Mutations of CEP83 cause infantile nephronophthisis and intellectual disability

Marion Failler; Heon Yung Gee; Pauline Krug; Kwangsic Joo; Jan Halbritter; Lilya Belkacem; Emilie Filhol; Jonathan D. Porath; Daniela A. Braun; Markus Schueler; Amandine Frigo; Olivier Alibeu; Cécile Masson; Karine Brochard; Bruno Hurault De Ligny; Robert Novo; Christine Pietrement; Hulya Kayserili; Rémi Salomon; Marie Claire Gubler; Edgar A. Otto; Corinne Antignac; Joon Kim; Alexandre Benmerah; Friedhelm Hildebrandt; Sophie Saunier

doi:10.1016/j.ajhg.2014.05.002

Mutations of CEP83 cause infantile nephronophthisis and intellectual disability

Marion Failler, Heon Yung Gee, Pauline Krug, Kwangsic Joo, Jan Halbritter, Lilya Belkacem, Emilie Filhol, Jonathan D. Porath, Daniela A. Braun, Markus Schueler, Amandine Frigo, Olivier Alibeu, Cécile Masson, Karine Brochard, Bruno Hurault De Ligny, Robert Novo, Christine Pietrement, Hulya Kayserili, Rémi Salomon, Marie Claire GublerEdgar A. Otto, Corinne Antignac, Joon Kim, Alexandre Benmerah, Friedhelm Hildebrandt, Sophie Saunier

Department of Pharmacology

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

70 Citations (Scopus)

Abstract

Ciliopathies are a group of hereditary disorders associated with defects in cilia structure and function. The distal appendages (DAPs) of centrioles are involved in the docking and anchoring of the mother centriole to the cellular membrane during ciliogenesis. The molecular composition of DAPs was recently elucidated and mutations in two genes encoding DAPs components (CEP164/NPHP15, SCLT1) have been associated with human ciliopathies, namely nephronophthisis and orofaciodigital syndrome. To identify additional DAP components defective in ciliopathies, we independently performed targeted exon sequencing of 1,221 genes associated with cilia and 5 known DAP protein-encoding genes in 1,255 individuals with a nephronophthisis-related ciliopathy. We thereby detected biallelic mutations in a key component of DAP-encoding gene, CEP83, in seven families. All affected individuals had early-onset nephronophthisis and four out of eight displayed learning disability and/or hydrocephalus. Fibroblasts and tubular renal cells from affected individuals showed an altered DAP composition and ciliary defects. In summary, we have identified mutations in CEP83, another DAP-component-encoding gene, as a cause of infantile nephronophthisis associated with central nervous system abnormalities in half of the individuals.

Original language	English
Pages (from-to)	905-914
Number of pages	10
Journal	American Journal of Human Genetics
Volume	94
Issue number	6
DOIs	https://doi.org/10.1016/j.ajhg.2014.05.002
Publication status	Published - 2014 Jun 5

Bibliographical note

Funding Information:
The authors thank the families who contributed to this study. We thank Vivette D. D’Agati and Michael B. Stokes (Columbia University) for a kidney biopsy report and images, as well as Gérard Pivert (Pathology Department, Necker Hospital) for kidney biopsy. We are grateful to James Sillibourne for his kind gift of the CEP89 antibody. We also thank Patrick Nitschké and the bioinformatic Plateform (Université Paris Descartes, Institut Imagine) as well as Christine Bole-Feysot, Solenn Pruvost, and Mohammed Zarhrate for their support in exome sequencing and Ludovic Lecompte and Lucie Sengmanivong from the Nikon Imaging Centre at Institut Curie-CNRS (Paris, France) for the help with the n-SIM. This research was supported by a grant from the NIH to F.H. (DK068306). H.Y.G. is a Research Fellow of the American Society of Nephrology (ASN). F.H. is an Investigator of the Howard Hughes Medical Institute and Warren E. Grupe Professor of Pediatrics at the Harvard Medical School. This work was supported by grants from the “Agence Nationale de la Recherche” (ANR) to S.S. (20100BLAN112202) and investments for the future program-ANR-10-IAHY-01 to S.S., the “Fondation pour la Recherche Médicale” (FRM) to S.S. (DEQ20071210558) and to P.K. (DEA20120624188); M.F. is supported by a fellowship from the “Région ile de France, CORDDIM” (RPH12173KKA).

All Science Journal Classification (ASJC) codes

Genetics
Genetics(clinical)

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10.1016/j.ajhg.2014.05.002

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Failler, M., Gee, H. Y., Krug, P., Joo, K., Halbritter, J., Belkacem, L., Filhol, E., Porath, J. D., Braun, D. A., Schueler, M., Frigo, A., Alibeu, O., Masson, C., Brochard, K., Hurault De Ligny, B., Novo, R., Pietrement, C., Kayserili, H., Salomon, R., ... Saunier, S. (2014). Mutations of CEP83 cause infantile nephronophthisis and intellectual disability. American Journal of Human Genetics, 94(6), 905-914. https://doi.org/10.1016/j.ajhg.2014.05.002

@article{230003a188c84e30b513fae087cf3a4b,

title = "Mutations of CEP83 cause infantile nephronophthisis and intellectual disability",

abstract = "Ciliopathies are a group of hereditary disorders associated with defects in cilia structure and function. The distal appendages (DAPs) of centrioles are involved in the docking and anchoring of the mother centriole to the cellular membrane during ciliogenesis. The molecular composition of DAPs was recently elucidated and mutations in two genes encoding DAPs components (CEP164/NPHP15, SCLT1) have been associated with human ciliopathies, namely nephronophthisis and orofaciodigital syndrome. To identify additional DAP components defective in ciliopathies, we independently performed targeted exon sequencing of 1,221 genes associated with cilia and 5 known DAP protein-encoding genes in 1,255 individuals with a nephronophthisis-related ciliopathy. We thereby detected biallelic mutations in a key component of DAP-encoding gene, CEP83, in seven families. All affected individuals had early-onset nephronophthisis and four out of eight displayed learning disability and/or hydrocephalus. Fibroblasts and tubular renal cells from affected individuals showed an altered DAP composition and ciliary defects. In summary, we have identified mutations in CEP83, another DAP-component-encoding gene, as a cause of infantile nephronophthisis associated with central nervous system abnormalities in half of the individuals.",

author = "Marion Failler and Gee, {Heon Yung} and Pauline Krug and Kwangsic Joo and Jan Halbritter and Lilya Belkacem and Emilie Filhol and Porath, {Jonathan D.} and Braun, {Daniela A.} and Markus Schueler and Amandine Frigo and Olivier Alibeu and C{\'e}cile Masson and Karine Brochard and {Hurault De Ligny}, Bruno and Robert Novo and Christine Pietrement and Hulya Kayserili and R{\'e}mi Salomon and Gubler, {Marie Claire} and Otto, {Edgar A.} and Corinne Antignac and Joon Kim and Alexandre Benmerah and Friedhelm Hildebrandt and Sophie Saunier",

note = "Funding Information: The authors thank the families who contributed to this study. We thank Vivette D. D{\textquoteright}Agati and Michael B. Stokes (Columbia University) for a kidney biopsy report and images, as well as G{\'e}rard Pivert (Pathology Department, Necker Hospital) for kidney biopsy. We are grateful to James Sillibourne for his kind gift of the CEP89 antibody. We also thank Patrick Nitschk{\'e} and the bioinformatic Plateform (Universit{\'e} Paris Descartes, Institut Imagine) as well as Christine Bole-Feysot, Solenn Pruvost, and Mohammed Zarhrate for their support in exome sequencing and Ludovic Lecompte and Lucie Sengmanivong from the Nikon Imaging Centre at Institut Curie-CNRS (Paris, France) for the help with the n-SIM. This research was supported by a grant from the NIH to F.H. (DK068306). H.Y.G. is a Research Fellow of the American Society of Nephrology (ASN). F.H. is an Investigator of the Howard Hughes Medical Institute and Warren E. Grupe Professor of Pediatrics at the Harvard Medical School. This work was supported by grants from the “Agence Nationale de la Recherche” (ANR) to S.S. (20100BLAN112202) and investments for the future program-ANR-10-IAHY-01 to S.S., the “Fondation pour la Recherche M{\'e}dicale” (FRM) to S.S. (DEQ20071210558) and to P.K. (DEA20120624188); M.F. is supported by a fellowship from the “R{\'e}gion ile de France, CORDDIM” (RPH12173KKA). ",

year = "2014",

month = jun,

day = "5",

doi = "10.1016/j.ajhg.2014.05.002",

language = "English",

volume = "94",

pages = "905--914",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "6",

}

Failler, M, Gee, HY, Krug, P, Joo, K, Halbritter, J, Belkacem, L, Filhol, E, Porath, JD, Braun, DA, Schueler, M, Frigo, A, Alibeu, O, Masson, C, Brochard, K, Hurault De Ligny, B, Novo, R, Pietrement, C, Kayserili, H, Salomon, R, Gubler, MC, Otto, EA, Antignac, C, Kim, J, Benmerah, A, Hildebrandt, F & Saunier, S 2014, 'Mutations of CEP83 cause infantile nephronophthisis and intellectual disability', American Journal of Human Genetics, vol. 94, no. 6, pp. 905-914. https://doi.org/10.1016/j.ajhg.2014.05.002

TY - JOUR

T1 - Mutations of CEP83 cause infantile nephronophthisis and intellectual disability

AU - Failler, Marion

AU - Gee, Heon Yung

AU - Krug, Pauline

AU - Joo, Kwangsic

AU - Halbritter, Jan

AU - Belkacem, Lilya

AU - Filhol, Emilie

AU - Porath, Jonathan D.

AU - Braun, Daniela A.

AU - Schueler, Markus

AU - Frigo, Amandine

AU - Alibeu, Olivier

AU - Masson, Cécile

AU - Brochard, Karine

AU - Hurault De Ligny, Bruno

AU - Novo, Robert

AU - Pietrement, Christine

AU - Kayserili, Hulya

AU - Salomon, Rémi

AU - Gubler, Marie Claire

AU - Otto, Edgar A.

AU - Antignac, Corinne

AU - Kim, Joon

AU - Benmerah, Alexandre

AU - Hildebrandt, Friedhelm

AU - Saunier, Sophie

N1 - Funding Information: The authors thank the families who contributed to this study. We thank Vivette D. D’Agati and Michael B. Stokes (Columbia University) for a kidney biopsy report and images, as well as Gérard Pivert (Pathology Department, Necker Hospital) for kidney biopsy. We are grateful to James Sillibourne for his kind gift of the CEP89 antibody. We also thank Patrick Nitschké and the bioinformatic Plateform (Université Paris Descartes, Institut Imagine) as well as Christine Bole-Feysot, Solenn Pruvost, and Mohammed Zarhrate for their support in exome sequencing and Ludovic Lecompte and Lucie Sengmanivong from the Nikon Imaging Centre at Institut Curie-CNRS (Paris, France) for the help with the n-SIM. This research was supported by a grant from the NIH to F.H. (DK068306). H.Y.G. is a Research Fellow of the American Society of Nephrology (ASN). F.H. is an Investigator of the Howard Hughes Medical Institute and Warren E. Grupe Professor of Pediatrics at the Harvard Medical School. This work was supported by grants from the “Agence Nationale de la Recherche” (ANR) to S.S. (20100BLAN112202) and investments for the future program-ANR-10-IAHY-01 to S.S., the “Fondation pour la Recherche Médicale” (FRM) to S.S. (DEQ20071210558) and to P.K. (DEA20120624188); M.F. is supported by a fellowship from the “Région ile de France, CORDDIM” (RPH12173KKA).

PY - 2014/6/5

Y1 - 2014/6/5

N2 - Ciliopathies are a group of hereditary disorders associated with defects in cilia structure and function. The distal appendages (DAPs) of centrioles are involved in the docking and anchoring of the mother centriole to the cellular membrane during ciliogenesis. The molecular composition of DAPs was recently elucidated and mutations in two genes encoding DAPs components (CEP164/NPHP15, SCLT1) have been associated with human ciliopathies, namely nephronophthisis and orofaciodigital syndrome. To identify additional DAP components defective in ciliopathies, we independently performed targeted exon sequencing of 1,221 genes associated with cilia and 5 known DAP protein-encoding genes in 1,255 individuals with a nephronophthisis-related ciliopathy. We thereby detected biallelic mutations in a key component of DAP-encoding gene, CEP83, in seven families. All affected individuals had early-onset nephronophthisis and four out of eight displayed learning disability and/or hydrocephalus. Fibroblasts and tubular renal cells from affected individuals showed an altered DAP composition and ciliary defects. In summary, we have identified mutations in CEP83, another DAP-component-encoding gene, as a cause of infantile nephronophthisis associated with central nervous system abnormalities in half of the individuals.

AB - Ciliopathies are a group of hereditary disorders associated with defects in cilia structure and function. The distal appendages (DAPs) of centrioles are involved in the docking and anchoring of the mother centriole to the cellular membrane during ciliogenesis. The molecular composition of DAPs was recently elucidated and mutations in two genes encoding DAPs components (CEP164/NPHP15, SCLT1) have been associated with human ciliopathies, namely nephronophthisis and orofaciodigital syndrome. To identify additional DAP components defective in ciliopathies, we independently performed targeted exon sequencing of 1,221 genes associated with cilia and 5 known DAP protein-encoding genes in 1,255 individuals with a nephronophthisis-related ciliopathy. We thereby detected biallelic mutations in a key component of DAP-encoding gene, CEP83, in seven families. All affected individuals had early-onset nephronophthisis and four out of eight displayed learning disability and/or hydrocephalus. Fibroblasts and tubular renal cells from affected individuals showed an altered DAP composition and ciliary defects. In summary, we have identified mutations in CEP83, another DAP-component-encoding gene, as a cause of infantile nephronophthisis associated with central nervous system abnormalities in half of the individuals.

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DO - 10.1016/j.ajhg.2014.05.002

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SP - 905

EP - 914

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 6

ER -

Mutations of CEP83 cause infantile nephronophthisis and intellectual disability

Abstract

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