KPNA3, VRK1 and ABHD16A proposed
Infantile-onset pure HSP cases investigated
KPNA3 potential new HSP gene & causal mechanism
Variants in the KPNA3 gene have been found to cause autosomal dominant, infantile-onset pure HSP in eight children. The genetic variant was found to be sporadic in four of the eight cases, meaning that the genetic variant was not inherited, neither parent carried the variant, it just occurred during the imperfect process of DNA replication. A new HSP causal mechanism (dysfunctional nucleocytoplasmic shuttling) is suggested.
Objective: Hereditary spastic paraplegia (HSP) is a highly heterogeneous neurologic disorder characterized by lower-extremity spasticity. Here, we set out to determine the genetic basis of an autosomal dominant, pure, and infantile-onset form of HSP in a cohort of 8 patients with a uniform clinical presentation.
Methods: Trio whole-exome sequencing was used in 5 index patients with infantile-onset pure HSP to determine the genetic cause of disease. The functional impact of identified genetic variants was verified using bioinformatics and complementary cellular and biochemical assays.
Results: Distinct heterozygous KPNA3 missense variants were found to segregate with the clinical phenotype in 8 patients; in 4 of them KPNA3 variants had occurred de novo. Mutant karyopherin-α3 proteins exhibited a variable pattern of altered expression level, subcellular distribution, and protein interaction.
Interpretation: Our genetic findings implicate heterozygous variants in KPNA3 as a novel cause for autosomal dominant, early-onset, and pure HSP. Mutant karyopherin-α3 proteins display varying deficits in molecular and cellular functions, thus, for the first time, implicating dysfunctional nucleocytoplasmic shuttling as a novel pathomechanism causing HSP.
SOURCE: Ann Neurol. 2021 Nov;90(5):738-750. doi: 10.1002/ana.26228. Epub 2021 Oct 14. PMID: 34564892 © 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
Dominant KPNA3 Mutations Cause Infantile-Onset Hereditary Spastic Paraplegia
Claudia Schob 1 , Maja Hempel 1 , Dana Safka Brozkova 2 , Huafang Jiang 3 , Soo Yeon Kim 4 , Nurit Assia Batzir 5 , Naama Orenstein 5 , Tatjana Bierhals 1 , Jessika Johannsen 6 , Anna Uhrova Meszarosova 2 , Jong-Hee Chae 4 7 , Pavel Seeman 2 , Mathias Woidy 6 , Fang Fang 3 , Christian Kubisch 1 , Stefan Kindler 1 , Jonas Denecke 6
1. Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
2. Neurogenetic Laboratory, Department of Pediatric Neurology, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic.
3. Department of Neurology, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China.
4. Department of Genomics Medicine, Rare Disease Center, Seoul National University Hospital, Seoul, Republic of Korea.
5. Pediatric Genetics Clinic, Schneider Children’s Medical Center of Israel, Petah-Tikva, Israel.
6. Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
7. Department of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea.
VRK1 a new candidate gene for HSP
Variant caused complicated HSP in a family
A very rare, recessively inherited variant in the VRK1 gene has been established as causing complicated HSP in members of one family. Specifically the variant impairs the DNA damage response and the assembly of Cajal bodies found in the cell nucleus and involved in mRNA processing.
Background and objectives: To conduct a genetic and molecular functional study of a family with members affected of hereditary spastic paraplegia (HSP) of unknown origin and carrying a novel pathogenic vaccinia-related kinase 1 (VRK1) variant.
Methods: Whole-exome sequencing was performed in 2 patients, and their parents diagnosed with HSP. The novel VRK1 variant was detected by whole-exome sequencing, molecularly modeled and biochemically characterized in kinase assays. Functionally, we studied the role of this VRK1 variant in DNA damage response and its effect on the assembly of Cajal bodies (CBs).
Results: We have identified a very rare homozygous variant VRK1-D263G with a neurologic phenotype associated with HSP and moderate intellectual disability. The molecular modeling of this VRK1 variant protein predicted an alteration in the folding of a loop that interferes with the access to the kinase catalytic site. The VRK1-D263G variant is kinase inactive and does not phosphorylate histones H2AX and H3, transcription factors activating transcription factor 2 and p53, coilin needed for assembly of CBs, and p53 binding protein 1, a DNA repair protein. Functionally, this VRK1 variant protein impairs CB formation and the DNA damage response.
Discussion: This report expands the neurologic spectrum of neuromotor syndromes associated with a new and rare VRK1 variant, representing a novel pathogenic participant in complicated HSP and demonstrates that CBs and the DNA damage response are impaired in these patients.
SOURCE: Neurol Genet. 2021 Sep 2;7(5):e624. doi: 10.1212/NXG.0000000000000624. eCollection 2021 Oct. PMID: 34504951 Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
Dysfunctional Homozygous VRK1-D263G Variant Impairs the Assembly of Cajal Bodies and DNA Damage Response in Hereditary Spastic Paraplegia
1. Molecular Mechanisms of Cancer Program (P.M.-G., P.A.L.), Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC) – Universidad de Salamanca; Instituto de Investigación Biomédica de Salamanca (IBSAL) (P.M.-G., P.A.L.), Hospital Universitario de Salamanca, Spain; Genetics Department (B.K.), La Pitié-Salpêtrière Hospital, APHP. Sorbonne Université, Paris, France; Molecular Modelling Group (I.M.-A.), Centro de Biología Molecular “Severo Ochoa”. CSIC – Universidad Autónoma de Madrid, Spain; Biosciences Research Institute (I.M.-A., P.G.-P.), School of Experimental Sciences, Universidad Francisco de Vitoria, Madrid, Spain; and Sorbonne Université – Université Pierre et Marie Curie (F.M.), Institut du Cerveau et de la Moelle épinière, INSERM U-1127, CNRS-UMR 7225, Paris, France.
ABHD16A gene associated with HSP
Not previously been linked with human disease
Harmful variants in a lipid gene (ABHD16A) that has not previously been linked to human disease have been found to cause complicated HSP in 11 people from six families.
ABHD16A (abhydrolase domain-containing protein 16A, phospholipase) encodes the major phosphatidylserine (PS) lipase in the brain. PS lipase synthesizes lysophosphatidylserine, an important signaling lipid that functions in the mammalian central nervous system. ABHD16A has not yet been associated with a human disease.
In this report, we present a cohort of 11 affected individuals from six unrelated families with a complicated form of hereditary spastic paraplegia (HSP) who carry bi-allelic deleterious variants in ABHD16A. Affected individuals present with a similar phenotype consisting of global developmental delay/intellectual disability, progressive spasticity affecting the upper and lower limbs, and corpus callosum and white matter anomalies. Immunoblot analysis on extracts from fibroblasts from four affected individuals demonstrated little to no ABHD16A protein levels compared to controls.
Our findings add ABHD16A to the growing list of lipid genes in which dysregulation can cause complicated forms of HSP and begin to describe the molecular etiology of this condition.
SOURCE: Am J Hum Genet. 2021 Oct 7;108(10):2017-2023. doi: 10.1016/j.ajhg.2021.09.005. Epub 2021 Sep 28. PMID: 34587489 Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
ABHD16A deficiency causes a complicated form of hereditary spastic paraplegia associated with intellectual disability and cerebral anomalies
Gabrielle Lemire 1 , Yoko A Ito 2 , Aren E Marshall 2 , Nicolas Chrestian 3 , Valentina Stanley 4 , Lauren Brady 5 , Mark Tarnopolsky 5 , Cynthia J Curry 6 , Taila Hartley 2 , Wendy Mears 2 , Alexa Derksen 7 , Nadie Rioux 8 , Nataly Laflamme 8 , Harrol T Hutchison 9 , Lynn S Pais 10 , Maha S Zaki 11 , Tipu Sultan 12 , Adrie D Dane 13 , Care4Rare Canada Consortium; Joseph G Gleeson 4 , Frédéric M Vaz 14 , Kristin D Kernohan 15 , Geneviève Bernard 16 , Kym M Boycott 17
1. Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada; Broad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
2. Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada.
3. Department of Paediatric Neurology, Paediatric Neuromuscular Disorder, Centre Mère Enfant Soleil, Laval University, Quebec City, QC G1V 4G2, Canada; Department of Molecular Medicine, Faculty of Medicine, Neuroscience Laboratory, CHU de Québec Research Center, Laval University, Quebec City, QC G1V 4G2, Canada.
4. Laboratory for Pediatric Brain Disease, Rady Children’s Institute for Genomic Medicine, University of California, San Diego, San Diego, CA 92093, USA.
5. Neuromuscular and Neurometabolics Division, Department of Pediatrics, McMaster University, Hamilton, ON L8N 3Z5, Canada.
6. Genetic Medicine Division, Department of Pediatrics, University of California, San Francisco, Fresno, CA 93701, USA.
7. Child Health and Human Development Program, McGill University Health Centre Research Institute, Montréal, QC H4A 3J1, Canada; Departments of Neurology and Neurosurgery, Pediatrics and Human Genetics, McGill University, Montreal, QC H3A 0G4, Canada.
8. Department of Molecular Medicine, Faculty of Medicine, Neuroscience Laboratory, CHU de Québec Research Center, Laval University, Quebec City, QC G1V 4G2, Canada.
9. Neurology Division, Department of Pediatrics, University of California, San Francisco, Fresno, CA 93701, USA.
10. Broad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
11. Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, 12311 Cairo, Egypt.
12. Department of Pediatric Neurology, Institute of Child Health, Children Hospital Lahore, 54000 Lahore, Pakistan.
13. Bioinformatics Laboratory, Department of Epidemiology and Data Science, Amsterdam Public Health Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam 1105, the Netherlands.
14. Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Departments of Clinical Chemistry and Pediatrics, Amsterdam Gastroenterology and Endocrinology Metabolism, Amsterdam 1105, the Netherlands; Department of Pediatrics, Emma 15. Children’s Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam 1105, the Netherlands; Core Facility Metabolomics, Amsterdam UMC, Amsterdam 1105, the Netherlands.
Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada; Newborn Screening Ontario, Children’s Hospital of Eastern Ontario, Ottawa, ON K1H 8L1, Canada.
16. Genetic Medicine Division, Department of Pediatrics, University of California, San Francisco, Fresno, CA 93701, USA; Child Health and Human Development Program, McGill University Health Centre Research Institute, Montréal, QC H4A 3J1, Canada; Department of Specialized Medicine, Division of Medical Genetics, McGill University Health Center, Montreal, QC H4A 3J1, Canada.
17. Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada.