Genes (Dec 2022)
A Whole-Genome Sequencing Study Implicates GRAMD1B in Multiple Sclerosis Susceptibility
- Federica Esposito,
- Ana Maria Osiceanu,
- Melissa Sorosina,
- Linda Ottoboni,
- Bryan Bollman,
- Silvia Santoro,
- Barbara Bettegazzi,
- Andrea Zauli,
- Ferdinando Clarelli,
- Elisabetta Mascia,
- Andrea Calabria,
- Daniele Zacchetti,
- Ruggero Capra,
- Maurizio Ferrari,
- Paolo Provero,
- Dejan Lazarevic,
- Davide Cittaro,
- Paola Carrera,
- Nikolaos Patsopoulos,
- Daniela Toniolo,
- A Dessa Sadovnick,
- Gianvito Martino,
- Philip L. De Jager,
- Giancarlo Comi,
- Elia Stupka,
- Carles Vilariño-Güell,
- Laura Piccio,
- Filippo Martinelli Boneschi
Affiliations
- Federica Esposito
- Laboratory of Human Genetics of Neurological Disorders, Institute of Experimental Neurology (INSpe), Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
- Ana Maria Osiceanu
- Laboratory of Human Genetics of Neurological Disorders, Institute of Experimental Neurology (INSpe), Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
- Melissa Sorosina
- Laboratory of Human Genetics of Neurological Disorders, Institute of Experimental Neurology (INSpe), Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
- Linda Ottoboni
- Unit of Neuroimmunology, Institute of Experimental Neurology (INSpe), Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milan, Italy
- Bryan Bollman
- Department of Neurology, Washington University School of Medicine, St Louis, MO 63110, USA
- Silvia Santoro
- Laboratory of Human Genetics of Neurological Disorders, Institute of Experimental Neurology (INSpe), Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
- Barbara Bettegazzi
- Gene Therapy of Neurodegenerative Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
- Andrea Zauli
- Laboratory of Human Genetics of Neurological Disorders, Institute of Experimental Neurology (INSpe), Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
- Ferdinando Clarelli
- Laboratory of Human Genetics of Neurological Disorders, Institute of Experimental Neurology (INSpe), Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
- Elisabetta Mascia
- Laboratory of Human Genetics of Neurological Disorders, Institute of Experimental Neurology (INSpe), Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
- Andrea Calabria
- San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), 20132 Milan, Italy
- Daniele Zacchetti
- Unit of Cellular Neurophysiology, Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milan, Italy
- Ruggero Capra
- Multiple Sclerosis Centre, Spedali Civili di Brescia, 25018 Montichiari, Italy
- Maurizio Ferrari
- Vita-Salute San Raffaele University, 20132 Milan, Italy
- Paolo Provero
- Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
- Dejan Lazarevic
- Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
- Davide Cittaro
- Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
- Paola Carrera
- Unit of Genomics for Human Disease Diagnosis, Laboratory of Genetics and Cytogenetics, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
- Nikolaos Patsopoulos
- Department of Neurology, Harvard Institutes of Medicine, Boston, MA 02115, USA
- Daniela Toniolo
- Department of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milan, Italy
- A Dessa Sadovnick
- Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada
- Gianvito Martino
- Unit of Neuroimmunology, Institute of Experimental Neurology (INSpe), Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milan, Italy
- Philip L. De Jager
- Department of Neurology, Columbia University, New York, NY 10027, USA
- Giancarlo Comi
- Neurology Unit, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
- Elia Stupka
- Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
- Carles Vilariño-Güell
- Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada
- Laura Piccio
- Department of Neurology, Washington University School of Medicine, St Louis, MO 63110, USA
- Filippo Martinelli Boneschi
- Neurology Unit, ASST Santi Paolo e Carlo, 20142 Milan, Italy
- DOI
- https://doi.org/10.3390/genes13122392
- Journal volume & issue
-
Vol. 13,
no. 12
p. 2392
Abstract
While the role of common genetic variants in multiple sclerosis (MS) has been elucidated in large genome-wide association studies, the contribution of rare variants to the disease remains unclear. Herein, a whole-genome sequencing study in four affected and four healthy relatives of a consanguineous Italian family identified a novel missense c.1801T > C (p.S601P) variant in the GRAMD1B gene that is shared within MS cases and resides under a linkage peak (LOD: 2.194). Sequencing GRAMD1B in 91 familial MS cases revealed two additional rare missense and two splice-site variants, two of which (rs755488531 and rs769527838) were not found in 1000 Italian healthy controls. Functional studies demonstrated that GRAMD1B, a gene with unknown function in the central nervous system (CNS), is expressed by several cell types, including astrocytes, microglia and neurons as well as by peripheral monocytes and macrophages. Notably, GRAMD1B was downregulated in vessel-associated astrocytes of active MS lesions in autopsied brains and by inflammatory stimuli in peripheral monocytes, suggesting a possible role in the modulation of inflammatory response and disease pathophysiology.
Keywords