Patricia Morejon-Garcia1, Boris Keren1, Iñigo Marcos-Alcalde1, Paulino Gomez-Puertas1, Fanny Mochel1, Pedro A Lazo1. 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.
Abstract
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.
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.
Authors: K E Tucker; M T Berciano; E Y Jacobs; D F LePage; K B Shpargel; J J Rossire; E K Chan; M Lafarga; R A Conlon; A G Matera Journal: J Cell Biol Date: 2001-07-23 Impact factor: 10.539