title: Heterozygous KIDINS220/ARMS nonsense variants cause spastic paraplegia, intellectual disability, nystagmus, and obesity.
abstract: We identified de novo nonsense variants in KIDINS220/ARMS in three unrelated patients with spastic paraplegia, intellectual disability, nystagmus, and obesity (SINO). KIDINS220 is an essential scaffold protein coordinating neurotrophin signal pathways in neurites and is spatially and temporally regulated in the brain. Molecular analysis of patients' variants confirmed expression and translation of truncated transcripts similar to recently characterized alternative terminal exon splice isoforms of KIDINS220 KIDINS220 undergoes extensive alternative splicing in specific neuronal populations and developmental time points, reflecting its complex role in neuronal maturation. In mice and humans, KIDINS220 is alternative spliced in the middle region as well as in the last exon. These full-length and KIDINS220 splice variants occur at precise moments in cortical, hippocampal, and motor neuron development, with splice variants similar to the variants seen in our patients and lacking the last exon of KIDINS220 occurring in adult rather than in embryonic brain. We conducted tissue-specific expression studies in zebrafish that resulted in spasms, confirming a functional link with disruption of the KIDINS220 levels in developing neurites. This work reveals a crucial physiological role of KIDINS220 in development and provides insight into how perturbation of the complex interplay of KIDINS220 isoforms and their relative expression can affect neuron control and human metabolism. Altogether, we here show that de novo protein-truncating KIDINS220 variants cause a new syndrome, SINO. This is the first report of KIDINS220 variants causing a human disease.
authors.affiliation: Department of Clinical Genetics, Guys' and St. Thomas' Hospital, London SE1 7EH, UK.
authors.forename: Dragana J
authors.initials: DJ
authors.lastname: Josifova
authors.affiliation: Department of Genetics Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584 CX, The Netherlands.
authors.forename: Glen R
authors.initials: GR
authors.lastname: Monroe
authors.affiliation: Department of Genetics Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584 CX, The Netherlands Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht 3584 CT, The Netherlands.
authors.forename: Federico
authors.initials: F
authors.lastname: Tessadori
authors.affiliation: Division of Cell Biology, Faculty of Science, University of Utrecht, Utrecht 3584 CH, The Netherlands.
authors.forename: Esther
authors.initials: E
authors.lastname: de Graaff
authors.affiliation: Department of Genetics.
authors.forename: Bert
authors.initials: B
authors.lastname: van der Zwaag
authors.affiliation: Department of Clinical Genetics, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors.forename: Sarju G
authors.initials: SG
authors.lastname: Mehta
authors.affiliation: Department of Genetics.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Harakalova
authors.affiliation: Department of Genetics Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584 CX, The Netherlands.
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Duran
authors.affiliation: Department of Genetics Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584 CX, The Netherlands.
authors.forename: Sanne M C
authors.initials: SM
authors.lastname: Savelberg
authors.affiliation: Department of Genetics Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584 CX, The Netherlands.
authors.forename: Isaäc J
authors.initials: IJ
authors.lastname: Nijman
authors.affiliation: Department of Paediatric Neurology, Evelina Children's Hospital, Guy's & St Thomas' Hospital NHS Foundation Trust, London SE1 7EH, UK Randall Division of Cell and Molecular Biophysics, Muscle Signalling Section, Department of Basic and Clinical Neuroscience, IoPPN, King's College, London WC2R 2LS, UK.
authors.forename: Heinz
authors.initials: H
authors.lastname: Jungbluth
authors.affiliation: Division of Cell Biology, Faculty of Science, University of Utrecht, Utrecht 3584 CH, The Netherlands.
authors.forename: Casper C
authors.initials: CC
authors.lastname: Hoogenraad
authors.affiliation: Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht 3584 CT, The Netherlands Department of Medical Physiology, University Medical Center Utrecht, Utrecht 3584 CX, The Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Bakkers
authors.affiliation: Department of Genetics Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584 CX, The Netherlands.
authors.forename: Nine V
authors.initials: NV
authors.lastname: Knoers
authors.affiliation: Department of Clinical Genetics, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1RQ, UK.
authors.forename: Helen V
authors.initials: HV
authors.lastname: Firth
authors.affiliation: Genetics and Genomics Medicine Program, UCL Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Philip L
authors.initials: PL
authors.lastname: Beales
authors.affiliation: Department of Genetics Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584 CX, The Netherlands.
authors.forename: Gijs
authors.initials: G
authors.lastname: van Haaften
authors.affiliation: Department of Genetics m.vanhaelst@umcutrecht.nl.
authors.forename: Mieke M
authors.initials: MM
authors.lastname: van Haelst
mesh_terms: D017398:Alternative Splicing / Q000235:genetics; D000818:Animals; D018389:Codon, Nonsense; D004195:Disease Models, Animal; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000503:physiopathology; D008565:Membrane Proteins / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D016501:Neurites / Q000378:metabolism / Q000473:pathology; D055495:Neurogenesis / Q000235:genetics; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D020417:Nystagmus, Congenital / Q000235:genetics* / Q000503:physiopathology; D009765:Obesity / Q000235:genetics* / Q000473:pathology; D016716:PC12 Cells; D010264:Paraplegia / Q000235:genetics* / Q000503:physiopathology; D011485:Protein Binding / Q000235:genetics; D051381:Rats; D015398:Signal Transduction; D029961:Zebrafish Proteins / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D029961:Zebrafish Proteins; C000591256:kidins220b protein, zebrafish