3:153–165
Forwell AL, Bernales CQ, Ross JP, Yee IM, Encarnacion M, Lee JD, Sadovnick AD, Traboulsee AL, Vilarino-Guell C (2016) Analysis of CH25H in multiple sclerosis and Neuromyelitis optica. J Neuroimmunol 291:70–72
Hor H, Francescatto L, Bartesaghi L et al (2015) Missense mutations in TENM4, a regulator of axon guidance and central myelination, cause essential tremor. Hum Mol Genet 24:5677–5686
Karim MA, Suzuki K, Fukai K et al (2002) Apparent genotype–phenotype correlation in childhood, adolescent, and adult Chediak–Higashi syndrome. Am J Med Genet 108:16–22
Kircher M, Witten DM, Jain P, O’Roak BJ, Cooper GM, Shendure J (2014) A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet 46:310–315
Klein C, Chuang R, Marras C, Lang AE (2011) The curious case of phenocopies in families with genetic Parkinson’s disease. Mov Disord 26:1793–1802
Kurtzke JF (1983) Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 33:1444–1452
Lee S, Abecasis GR, Boehnke M, Lin X (2014) Rare-variant association analysis: study designs and statistical tests. Am J Hum Genet 95:5–23
Malecki MT, Klupa T, Frey J, Cyganek K, Galicka-Stankowska D, Wanic K, Sieradzki J (2001) Identification of a new mutation in the hepatocyte nuclear factor-1alpha gene in a Polish family with early-onset type 2 diabetes mellitus. Diabetes Nutr Metab 14:288–291
McDonald WI, Compston A, Edan G et al (2001) Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 50:121–127
Nicholas R, Rashid W (2012) Multiple sclerosis. Clin Evid (Online)
Nie S, Chen G, Cao X, Zhang Y (2014) Cerebrotendinous xanthomatosis: a comprehensive review of pathogenesis, clinical manifestations, diagnosis, and management. Orphanet J Rare Dis 9:179
Nishioka K, Wider C, Vilarino-Guell C, Soto-Ortolaza AI, Lincoln SJ, Kachergus JM, Jasinska-Myga B, Ross OA, Rajput A, Robinson CA, Ferman TJ, Wszolek ZK, Dickson DW, Farrer MJ (2010) Association of alpha-, beta-, and gamma-synuclein with diffuse lewy body disease. Arch Neurol 67:970–975
Noseworthy JH (1999) Progress in determining the causes and treatment of multiple sclerosis. Nature 399:A40–A47
Pilo-de-la-Fuente B, Jimenez-Escrig A, Lorenzo JR, Pardo J, Arias M, Ares-Luque A, Duarte J, Muniz-Perez S, Sobrido MJ (2011) Cerebrotendinous xanthomatosis in Spain: clinical, prognostic, and genetic survey. Eur J Neurol 18:1203–1211
Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC, Johnson KP, Sibley WA, Silberberg DH, Tourtellotte WW (1983) New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 13:227–231
Rosati G (2001) The prevalence of multiple sclerosis in the world: an update. Neurol Sci 22:117–139
Ross JP, Bernales CQ, Lee JD, Sadovnick AD, Traboulsee AL, Vilarino-Guell C (2014) Analysis of CYP27B1 in multiple sclerosis. J Neuroimmunol 266:64–66
Sadovnick AD (1993) Familial recurrence risks and inheritance of multiple sclerosis. Curr Opin Neurol Neurosurg 6:189–194
Sadovnick AD, Risch NJ, Ebers GC (1998) Canadian collaborative project on genetic susceptibility to MS, phase 2: rationale and method. Canadian Collaborative Study Group. Can J Neurol Sci 25:216–221
Sadovnick AD, Traboulsee AL, Bernales CQ et al (2016) Analysis of plasminogen genetic variants in multiple sclerosis patients. G3 Genes Genomes Genet 6:2073–2079
Sanchez-Guiu I, Anton AI, Garcia-Barbera N, Navarro-Fernandez J, Martinez C, Fuster JL, Couselo JM, Ortuno FJ, Vicente V, Rivera J, Lozano ML (2014) Chediak–Higashi syndrome: description of two novel homozygous missense mutations causing divergent clinical phenotype. Eur J Haematol 92:49–58
Schubert D, Bode C, Kenefeck R et al (2014) Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nat Med 20:1410–1416
Shimazaki H, Honda J, Naoi T et al (2014) Autosomal-recessive complicated spastic paraplegia with a novel lysosomal trafficking regulator gene mutation. J Neurol Neurosurg Psychiatry 85:1024–1028
Spann NJ, Glass CK (2013) Sterols and oxysterols in immune cell function. Nat Immunol 14:893–900
Sperl W, Fleuren L, Freisinger P, Haack TB, Ribes A, Feichtinger RG, Rodenburg RJ, Zimmermann FA, Koch J, Rivera I, Prokisch H, Smeitink JA, Mayr JA (2015) The spectrum of pyruvate oxidation defects in the diagnosis of mitochondrial disorders. J Inherit Metab Dis 38:391–403
Sugama S, Kimura A, Chen W, Kubota S, Seyama Y, Taira N, Eto Y (2001) Frontal lobe dementia with abnormal cholesterol metabolism and heterozygous mutation in sterol 27-hydroxylase gene (CYP27). J Inherit Metab Dis 24:379–392
Szutowicz A, Bielarczyk H, Jankowska-Kulawy A, Pawelczyk T, Ronowska A (2013) Acetyl-CoA the key factor for survival or death of cholinergic neurons in course of neurodegenerative diseases. Neurochem Res 38:1523–1542
Traboulsee AL, Bernales CQ, Ross JP, Lee JD, Sadovnick AD, Vilarino-Guell C (2014) Genetic variants in IL2RA and IL7R affect multiple sclerosis disease risk and progression. Neurogenetics 15:165–169
Trinh J, Vilarino-Guell C, Donald A, Shah B, Yu I, Szu-Tu C, Aasly JO, Wu RM, Hentati F, Rajput AH, Rajput A, Farrer MJ (2013) STX6 rs1411478 is not associated with increased risk of Parkinson’s disease. Parkinsonism Relat Disord 19:563–565
Trinh J, Amouri R, Duda JE et al (2014) Comparative study of Parkinson’s disease and leucine-rich repeat kinase 2 p.G2019S parkinsonism. Neurobiol Aging 35:1125–1131
van de Kraats C, Killestein J, Popescu V, Rijkers E, Vrenken H, Lutjohann D, Barkhof F, Polman CH, Teunissen CE (2014) Oxysterols and cholesterol precursors correlate to magnetic resonance imaging measures of neurodegeneration in multiple sclerosis. Mult Scler 20:412–417
Verrips A, Hoefsloot LH, Steenbergen GC, Theelen JP, Wevers RA, Gabreels FJ, van Engelen BG, van den Heuvel LP (2000) Clinical and molecular genetic characteristics of patients with cerebrotendinous xanthomatosis. Brain 123(Pt 5):908–919
Wang K, Li M, Hakonarson H (2010) ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 38:e164
Wang Z, Sadovnick AD, Traboulsee AL et al (2016a) Case-Control Studies Are Not Familial Studies. Neuron 92:339–341
Wang Z, Sadovnick AD, Traboulsee AL et al (2016b) Nuclear receptor NR1H3 in familial multiple sclerosis. Neuron 90:948–954
Weisfeld-Adams JD, Katz Sand IB, Honce JM, Lublin FD (2015) Differential diagnosis of Mendelian and mitochondrial disorders in patients with suspected multiple sclerosis. Brain 138:517–539
Wingerchuk DM, Carter JL (2014) Multiple sclerosis: current and emerging disease-modifying therapies and treatment strategies. Mayo Clin Proc 89:225–240
Zhornitsky S, McKay KA, Metz LM, Teunissen CE, Rangachari M (2016) Cholesterol and markers of cholesterol turnover in multiple sclerosis: relationship with disease outcomes. Mult Scler Relat Disord 5:53–65
Acknowledgements
We are grateful to all individuals who generously participated in this study. We thank Kevin Atkins for data collection and extraction. This research was undertaken thanks to funding from the Canada Research Chair (950-228408) and Canada Excellence Research Chair (214444) programs, Canadian Institutes of Health Research (MOP-137051), Vancouver Coastal Health Research Institute, the Milan & Maureen Ilich Foundation (11-32095000), and the Vancouver Foundation (ADV14-1597).
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Traboulsee, A.L., Sadovnick, A.D., Encarnacion, M. et al. Common genetic etiology between “multiple sclerosis-like” single-gene disorders and familial multiple sclerosis. Hum Genet 136, 705–714 (2017). https://doi.org/10.1007/s00439-017-1784-9
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DOI: https://doi.org/10.1007/s00439-017-1784-9