Mutations in CSPP1 lead to classical joubert syndrome

Naiara Akizu; Jennifer L. Silhavy; Rasim Ozgur Rosti; Eric Scott; Ali G. Fenstermaker; Jana Schroth; Maha S. Zaki; Henry Sanchez; Neerja Gupta; Madhulika Kabra; Majdi Kara; Tawfeg Ben-Omran; Basak Rosti; Alicia Guemez-Gamboa; Emily Spencer; Roger Pan; Na Cai; Mostafa Abdellateef; Stacey Gabriel; Jan Halbritter; Friedhelm Hildebrandt; Hans Van Bokhoven; Murat Gunel; Joseph G. Gleeson

doi:10.1016/j.ajhg.2013.11.015

Mutations in CSPP1 lead to classical joubert syndrome

Naiara Akizu, Jennifer L. Silhavy, Rasim Ozgur Rosti, Eric Scott, Ali G. Fenstermaker, Jana Schroth, Maha S. Zaki, Henry Sanchez, Neerja Gupta, Madhulika Kabra, Majdi Kara, Tawfeg Ben-Omran, Basak Rosti, Alicia Guemez-Gamboa, Emily Spencer, Roger Pan, Na Cai, Mostafa Abdellateef, Stacey Gabriel, Jan HalbritterFriedhelm Hildebrandt, Hans Van Bokhoven, Murat Gunel, Joseph G. Gleeson^*

^*Corresponding author for this work

Neuroscience

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

65 Scopus citations

Abstract

Joubert syndrome and related disorders (JSRDs) are genetically heterogeneous and characterized by a distinctive mid-hindbrain malformation. Causative mutations lead to primary cilia dysfunction, which often results in variable involvement of other organs such as the liver, retina, and kidney. We identified predicted null mutations in CSPP1 in six individuals affected by classical JSRDs. CSPP1 encodes a protein localized to centrosomes and spindle poles, as well as to the primary cilium. Despite the known interaction between CSPP1 and nephronophthisis-associated proteins, none of the affected individuals in our cohort presented with kidney disease, and further, screening of a large cohort of individuals with nephronophthisis demonstrated no mutations. CSPP1 is broadly expressed in neural tissue, and its encoded protein localizes to the primary cilium in an in vitro model of human neurogenesis. Here, we show abrogated protein levels and ciliogenesis in affected fibroblasts. Our data thus suggest that CSPP1 is involved in neural-specific functions of primary cilia.

Original language	English (US)
Pages (from-to)	80-86
Number of pages	7
Journal	American journal of human genetics
Volume	94
Issue number	1
DOIs	https://doi.org/10.1016/j.ajhg.2013.11.015
State	Published - Jan 2 2014

Funding

We thank the affected children and their families for their invaluable contributions to this study, supported by National Institutes of Health grants R01NS041537, R01NS048453, R01NS052455, P01HD070494, and P30NS047101 (J.G.G.) and DK068306 (F.H.), the Howard Hughes Medical Institute (J.G.G. and F.H.), and the California Institute of Regenerative Medicine (N.A.). We thank the Broad Institute (U54HG003067 to E. Lander), the Yale Center for Mendelian Disorders (U54HG006504 to R. Lifton and M. Gunel) for sequencing support, T. Caspary for ARL13B antibody, and J. Santini at the University of California, San Diego Neuroscience Microscopy Core. CSPP1 has been designated as JBTS21 by the HUGO Gene Nomenclature Committee.

ASJC Scopus subject areas

Genetics
Genetics(clinical)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ajhg.2013.11.015

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Akizu, N., Silhavy, J. L., Rosti, R. O., Scott, E., Fenstermaker, A. G., Schroth, J., Zaki, M. S., Sanchez, H., Gupta, N., Kabra, M., Kara, M., Ben-Omran, T., Rosti, B., Guemez-Gamboa, A., Spencer, E., Pan, R., Cai, N., Abdellateef, M., Gabriel, S., ... Gleeson, J. G. (2014). Mutations in CSPP1 lead to classical joubert syndrome. American journal of human genetics, 94(1), 80-86. https://doi.org/10.1016/j.ajhg.2013.11.015

@article{7fa11cbb76814ab29eafda1c839320a6,

title = "Mutations in CSPP1 lead to classical joubert syndrome",

abstract = "Joubert syndrome and related disorders (JSRDs) are genetically heterogeneous and characterized by a distinctive mid-hindbrain malformation. Causative mutations lead to primary cilia dysfunction, which often results in variable involvement of other organs such as the liver, retina, and kidney. We identified predicted null mutations in CSPP1 in six individuals affected by classical JSRDs. CSPP1 encodes a protein localized to centrosomes and spindle poles, as well as to the primary cilium. Despite the known interaction between CSPP1 and nephronophthisis-associated proteins, none of the affected individuals in our cohort presented with kidney disease, and further, screening of a large cohort of individuals with nephronophthisis demonstrated no mutations. CSPP1 is broadly expressed in neural tissue, and its encoded protein localizes to the primary cilium in an in vitro model of human neurogenesis. Here, we show abrogated protein levels and ciliogenesis in affected fibroblasts. Our data thus suggest that CSPP1 is involved in neural-specific functions of primary cilia.",

author = "Naiara Akizu and Silhavy, \{Jennifer L.\} and Rosti, \{Rasim Ozgur\} and Eric Scott and Fenstermaker, \{Ali G.\} and Jana Schroth and Zaki, \{Maha S.\} and Henry Sanchez and Neerja Gupta and Madhulika Kabra and Majdi Kara and Tawfeg Ben-Omran and Basak Rosti and Alicia Guemez-Gamboa and Emily Spencer and Roger Pan and Na Cai and Mostafa Abdellateef and Stacey Gabriel and Jan Halbritter and Friedhelm Hildebrandt and \{Van Bokhoven\}, Hans and Murat Gunel and Gleeson, \{Joseph G.\}",

note = "Funding Information: We thank the affected children and their families for their invaluable contributions to this study, supported by National Institutes of Health grants R01NS041537, R01NS048453, R01NS052455, P01HD070494, and P30NS047101 (J.G.G.) and DK068306 (F.H.), the Howard Hughes Medical Institute (J.G.G. and F.H.), and the California Institute of Regenerative Medicine (N.A.). We thank the Broad Institute (U54HG003067 to E. Lander), the Yale Center for Mendelian Disorders (U54HG006504 to R. Lifton and M. Gunel) for sequencing support, T. Caspary for ARL13B antibody, and J. Santini at the University of California, San Diego Neuroscience Microscopy Core. CSPP1 has been designated as JBTS21 by the HUGO Gene Nomenclature Committee. ",

year = "2014",

month = jan,

day = "2",

doi = "10.1016/j.ajhg.2013.11.015",

language = "English (US)",

volume = "94",

pages = "80--86",

journal = "American journal of human genetics",

issn = "0002-9297",

publisher = "Cell Press",

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}

Akizu, N, Silhavy, JL, Rosti, RO, Scott, E, Fenstermaker, AG, Schroth, J, Zaki, MS, Sanchez, H, Gupta, N, Kabra, M, Kara, M, Ben-Omran, T, Rosti, B, Guemez-Gamboa, A, Spencer, E, Pan, R, Cai, N, Abdellateef, M, Gabriel, S, Halbritter, J, Hildebrandt, F, Van Bokhoven, H, Gunel, M & Gleeson, JG 2014, 'Mutations in CSPP1 lead to classical joubert syndrome', American journal of human genetics, vol. 94, no. 1, pp. 80-86. https://doi.org/10.1016/j.ajhg.2013.11.015

TY - JOUR

T1 - Mutations in CSPP1 lead to classical joubert syndrome

AU - Akizu, Naiara

AU - Silhavy, Jennifer L.

AU - Rosti, Rasim Ozgur

AU - Scott, Eric

AU - Fenstermaker, Ali G.

AU - Schroth, Jana

AU - Zaki, Maha S.

AU - Sanchez, Henry

AU - Gupta, Neerja

AU - Kabra, Madhulika

AU - Kara, Majdi

AU - Ben-Omran, Tawfeg

AU - Rosti, Basak

AU - Guemez-Gamboa, Alicia

AU - Spencer, Emily

AU - Pan, Roger

AU - Cai, Na

AU - Abdellateef, Mostafa

AU - Gabriel, Stacey

AU - Halbritter, Jan

AU - Hildebrandt, Friedhelm

AU - Van Bokhoven, Hans

AU - Gunel, Murat

AU - Gleeson, Joseph G.

N1 - Funding Information: We thank the affected children and their families for their invaluable contributions to this study, supported by National Institutes of Health grants R01NS041537, R01NS048453, R01NS052455, P01HD070494, and P30NS047101 (J.G.G.) and DK068306 (F.H.), the Howard Hughes Medical Institute (J.G.G. and F.H.), and the California Institute of Regenerative Medicine (N.A.). We thank the Broad Institute (U54HG003067 to E. Lander), the Yale Center for Mendelian Disorders (U54HG006504 to R. Lifton and M. Gunel) for sequencing support, T. Caspary for ARL13B antibody, and J. Santini at the University of California, San Diego Neuroscience Microscopy Core. CSPP1 has been designated as JBTS21 by the HUGO Gene Nomenclature Committee.

PY - 2014/1/2

Y1 - 2014/1/2

N2 - Joubert syndrome and related disorders (JSRDs) are genetically heterogeneous and characterized by a distinctive mid-hindbrain malformation. Causative mutations lead to primary cilia dysfunction, which often results in variable involvement of other organs such as the liver, retina, and kidney. We identified predicted null mutations in CSPP1 in six individuals affected by classical JSRDs. CSPP1 encodes a protein localized to centrosomes and spindle poles, as well as to the primary cilium. Despite the known interaction between CSPP1 and nephronophthisis-associated proteins, none of the affected individuals in our cohort presented with kidney disease, and further, screening of a large cohort of individuals with nephronophthisis demonstrated no mutations. CSPP1 is broadly expressed in neural tissue, and its encoded protein localizes to the primary cilium in an in vitro model of human neurogenesis. Here, we show abrogated protein levels and ciliogenesis in affected fibroblasts. Our data thus suggest that CSPP1 is involved in neural-specific functions of primary cilia.

AB - Joubert syndrome and related disorders (JSRDs) are genetically heterogeneous and characterized by a distinctive mid-hindbrain malformation. Causative mutations lead to primary cilia dysfunction, which often results in variable involvement of other organs such as the liver, retina, and kidney. We identified predicted null mutations in CSPP1 in six individuals affected by classical JSRDs. CSPP1 encodes a protein localized to centrosomes and spindle poles, as well as to the primary cilium. Despite the known interaction between CSPP1 and nephronophthisis-associated proteins, none of the affected individuals in our cohort presented with kidney disease, and further, screening of a large cohort of individuals with nephronophthisis demonstrated no mutations. CSPP1 is broadly expressed in neural tissue, and its encoded protein localizes to the primary cilium in an in vitro model of human neurogenesis. Here, we show abrogated protein levels and ciliogenesis in affected fibroblasts. Our data thus suggest that CSPP1 is involved in neural-specific functions of primary cilia.

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UR - http://www.scopus.com/inward/citedby.url?scp=84891834962&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2013.11.015

DO - 10.1016/j.ajhg.2013.11.015

M3 - Article

C2 - 24360807

AN - SCOPUS:84891834962

SN - 0002-9297

VL - 94

SP - 80

EP - 86

JO - American journal of human genetics

JF - American journal of human genetics

IS - 1

ER -

Mutations in CSPP1 lead to classical joubert syndrome

Abstract

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UN SDGs

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