Human CHN1 mutations hyperactivate alpha2-chimaerin and cause Duane's retraction syndrome

Noriko Miyake, John Chilton, Maria Psatha, Long Cheng, Stuart Christopher Andrews, Wai-Man Chan, Krystal Law, Moira Crosier, Sandra Lindsay, Michelle Cheung, James Allen, Nick J Gutowski, Sian Ellard, Elizabeth Iona Margaret Young, Alessandro Iannaccone, Binoy Appukuttan, J Timothy Stout, Stephen Christiansen, Maria Laura Ciccarelli, Alfonso Baldi & 7 others Mara Campioni, Juan C Zenteno, Dominic Davenport, Laura E Mariani, Mustafa Sahin, Sarah Guthrie, Elizabeth C Engle

Research output: Contribution to journalArticle

101 Citations (Scopus)

Abstract

Duane's retraction syndrome (DRS) is a complex congenital eye movement disorder caused by aberrant innervation of the extraocular muscles by axons of brainstem motor neurons. Studying families with a variant form of the disorder (DURS2-DRS), we have identified causative heterozygous missense mutations in CHN1, a gene on chromosome 2q31 that encodes alpha2-chimaerin, a Rac guanosine triphosphatase-activating protein (RacGAP) signaling protein previously implicated in the pathfinding of corticospinal axons in mice. We found that these are gain-of-function mutations that increase alpha2-chimaerin RacGAP activity in vitro. Several of the mutations appeared to enhance alpha2-chimaerin translocation to the cell membrane or enhance its ability to self-associate. Expression of mutant alpha2-chimaerin constructs in chick embryos resulted in failure of oculomotor axons to innervate their target extraocular muscles. We conclude that alpha2-chimaerin has a critical developmental function in ocular motor axon pathfinding.
Original languageEnglish
Pages (from-to)839-843
Number of pages5
JournalScience
Volume321
Issue number5890
Early online date24 Jul 2008
DOIs
Publication statusPublished - 8 Aug 2008

Fingerprint

Duane Retraction Syndrome
Oculomotor Muscles
Guanosine
Mutation
Axons
Ocular Motility Disorders
Proteins
Motor Neurons
Missense Mutation
Chick Embryo
Brain Stem
Chromosomes
Cell Membrane
Genes
Axon Guidance

Keywords

  • Abducens Nerve
  • Amino Acid Sequence
  • Animals
  • Axons
  • Cell Line
  • Cell Membrane
  • Chick Embryo
  • Chimerin 1
  • Duane Retraction Syndrome
  • Female
  • Gene Expression Profiling
  • Heterozygote
  • Humans
  • Male
  • Molecular Sequence Data
  • Mutation, Missense
  • Oculomotor Muscles
  • Oculomotor Nerve
  • Pedigree

Cite this

Miyake, N., Chilton, J., Psatha, M., Cheng, L., Andrews, S. C., Chan, W-M., ... Engle, E. C. (2008). Human CHN1 mutations hyperactivate alpha2-chimaerin and cause Duane's retraction syndrome. Science, 321(5890), 839-843. https://doi.org/10.1126/science.1156121

Human CHN1 mutations hyperactivate alpha2-chimaerin and cause Duane's retraction syndrome. / Miyake, Noriko; Chilton, John; Psatha, Maria; Cheng, Long; Andrews, Stuart Christopher; Chan, Wai-Man; Law, Krystal; Crosier, Moira; Lindsay, Sandra; Cheung, Michelle; Allen, James; Gutowski, Nick J; Ellard, Sian; Young, Elizabeth Iona Margaret; Iannaccone, Alessandro; Appukuttan, Binoy; Stout, J Timothy; Christiansen, Stephen; Ciccarelli, Maria Laura; Baldi, Alfonso; Campioni, Mara; Zenteno, Juan C; Davenport, Dominic; Mariani, Laura E; Sahin, Mustafa; Guthrie, Sarah; Engle, Elizabeth C.

In: Science, Vol. 321, No. 5890, 08.08.2008, p. 839-843.

Research output: Contribution to journalArticle

Miyake, N, Chilton, J, Psatha, M, Cheng, L, Andrews, SC, Chan, W-M, Law, K, Crosier, M, Lindsay, S, Cheung, M, Allen, J, Gutowski, NJ, Ellard, S, Young, EIM, Iannaccone, A, Appukuttan, B, Stout, JT, Christiansen, S, Ciccarelli, ML, Baldi, A, Campioni, M, Zenteno, JC, Davenport, D, Mariani, LE, Sahin, M, Guthrie, S & Engle, EC 2008, 'Human CHN1 mutations hyperactivate alpha2-chimaerin and cause Duane's retraction syndrome', Science, vol. 321, no. 5890, pp. 839-843. https://doi.org/10.1126/science.1156121
Miyake N, Chilton J, Psatha M, Cheng L, Andrews SC, Chan W-M et al. Human CHN1 mutations hyperactivate alpha2-chimaerin and cause Duane's retraction syndrome. Science. 2008 Aug 8;321(5890):839-843. https://doi.org/10.1126/science.1156121
Miyake, Noriko ; Chilton, John ; Psatha, Maria ; Cheng, Long ; Andrews, Stuart Christopher ; Chan, Wai-Man ; Law, Krystal ; Crosier, Moira ; Lindsay, Sandra ; Cheung, Michelle ; Allen, James ; Gutowski, Nick J ; Ellard, Sian ; Young, Elizabeth Iona Margaret ; Iannaccone, Alessandro ; Appukuttan, Binoy ; Stout, J Timothy ; Christiansen, Stephen ; Ciccarelli, Maria Laura ; Baldi, Alfonso ; Campioni, Mara ; Zenteno, Juan C ; Davenport, Dominic ; Mariani, Laura E ; Sahin, Mustafa ; Guthrie, Sarah ; Engle, Elizabeth C. / Human CHN1 mutations hyperactivate alpha2-chimaerin and cause Duane's retraction syndrome. In: Science. 2008 ; Vol. 321, No. 5890. pp. 839-843.
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abstract = "Duane's retraction syndrome (DRS) is a complex congenital eye movement disorder caused by aberrant innervation of the extraocular muscles by axons of brainstem motor neurons. Studying families with a variant form of the disorder (DURS2-DRS), we have identified causative heterozygous missense mutations in CHN1, a gene on chromosome 2q31 that encodes alpha2-chimaerin, a Rac guanosine triphosphatase-activating protein (RacGAP) signaling protein previously implicated in the pathfinding of corticospinal axons in mice. We found that these are gain-of-function mutations that increase alpha2-chimaerin RacGAP activity in vitro. Several of the mutations appeared to enhance alpha2-chimaerin translocation to the cell membrane or enhance its ability to self-associate. Expression of mutant alpha2-chimaerin constructs in chick embryos resulted in failure of oculomotor axons to innervate their target extraocular muscles. We conclude that alpha2-chimaerin has a critical developmental function in ocular motor axon pathfinding.",
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AU - Miyake, Noriko

AU - Chilton, John

AU - Psatha, Maria

AU - Cheng, Long

AU - Andrews, Stuart Christopher

AU - Chan, Wai-Man

AU - Law, Krystal

AU - Crosier, Moira

AU - Lindsay, Sandra

AU - Cheung, Michelle

AU - Allen, James

AU - Gutowski, Nick J

AU - Ellard, Sian

AU - Young, Elizabeth Iona Margaret

AU - Iannaccone, Alessandro

AU - Appukuttan, Binoy

AU - Stout, J Timothy

AU - Christiansen, Stephen

AU - Ciccarelli, Maria Laura

AU - Baldi, Alfonso

AU - Campioni, Mara

AU - Zenteno, Juan C

AU - Davenport, Dominic

AU - Mariani, Laura E

AU - Sahin, Mustafa

AU - Guthrie, Sarah

AU - Engle, Elizabeth C

PY - 2008/8/8

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N2 - Duane's retraction syndrome (DRS) is a complex congenital eye movement disorder caused by aberrant innervation of the extraocular muscles by axons of brainstem motor neurons. Studying families with a variant form of the disorder (DURS2-DRS), we have identified causative heterozygous missense mutations in CHN1, a gene on chromosome 2q31 that encodes alpha2-chimaerin, a Rac guanosine triphosphatase-activating protein (RacGAP) signaling protein previously implicated in the pathfinding of corticospinal axons in mice. We found that these are gain-of-function mutations that increase alpha2-chimaerin RacGAP activity in vitro. Several of the mutations appeared to enhance alpha2-chimaerin translocation to the cell membrane or enhance its ability to self-associate. Expression of mutant alpha2-chimaerin constructs in chick embryos resulted in failure of oculomotor axons to innervate their target extraocular muscles. We conclude that alpha2-chimaerin has a critical developmental function in ocular motor axon pathfinding.

AB - Duane's retraction syndrome (DRS) is a complex congenital eye movement disorder caused by aberrant innervation of the extraocular muscles by axons of brainstem motor neurons. Studying families with a variant form of the disorder (DURS2-DRS), we have identified causative heterozygous missense mutations in CHN1, a gene on chromosome 2q31 that encodes alpha2-chimaerin, a Rac guanosine triphosphatase-activating protein (RacGAP) signaling protein previously implicated in the pathfinding of corticospinal axons in mice. We found that these are gain-of-function mutations that increase alpha2-chimaerin RacGAP activity in vitro. Several of the mutations appeared to enhance alpha2-chimaerin translocation to the cell membrane or enhance its ability to self-associate. Expression of mutant alpha2-chimaerin constructs in chick embryos resulted in failure of oculomotor axons to innervate their target extraocular muscles. We conclude that alpha2-chimaerin has a critical developmental function in ocular motor axon pathfinding.

KW - Abducens Nerve

KW - Amino Acid Sequence

KW - Animals

KW - Axons

KW - Cell Line

KW - Cell Membrane

KW - Chick Embryo

KW - Chimerin 1

KW - Duane Retraction Syndrome

KW - Female

KW - Gene Expression Profiling

KW - Heterozygote

KW - Humans

KW - Male

KW - Molecular Sequence Data

KW - Mutation, Missense

KW - Oculomotor Muscles

KW - Oculomotor Nerve

KW - Pedigree

U2 - 10.1126/science.1156121

DO - 10.1126/science.1156121

M3 - Article

VL - 321

SP - 839

EP - 843

JO - Science

JF - Science

SN - 0036-8075

IS - 5890

ER -