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A restricted repertoire of de novo mutations in ITPR1 cause Gillespie syndrome with evidence for dominant-negative effect

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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.
Keywords
MISSENSE MUTATIONS, GENE DELETION, SPINOCEREBELLAR ATAXIA, ATAXIA TYPE 15, CEREBELLAR-ATAXIA, PROTEIN COMPLEXES, ANIRIDIA, CHANNELOPATHIES, PHENOTYPE, FAMILIES

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Chicago
McEntagart, Meriel, Kathleen A Williamson, Jacqueline K Rainger, Ann Wheeler, Anne Seawright, Elfride De Baere, Hannah Verdin, et al. 2016. “A Restricted Repertoire of De Novo Mutations in ITPR1 Cause Gillespie Syndrome with Evidence for Dominant-negative Effect.” American Journal of Human Genetics 98 (5): 981–992.
APA
McEntagart, M., Williamson, K. A., Rainger, J. K., Wheeler, A., Seawright, A., De Baere, E., Verdin, H., et al. (2016). A restricted repertoire of de novo mutations in ITPR1 cause Gillespie syndrome with evidence for dominant-negative effect. AMERICAN JOURNAL OF HUMAN GENETICS, 98(5), 981–992.
Vancouver
1.
McEntagart M, Williamson KA, Rainger JK, Wheeler A, Seawright A, De Baere E, et al. A restricted repertoire of de novo mutations in ITPR1 cause Gillespie syndrome with evidence for dominant-negative effect. AMERICAN JOURNAL OF HUMAN GENETICS. 2016;98(5):981–92.
MLA
McEntagart, Meriel, Kathleen A Williamson, Jacqueline K Rainger, et al. “A Restricted Repertoire of De Novo Mutations in ITPR1 Cause Gillespie Syndrome with Evidence for Dominant-negative Effect.” AMERICAN JOURNAL OF HUMAN GENETICS 98.5 (2016): 981–992. Print.
@article{8099571,
  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.},
  author       = {McEntagart, Meriel and Williamson, Kathleen A and Rainger, Jacqueline K and Wheeler, Ann and Seawright, Anne and De Baere, Elfride and Verdin, Hannah and Bergendahl, L Therese and Quigley, Alan and Rainger, Joe and Dixit, Abhijit and Sarkar, Ajoy and L{\'o}pez laso, Eduardo and Sanchez-Carpintero, Rocio and Barrio, Jesus and Bitoun, Pierre and Prescott, Trine and Riise, Ruth and McKee, Shane and Cook, Jackie and McKie, Lisa and Ceulemans, Berten and Meire, Fran\c{c}oise and Temple, I Karen and Prieur, Fabienne and Williams, Jonathan and Clouston, Penny and N{\'e}meth, Andrea H and Banka, Siddharth and Bengani, Hemant and Handley, Mark and Freyer, Elisabeth and Ross, Allyson and van Heyningen, Veronica and Marsh, Joseph A and Elmslie, Frances and FitzPatrick, David R},
  issn         = {0002-9297},
  journal      = {AMERICAN JOURNAL OF HUMAN GENETICS},
  keyword      = {MISSENSE MUTATIONS,GENE DELETION,SPINOCEREBELLAR ATAXIA,ATAXIA TYPE 15,CEREBELLAR-ATAXIA,PROTEIN COMPLEXES,ANIRIDIA,CHANNELOPATHIES,PHENOTYPE,FAMILIES},
  language     = {eng},
  number       = {5},
  pages        = {981--992},
  title        = {A restricted repertoire of de novo mutations in ITPR1 cause Gillespie syndrome with evidence for dominant-negative effect},
  url          = {http://dx.doi.org/10.1016/j.ajhg.2016.03.018},
  volume       = {98},
  year         = {2016},
}

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