TMEM237 is mutated in individuals with a Joubert syndrome related disorder and expands the role of the TMEM family at the ciliary transition zone

Lijia Huang; Katarzyna Szymanska; Victor L. Jensen; Andreas R. Janecke; A. Micheil Innes; Erica Ellen Davis; Patrick Frosk; Chunmei Li; Jason R. Willer; Bernard N. Chodirker; Cheryl R. Greenberg; D. Ross McLeod; Francois P. Bernier; Albert E. Chudley; Thomas Müller; Mohammad Shboul; Clare V. Logan; Catrina M. Loucks; Chandree L. Beaulieu; Rachel V. Bowie; Sandra M. Bell; Jonathan Adkins; Freddi I. Zuniga; Kevin D. Ross; Jian Wang; Matthew R. Ban; Christian Becker; Peter Nürnberg; Stuart Douglas; Cheryl M. Craft; Marie Andree Akimenko; Robert A. Hegele; Carole Ober; Gerd Utermann; Hanno J. Bolz; Dennis E. Bulman; Elias Nicholas Katsanis; Oliver E. Blacque; Dan Doherty; Jillian S. Parboosingh; Michel R. Leroux; Colin A. Johnson; Kym M. Boycott

doi:10.1016/j.ajhg.2011.11.005

TMEM237 is mutated in individuals with a Joubert syndrome related disorder and expands the role of the TMEM family at the ciliary transition zone

Lijia Huang, Katarzyna Szymanska, Victor L. Jensen, Andreas R. Janecke, A. Micheil Innes, Erica Ellen Davis, Patrick Frosk, Chunmei Li, Jason R. Willer, Bernard N. Chodirker, Cheryl R. Greenberg, D. Ross McLeod, Francois P. Bernier, Albert E. Chudley, Thomas Müller, Mohammad Shboul, Clare V. Logan, Catrina M. Loucks, Chandree L. Beaulieu, Rachel V. BowieSandra M. Bell, Jonathan Adkins, Freddi I. Zuniga, Kevin D. Ross, Jian Wang, Matthew R. Ban, Christian Becker, Peter Nürnberg, Stuart Douglas, Cheryl M. Craft, Marie Andree Akimenko, Robert A. Hegele, Carole Ober, Gerd Utermann, Hanno J. Bolz, Dennis E. Bulman, Elias Nicholas Katsanis, Oliver E. Blacque, Dan Doherty, Jillian S. Parboosingh, Michel R. Leroux^*, Colin A. Johnson, Kym M. Boycott

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

160 Scopus citations

Abstract

Joubert syndrome related disorders (JSRDs) have broad but variable phenotypic overlap with other ciliopathies. The molecular etiology of this overlap is unclear but probably arises from disrupting common functional module components within primary cilia. To identify additional module elements associated with JSRDs, we performed homozygosity mapping followed by next-generation sequencing (NGS) and uncovered mutations in TMEM237 (previously known as ALS2CR4). We show that loss of the mammalian TMEM237, which localizes to the ciliary transition zone (TZ), results in defective ciliogenesis and deregulation of Wnt signaling. Furthermore, disruption of Danio rerio (zebrafish) tmem237 expression produces gastrulation defects consistent with ciliary dysfunction, and Caenorhabditis elegans jbts-14 genetically interacts with nphp-4, encoding another TZ protein, to control basal body-TZ anchoring to the membrane and ciliogenesis. Both mammalian and C. elegans TMEM237/JBTS-14 require RPGRIP1L/MKS5 for proper TZ localization, and we demonstrate additional functional interactions between C. elegans JBTS-14 and MKS-2/TMEM216, MKSR-1/B9D1, and MKSR-2/B9D2. Collectively, our findings integrate TMEM237/JBTS-14 in a complex interaction network of TZ-associated proteins and reveal a growing contribution of a TZ functional module to the spectrum of ciliopathy phenotypes.

Original language	English (US)
Pages (from-to)	713-730
Number of pages	18
Journal	American journal of human genetics
Volume	89
Issue number	6
DOIs	https://doi.org/10.1016/j.ajhg.2011.11.005
State	Published - Dec 9 2011

Funding

We thank the families for participation in this study, L. Racacho (D.E.B.) and J. Zhang (M.-A.A.) for technical support, R.T. Moon at University of Washington for the Topflash and Fopflash constructs, and D.G. Moerman (University of British Columbia; funded by Genome Canada, Genome British Columbia, and Canadian Insitutes of Health Research [CIHR]) and R. Waterston (University of Washington; funded by American Recovery and Reinvestment Act grant HG 005921 from the National Human Genome Research Institute) for the C. elegans jbts-14 mutant strain. V.L.J. was supported by a postdoctoral fellowship from the Michael Smith Foundation for Health Research (MSFHR). A.R.J. received funding from the Austrian Science Foundation (FWF grant P18470) and the Dr.-Legerlotz foundation Austria. E.E.D. is supported by National Institutes of Health (NIH) grant R01EY021872. P.F. and C.M.L. were supported by the Canadian Insitutes of Health Research (CIHR) Training Program in Genetics, Child Development, and Health. T.M. received funding from the Tiroler Wissenschaftsfonds. C.M.C. is the Mary D. Allen Chair and acknowledges funding from NIH EY015851, EY03040, 1F31GM079910, and Research to Prevent Blindness. H.J.B. received funding from the Gertrud-Kusen-Stiftung. N.K. acknowledges funding from NIH R01HD04260, R01DK072301, and R01DK075972 and is the Distinguished George W. Brumley Professor. O.E.B. acknowledges a Science Foundation Ireland President of Ireland Young Researcher Award (06/Y12/B928). D.D. is funded by the NIH grants KL2RR025015 and R01NS064077. J.S.P acknowledges funding from the Alberta Children's Hospital Foundation. M.R.L. is funded by the March of Dimes and a senior scholar award from the MSFHR. C.A.J. acknowledges funding from a Sir Jules Thorn Charitable Trust Biomedical Research Award (09/JTA). C.A.J. and N.K. are supported by the European Community's Seventh Framework Programme FP7/2009 under grant agreement 241955, SYSCILIA. K.M.B. is funded by the SickKids Foundation/CIHR IHDCYH (NI10-008), and a Clinical Investigatorship Award from the CIHR Institute of Genetics.

ASJC Scopus subject areas

Genetics(clinical)
Genetics

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10.1016/j.ajhg.2011.11.005

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Huang, L., Szymanska, K., Jensen, V. L., Janecke, A. R., Innes, A. M., Davis, E. E., Frosk, P., Li, C., Willer, J. R., Chodirker, B. N., Greenberg, C. R., McLeod, D. R., Bernier, F. P., Chudley, A. E., Müller, T., Shboul, M., Logan, C. V., Loucks, C. M., Beaulieu, C. L., ... Boycott, K. M. (2011). TMEM237 is mutated in individuals with a Joubert syndrome related disorder and expands the role of the TMEM family at the ciliary transition zone. American journal of human genetics, 89(6), 713-730. https://doi.org/10.1016/j.ajhg.2011.11.005

@article{b6eccc8fbf714e429b0a155622f89d55,

title = "TMEM237 is mutated in individuals with a Joubert syndrome related disorder and expands the role of the TMEM family at the ciliary transition zone",

abstract = "Joubert syndrome related disorders (JSRDs) have broad but variable phenotypic overlap with other ciliopathies. The molecular etiology of this overlap is unclear but probably arises from disrupting common functional module components within primary cilia. To identify additional module elements associated with JSRDs, we performed homozygosity mapping followed by next-generation sequencing (NGS) and uncovered mutations in TMEM237 (previously known as ALS2CR4). We show that loss of the mammalian TMEM237, which localizes to the ciliary transition zone (TZ), results in defective ciliogenesis and deregulation of Wnt signaling. Furthermore, disruption of Danio rerio (zebrafish) tmem237 expression produces gastrulation defects consistent with ciliary dysfunction, and Caenorhabditis elegans jbts-14 genetically interacts with nphp-4, encoding another TZ protein, to control basal body-TZ anchoring to the membrane and ciliogenesis. Both mammalian and C. elegans TMEM237/JBTS-14 require RPGRIP1L/MKS5 for proper TZ localization, and we demonstrate additional functional interactions between C. elegans JBTS-14 and MKS-2/TMEM216, MKSR-1/B9D1, and MKSR-2/B9D2. Collectively, our findings integrate TMEM237/JBTS-14 in a complex interaction network of TZ-associated proteins and reveal a growing contribution of a TZ functional module to the spectrum of ciliopathy phenotypes.",

author = "Lijia Huang and Katarzyna Szymanska and Jensen, {Victor L.} and Janecke, {Andreas R.} and Innes, {A. Micheil} and Davis, {Erica Ellen} and Patrick Frosk and Chunmei Li and Willer, {Jason R.} and Chodirker, {Bernard N.} and Greenberg, {Cheryl R.} and McLeod, {D. Ross} and Bernier, {Francois P.} and Chudley, {Albert E.} and Thomas M{\"u}ller and Mohammad Shboul and Logan, {Clare V.} and Loucks, {Catrina M.} and Beaulieu, {Chandree L.} and Bowie, {Rachel V.} and Bell, {Sandra M.} and Jonathan Adkins and Zuniga, {Freddi I.} and Ross, {Kevin D.} and Jian Wang and Ban, {Matthew R.} and Christian Becker and Peter N{\"u}rnberg and Stuart Douglas and Craft, {Cheryl M.} and Akimenko, {Marie Andree} and Hegele, {Robert A.} and Carole Ober and Gerd Utermann and Bolz, {Hanno J.} and Bulman, {Dennis E.} and Katsanis, {Elias Nicholas} and Blacque, {Oliver E.} and Dan Doherty and Parboosingh, {Jillian S.} and Leroux, {Michel R.} and Johnson, {Colin A.} and Boycott, {Kym M.}",

note = "Funding Information: We thank the families for participation in this study, L. Racacho (D.E.B.) and J. Zhang (M.-A.A.) for technical support, R.T. Moon at University of Washington for the Topflash and Fopflash constructs, and D.G. Moerman (University of British Columbia; funded by Genome Canada, Genome British Columbia, and Canadian Insitutes of Health Research [CIHR]) and R. Waterston (University of Washington; funded by American Recovery and Reinvestment Act grant HG 005921 from the National Human Genome Research Institute) for the C. elegans jbts-14 mutant strain. V.L.J. was supported by a postdoctoral fellowship from the Michael Smith Foundation for Health Research (MSFHR). A.R.J. received funding from the Austrian Science Foundation (FWF grant P18470) and the Dr.-Legerlotz foundation Austria. E.E.D. is supported by National Institutes of Health (NIH) grant R01EY021872. P.F. and C.M.L. were supported by the Canadian Insitutes of Health Research (CIHR) Training Program in Genetics, Child Development, and Health. T.M. received funding from the Tiroler Wissenschaftsfonds. C.M.C. is the Mary D. Allen Chair and acknowledges funding from NIH EY015851, EY03040, 1F31GM079910, and Research to Prevent Blindness. H.J.B. received funding from the Gertrud-Kusen-Stiftung. N.K. acknowledges funding from NIH R01HD04260, R01DK072301, and R01DK075972 and is the Distinguished George W. Brumley Professor. O.E.B. acknowledges a Science Foundation Ireland President of Ireland Young Researcher Award (06/Y12/B928). D.D. is funded by the NIH grants KL2RR025015 and R01NS064077. J.S.P acknowledges funding from the Alberta Children's Hospital Foundation. M.R.L. is funded by the March of Dimes and a senior scholar award from the MSFHR. C.A.J. acknowledges funding from a Sir Jules Thorn Charitable Trust Biomedical Research Award (09/JTA). C.A.J. and N.K. are supported by the European Community's Seventh Framework Programme FP7/2009 under grant agreement 241955, SYSCILIA. K.M.B. is funded by the SickKids Foundation/CIHR IHDCYH (NI10-008), and a Clinical Investigatorship Award from the CIHR Institute of Genetics. ",

year = "2011",

month = dec,

day = "9",

doi = "10.1016/j.ajhg.2011.11.005",

language = "English (US)",

volume = "89",

pages = "713--730",

journal = "American journal of human genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "6",

}

Huang, L, Szymanska, K, Jensen, VL, Janecke, AR, Innes, AM, Davis, EE, Frosk, P, Li, C, Willer, JR, Chodirker, BN, Greenberg, CR, McLeod, DR, Bernier, FP, Chudley, AE, Müller, T, Shboul, M, Logan, CV, Loucks, CM, Beaulieu, CL, Bowie, RV, Bell, SM, Adkins, J, Zuniga, FI, Ross, KD, Wang, J, Ban, MR, Becker, C, Nürnberg, P, Douglas, S, Craft, CM, Akimenko, MA, Hegele, RA, Ober, C, Utermann, G, Bolz, HJ, Bulman, DE, Katsanis, EN, Blacque, OE, Doherty, D, Parboosingh, JS, Leroux, MR, Johnson, CA & Boycott, KM 2011, 'TMEM237 is mutated in individuals with a Joubert syndrome related disorder and expands the role of the TMEM family at the ciliary transition zone', American journal of human genetics, vol. 89, no. 6, pp. 713-730. https://doi.org/10.1016/j.ajhg.2011.11.005

TY - JOUR

T1 - TMEM237 is mutated in individuals with a Joubert syndrome related disorder and expands the role of the TMEM family at the ciliary transition zone

AU - Huang, Lijia

AU - Szymanska, Katarzyna

AU - Jensen, Victor L.

AU - Janecke, Andreas R.

AU - Innes, A. Micheil

AU - Davis, Erica Ellen

AU - Frosk, Patrick

AU - Li, Chunmei

AU - Willer, Jason R.

AU - Chodirker, Bernard N.

AU - Greenberg, Cheryl R.

AU - McLeod, D. Ross

AU - Bernier, Francois P.

AU - Chudley, Albert E.

AU - Müller, Thomas

AU - Shboul, Mohammad

AU - Logan, Clare V.

AU - Loucks, Catrina M.

AU - Beaulieu, Chandree L.

AU - Bowie, Rachel V.

AU - Bell, Sandra M.

AU - Adkins, Jonathan

AU - Zuniga, Freddi I.

AU - Ross, Kevin D.

AU - Wang, Jian

AU - Ban, Matthew R.

AU - Becker, Christian

AU - Nürnberg, Peter

AU - Douglas, Stuart

AU - Craft, Cheryl M.

AU - Akimenko, Marie Andree

AU - Hegele, Robert A.

AU - Ober, Carole

AU - Utermann, Gerd

AU - Bolz, Hanno J.

AU - Bulman, Dennis E.

AU - Katsanis, Elias Nicholas

AU - Blacque, Oliver E.

AU - Doherty, Dan

AU - Parboosingh, Jillian S.

AU - Leroux, Michel R.

AU - Johnson, Colin A.

AU - Boycott, Kym M.

N1 - Funding Information: We thank the families for participation in this study, L. Racacho (D.E.B.) and J. Zhang (M.-A.A.) for technical support, R.T. Moon at University of Washington for the Topflash and Fopflash constructs, and D.G. Moerman (University of British Columbia; funded by Genome Canada, Genome British Columbia, and Canadian Insitutes of Health Research [CIHR]) and R. Waterston (University of Washington; funded by American Recovery and Reinvestment Act grant HG 005921 from the National Human Genome Research Institute) for the C. elegans jbts-14 mutant strain. V.L.J. was supported by a postdoctoral fellowship from the Michael Smith Foundation for Health Research (MSFHR). A.R.J. received funding from the Austrian Science Foundation (FWF grant P18470) and the Dr.-Legerlotz foundation Austria. E.E.D. is supported by National Institutes of Health (NIH) grant R01EY021872. P.F. and C.M.L. were supported by the Canadian Insitutes of Health Research (CIHR) Training Program in Genetics, Child Development, and Health. T.M. received funding from the Tiroler Wissenschaftsfonds. C.M.C. is the Mary D. Allen Chair and acknowledges funding from NIH EY015851, EY03040, 1F31GM079910, and Research to Prevent Blindness. H.J.B. received funding from the Gertrud-Kusen-Stiftung. N.K. acknowledges funding from NIH R01HD04260, R01DK072301, and R01DK075972 and is the Distinguished George W. Brumley Professor. O.E.B. acknowledges a Science Foundation Ireland President of Ireland Young Researcher Award (06/Y12/B928). D.D. is funded by the NIH grants KL2RR025015 and R01NS064077. J.S.P acknowledges funding from the Alberta Children's Hospital Foundation. M.R.L. is funded by the March of Dimes and a senior scholar award from the MSFHR. C.A.J. acknowledges funding from a Sir Jules Thorn Charitable Trust Biomedical Research Award (09/JTA). C.A.J. and N.K. are supported by the European Community's Seventh Framework Programme FP7/2009 under grant agreement 241955, SYSCILIA. K.M.B. is funded by the SickKids Foundation/CIHR IHDCYH (NI10-008), and a Clinical Investigatorship Award from the CIHR Institute of Genetics.

PY - 2011/12/9

Y1 - 2011/12/9

N2 - Joubert syndrome related disorders (JSRDs) have broad but variable phenotypic overlap with other ciliopathies. The molecular etiology of this overlap is unclear but probably arises from disrupting common functional module components within primary cilia. To identify additional module elements associated with JSRDs, we performed homozygosity mapping followed by next-generation sequencing (NGS) and uncovered mutations in TMEM237 (previously known as ALS2CR4). We show that loss of the mammalian TMEM237, which localizes to the ciliary transition zone (TZ), results in defective ciliogenesis and deregulation of Wnt signaling. Furthermore, disruption of Danio rerio (zebrafish) tmem237 expression produces gastrulation defects consistent with ciliary dysfunction, and Caenorhabditis elegans jbts-14 genetically interacts with nphp-4, encoding another TZ protein, to control basal body-TZ anchoring to the membrane and ciliogenesis. Both mammalian and C. elegans TMEM237/JBTS-14 require RPGRIP1L/MKS5 for proper TZ localization, and we demonstrate additional functional interactions between C. elegans JBTS-14 and MKS-2/TMEM216, MKSR-1/B9D1, and MKSR-2/B9D2. Collectively, our findings integrate TMEM237/JBTS-14 in a complex interaction network of TZ-associated proteins and reveal a growing contribution of a TZ functional module to the spectrum of ciliopathy phenotypes.

AB - Joubert syndrome related disorders (JSRDs) have broad but variable phenotypic overlap with other ciliopathies. The molecular etiology of this overlap is unclear but probably arises from disrupting common functional module components within primary cilia. To identify additional module elements associated with JSRDs, we performed homozygosity mapping followed by next-generation sequencing (NGS) and uncovered mutations in TMEM237 (previously known as ALS2CR4). We show that loss of the mammalian TMEM237, which localizes to the ciliary transition zone (TZ), results in defective ciliogenesis and deregulation of Wnt signaling. Furthermore, disruption of Danio rerio (zebrafish) tmem237 expression produces gastrulation defects consistent with ciliary dysfunction, and Caenorhabditis elegans jbts-14 genetically interacts with nphp-4, encoding another TZ protein, to control basal body-TZ anchoring to the membrane and ciliogenesis. Both mammalian and C. elegans TMEM237/JBTS-14 require RPGRIP1L/MKS5 for proper TZ localization, and we demonstrate additional functional interactions between C. elegans JBTS-14 and MKS-2/TMEM216, MKSR-1/B9D1, and MKSR-2/B9D2. Collectively, our findings integrate TMEM237/JBTS-14 in a complex interaction network of TZ-associated proteins and reveal a growing contribution of a TZ functional module to the spectrum of ciliopathy phenotypes.

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DO - 10.1016/j.ajhg.2011.11.005

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AN - SCOPUS:83455253776

SN - 0002-9297

VL - 89

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EP - 730

JO - American journal of human genetics

JF - American journal of human genetics

IS - 6

ER -

TMEM237 is mutated in individuals with a Joubert syndrome related disorder and expands the role of the TMEM family at the ciliary transition zone

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