Variants in LSM7 impair LSM complexes assembly, neurodevelopment in zebrafish and may be associated with an ultra-rare neurological disease
Alexa Derksen,
Hung-Yu Shih,
Diane Forget,
Lama Darbelli,
Luan T. Tran,
Christian Poitras,
Kether Guerrero,
Sundaresan Tharun,
Fowzan S. Alkuraya,
Wesam I. Kurdi,
Cam-Tu Emilie Nguyen,
Anne-Marie Laberge,
Yue Si,
Marie-Soleil Gauthier,
Joshua L. Bonkowsky,
Benoit Coulombe,
Geneviève Bernard
Affiliations
Alexa Derksen
Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montréal, QC H4A 3J1, Canada; Translational Proteomics Laboratory, Institut de Recherches Cliniques de Montréal, Montréal, QC H2W 1R7, Canada; Department of Neurology and Neurosurgery, McGill University, Montréal, QC H3A 0G4, Canada
Hung-Yu Shih
Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT 84132, USA
Diane Forget
Translational Proteomics Laboratory, Institut de Recherches Cliniques de Montréal, Montréal, QC H2W 1R7, Canada
Lama Darbelli
Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montréal, QC H4A 3J1, Canada
Luan T. Tran
Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montréal, QC H4A 3J1, Canada
Christian Poitras
Translational Proteomics Laboratory, Institut de Recherches Cliniques de Montréal, Montréal, QC H2W 1R7, Canada
Kether Guerrero
Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montréal, QC H4A 3J1, Canada
Sundaresan Tharun
Department of Biochemistry, Uniformed Services University of Health Sciences (USUHS), Bethesda, MD 20814, USA
Fowzan S. Alkuraya
Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh 12713, Saudi Arabia
Wesam I. Kurdi
Department of Obstetrics and Gynecology, Maternal Fetal Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh 12713, Saudi Arabia
Cam-Tu Emilie Nguyen
Neurosciences Department, Université de Montréal, Montréal, QC H3T 1J4, Canada
Anne-Marie Laberge
Service de Génétique Médical, CHU Sainte-Justine, Montréal, QC H3T 1C5, Canada
Yue Si
GeneDx, Gaithersburg, MD 20877, USA
Marie-Soleil Gauthier
Translational Proteomics Laboratory, Institut de Recherches Cliniques de Montréal, Montréal, QC H2W 1R7, Canada
Joshua L. Bonkowsky
Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT 84132, USA; Brain and Spine Center and Primary Children’s Center for Personalized Medicine, Primary Children’s Hospital, Salt Lake City, UT 84113, USA
Benoit Coulombe
Translational Proteomics Laboratory, Institut de Recherches Cliniques de Montréal, Montréal, QC H2W 1R7, Canada; Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, QC H3T 1J4, Canada
Geneviève Bernard
Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montréal, QC H4A 3J1, Canada; Department of Neurology and Neurosurgery, McGill University, Montréal, QC H3A 0G4, Canada; Department of Pediatrics, McGill University, Montréal, QC H3A 0G4, Canada; Department of Human Genetics, McGill University, Montréal, H3A 0G4, Canada; Division of Medical Genetics, Department of Specialized Medicine, McGill University Health Centre, Montréal, QC H4A 3J1, Canada; Corresponding author
Summary: Leukodystrophies, genetic neurodevelopmental and/or neurodegenerative disorders of cerebral white matter, result from impaired myelin homeostasis and metabolism. Numerous genes have been implicated in these heterogeneous disorders; however, many individuals remain without a molecular diagnosis. Using whole-exome sequencing, biallelic variants in LSM7 were uncovered in two unrelated individuals, one with a leukodystrophy and the other who died in utero. LSM7 is part of the two principle LSM protein complexes in eukaryotes, namely LSM1-7 and LSM2-8. Here, we investigate the molecular and functional outcomes of these LSM7 biallelic variants in vitro and in vivo. Affinity purification-mass spectrometry of the LSM7 variants showed defects in the assembly of both LSM complexes. Lsm7 knockdown in zebrafish led to central nervous system defects, including impaired oligodendrocyte development and motor behavior. Our findings demonstrate that variants in LSM7 cause misassembly of the LSM complexes, impair neurodevelopment of the zebrafish, and may be implicated in human disease. The identification of more affected individuals is needed before the molecular mechanisms of mRNA decay and splicing regulation are added to the categories of biological dysfunctions implicated in leukodystrophies, neurodevelopmental and/or neurodegenerative diseases.
