Publicaciones científicas

A Restricted Repertoire of De Novo Mutations in ITPR1 Cause Gillespie Syndrome with Evidence for Dominant-Negative Effect

05-may-2016 | Revista: American Journal of Human Genetics

McEntagart M (1), Williamson KA (2), Rainger JK (2), Wheeler A (2), Seawright A (2), De Baere E (3), Verdin H (3), Bergendahl LT (2), Quigley A (4), Rainger J (5), Dixit A (6), Sarkar A (6), López Laso E (7), Sanchez-Carpintero R (8), Barrio J (9), Bitoun P (10), Prescott T (11), Riise R (12), McKee S (13), Cook J (14), McKie L (2), Ceulemans B (15), Meire F (16), Temple IK (17), Prieur F (18), Williams J (19), Clouston P (19), Németh AH (20), Banka S (21), Bengani H (2), Handley M (2), Freyer E (2), Ross A (2); DDD Study, van Heyningen V (2), Marsh JA (2), Elmslie F (1), FitzPatrick DR (22).
(1) Medical Genetics, St George's University Hospitals NHS Foundation Trust, Cranmer Terrace, London SW17 0RE, UK.
(2) MRC Human Genetics Unit, IGMM, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK.
(3) Center for Medical Genetics Ghent (CMGG), Ghent University Hospital, Medical Research Building (MRB), 1st Floor, Room 110.029, De Pintelaan 185, 9000 Ghent, Belgium.
(4) Department of Radiology, Royal Hospital for Sick Children, Edinburgh EH9 1LF, UK.
(5) MRC Human Genetics Unit, IGMM, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK; Roslin Institute, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, UK.
(6) Clinical Genetics, Nottingham City Hospital, Hucknall Road, Nottingham NG5 1PB, UK.
(7) Pediatric Neurology Unit, Department of Pediatrics, Reina Sofia University Hospital, Av. Menéndez Pidal s/n, 14004 Córdoba, Spain.
(8) Paediatric Neurology Unit, Department of Paediatrics, Clinica Universidad de Navarra, 31008 Pamplona, Spain.
(9) Department of Ophthalmology, Clinica Universidad de Navarra, 31008 Pamplona, Spain.
(10) Service de pédiatrie, CHU Paris Seine-Saint-Denis - Hôpital Jean Verdier Avenue du 14 juillet, 93140 Bondy, France.
(11) Department of Medical Genetics, Oslo University Hospital, 0424 Oslo, Norway.
(12) Department of Ophthalmology, Innland Hospital, 2418 Elverum, Norway.
(13) Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast BT9 7AB, UK.
(14) Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Western Bank, Sheffield S10 2TH, UK.
(15) Department of Neurology-Pediatric Neurology, University and University Hospital Antwerp, Antwerp 2650, Belgium.
(16) Department of Ophthalmology, Queen Fabiola Children's University Hospital, 1020 Brussels, Belgium.
(17) Human Development and Health Academic Unit, University Hospital Southampton, Tremona Road, University of Southampton, Southampton SO16 6YD, UK.
(18) Service Génétique, Plateau de biologie, CHU Saint Etienne, 42055 Saint Etienne cedex 2, France.
(19) Oxford University Hospitals NHS Trust, Oxford Medical Genetics Laboratories, The Churchill Hospital, Old Road, Headington, Oxford OX3 7LE, UK.
(20) Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 7LJ, UK.
(21) Manchester Centre for Genomic Medicine, University of Manchester, St. Mary's Hospital, Oxford Road, Manchester M13 9WL, UK.
(22) MRC Human Genetics Unit, IGMM, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK.


Gillespie syndrome (GS) is characterized by bilateral iris hypoplasia, congenital hypotonia, non-progressive ataxia, and progressive cerebellar atrophy. Trio-based exome sequencing identified de novo mutations in ITPR1 in three unrelated individuals with GS recruited to the Deciphering Developmental Disorders study.

Whole-exome or targeted sequence analysis identified plausible disease-causing ITPR1 mutations in 10/10 additional GS-affected individuals. These ultra-rare protein-altering variants affected only three residues in ITPR1: Glu2094 missense (one de novo, one co-segregating), Gly2539 missense (five de novo, one inheritance uncertain), and Lys2596 in-frame deletion (four de novo).

No clinical or radiological differences were evident between individuals with different mutations. ITPR1 encodes an inositol 1,4,5-triphosphate-responsive calcium channel. The homo-tetrameric structure has been solved by cryoelectron microscopy. Using estimations of the degree of structural change induced by known recessive- and dominant-negative mutations in other disease-associated multimeric channels, we developed a generalizable computational approach to indicate the likely mutational mechanism.

This analysis supports a dominant-negative mechanism for GS variants in ITPR1. In GS-derived lymphoblastoid cell lines (LCLs), the proportion of ITPR1-positive cells using immunofluorescence was significantly higher in mutant than control LCLs, consistent with an abnormality of nuclear calcium signaling feedback control.

Super-resolution imaging supports the existence of an ITPR1-lined nucleoplasmic reticulum. Mice with Itpr1 heterozygous null mutations showed no major iris defects. Purkinje cells of the cerebellum appear to be the most sensitive to impaired ITPR1 function in humans. Iris hypoplasia is likely to result from either complete loss of ITPR1 activity or structure-specific disruption of multimeric interactions.

CITA DEL ARTÍCULO  Am J Hum Genet. 2016 May 5;98(5):981-92. doi: 10.1016/j.ajhg.2016.03.018. Epub 2016 Apr 21.

Nuestros autores

Responsable Unidad de Dravet
Sede Pamplona
Sede Madrid