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A restricted repertoire of De Novo Mutations in ITPR1 cause Gillespie Syndrome with evidence for dominant negative effect

A restricted repertoire of De Novo Mutations in ITPR1 cause Gillespie Syndrome with evidence for dominant negative effect
A restricted repertoire of De Novo Mutations in ITPR1 cause Gillespie Syndrome with evidence for dominant negative effect
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.
0002-9297
981-992
McEntagart, M.
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Williamson, K.A.
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Rainger, J.K.
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Rainger, J.
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Bitoun, P.
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Prescott, T.
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Riise, R.
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Ceulemans, B.
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Temple, I.K.
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Clouston, P.
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Ross, A.
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van Heyningen, V.
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Marsh, J.A.
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Elmslie, F.
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FitzPatrick, D.R.
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McEntagart, M.
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Williamson, K.A.
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Rainger, J.K.
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Seawright, A.
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De Baere, E.
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Verdin, H.
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Quigley, A.
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Rainger, J.
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Dixit, A.
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Cook, J.
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McKie, L.
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Ceulemans, B.
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Temple, I.K.
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Williams, J.
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Banka, S.
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Bengani, H.
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Handley, M.
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Ross, A.
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van Heyningen, V.
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Marsh, J.A.
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Elmslie, F.
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FitzPatrick, D.R.
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McEntagart, M., Williamson, K.A., Rainger, J.K., Wheeler, A., Seawright, A., De Baere, E., Verdin, H., Bergendahl, L. T., Quigley, A., Rainger, J., Dixit, A., Sarkar, A., Lopez Laso, E., Sanchez-Carpintero, R., Barrio, J., Bitoun, P., Prescott, T., Riise, R., McKee, S., Cook, J., McKie, L., Ceulemans, B., Meire, F., Temple, I.K., Prieur, F., Williams, J., Clouston, P., Nemeth, A.H., Banka, S., Bengani, H., Handley, M., Freyer, E., Ross, A., van Heyningen, V., Marsh, J.A., Elmslie, F. and FitzPatrick, D.R. (2016) A restricted repertoire of De Novo Mutations in ITPR1 cause Gillespie Syndrome with evidence for dominant negative effect. The American Journal of Human Genetics, 98 (5), 981-992. (doi:10.1016/j.ajhg.2016.03.018).

Record type: Article

Abstract

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.

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Accepted/In Press date: 16 March 2016
e-pub ahead of print date: 21 April 2016
Published date: 5 May 2016
Organisations: Human Development & Health

Identifiers

Local EPrints ID: 392037
URI: http://eprints.soton.ac.uk/id/eprint/392037
ISSN: 0002-9297
PURE UUID: 23bb3d06-8373-4308-a30a-41c2a67f8f70
ORCID for I.K. Temple: ORCID iD orcid.org/0000-0002-6045-1781

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Date deposited: 14 Apr 2016 09:08
Last modified: 18 Feb 2021 16:52

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Contributors

Author: M. McEntagart
Author: K.A. Williamson
Author: J.K. Rainger
Author: A. Wheeler
Author: A. Seawright
Author: E. De Baere
Author: H. Verdin
Author: L. T. Bergendahl
Author: A. Quigley
Author: J. Rainger
Author: A. Dixit
Author: A. Sarkar
Author: E. Lopez Laso
Author: R. Sanchez-Carpintero
Author: J. Barrio
Author: P. Bitoun
Author: T. Prescott
Author: R. Riise
Author: S. McKee
Author: J. Cook
Author: L. McKie
Author: B. Ceulemans
Author: F. Meire
Author: I.K. Temple ORCID iD
Author: F. Prieur
Author: J. Williams
Author: P. Clouston
Author: A.H. Nemeth
Author: S. Banka
Author: H. Bengani
Author: M. Handley
Author: E. Freyer
Author: A. Ross
Author: V. van Heyningen
Author: J.A. Marsh
Author: F. Elmslie
Author: D.R. FitzPatrick

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