Gene not previously linked to disease
A gene never previously linked to disease, KIDINS220, has been found as the cause of a complex new syndrome called SINO that includes spastic paraplegia, intellectual disability, involuntary eye movement and obesity.
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.
SOURCE: Hum Mol Genet. 2016 Jun 1;25(11):2158-2167. Epub 2016 Mar 22. PMID: 27005418
Heterozygous KIDINS220/ARMS nonsense variants cause spastic paraplegia, intellectual disability, nystagmus, and obesity.
Josifova DJ1, Monroe GR2, Tessadori F3, de Graaff E4, van der Zwaag B5, Mehta SG6; DDD Study, Harakalova M5, Duran KJ2, Savelberg SM2, Nijman IJ2, Jungbluth H7, Hoogenraad CC4, Bakkers J8, Knoers NV2, Firth HV9, Beales PL10, van Haaften G2, van Haelst MM11.
1 Department of Clinical Genetics, Guys’ and St. Thomas’ Hospital, London SE1 7EH, UK.
2 Department of Genetics Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584 CX, The Netherlands.
3 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.
4 Division of Cell Biology, Faculty of Science, University of Utrecht, Utrecht 3584 CH, The Netherlands.
5 Department of Genetics.
6 Department of Clinical Genetics, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK.
7 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.
8 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.
9 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.
10 Genetics and Genomics Medicine Program, UCL Institute of Child Health, London WC1N 1EH, UK.
11 Department of Genetics [email protected]