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

doi:10.1016/j.xhgg.2021.100034

Variants in LSM7 impair LSM complexes assembly, neurodevelopment in zebrafish and may be associated with an ultra-rare neurological disease

HGG Adv. 2021 May 5;2(3):100034. doi: 10.1016/j.xhgg.2021.100034. eCollection 2021 Jul 8.

Authors

Alexa Derksen^{1

2

3}, Hung-Yu Shih⁴, Diane Forget², Lama Darbelli¹, Luan T Tran¹, Christian Poitras², Kether Guerrero¹, Sundaresan Tharun⁵, Fowzan S Alkuraya⁶, Wesam I Kurdi⁷, Cam-Tu Emilie Nguyen⁸, Anne-Marie Laberge⁹, Yue Si¹⁰, Marie-Soleil Gauthier², Joshua L Bonkowsky^{4

11}, Benoit Coulombe^{2

12}, Geneviève Bernard^{1

3

13

14

15}

Affiliations

¹ Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montréal, QC H4A 3J1, Canada.
² Translational Proteomics Laboratory, Institut de Recherches Cliniques de Montréal, Montréal, QC H2W 1R7, Canada.
³ Department of Neurology and Neurosurgery, McGill University, Montréal, QC H3A 0G4, Canada.
⁴ Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
⁵ Department of Biochemistry, Uniformed Services University of Health Sciences (USUHS), Bethesda, MD 20814, USA.
⁶ Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh 12713, Saudi Arabia.
⁷ Department of Obstetrics and Gynecology, Maternal Fetal Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh 12713, Saudi Arabia.
⁸ Neurosciences Department, Université de Montréal, Montréal, QC H3T 1J4, Canada.
⁹ Service de Génétique Médical, CHU Sainte-Justine, Montréal, QC H3T 1C5, Canada.
¹⁰ GeneDx, Gaithersburg, MD 20877, USA.
¹¹ Brain and Spine Center and Primary Children's Center for Personalized Medicine, Primary Children's Hospital, Salt Lake City, UT 84113, USA.
¹² Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, QC H3T 1J4, Canada.
¹³ Department of Pediatrics, McGill University, Montréal, QC H3A 0G4, Canada.
¹⁴ Department of Human Genetics, McGill University, Montréal, H3A 0G4, Canada.
¹⁵ Division of Medical Genetics, Department of Specialized Medicine, McGill University Health Centre, Montréal, QC H4A 3J1, Canada.

Abstract

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.

Keywords: LSM1-7 complex; LSM2-8 complex; LSM7; leukodystrophy; leukoencephalopathy; neurodevelopment.