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

Research output: Contribution to journalArticle

30 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 languageEnglish
Pages (from-to)905-914
Number of pages10
JournalAmerican Journal of Human Genetics
Volume94
Issue number6
DOIs
Publication statusPublished - 2014 Jun 5

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Intellectual Disability
Centrioles
Mutation
Cilia
Orofaciodigital Syndromes
Genes
Nervous System Malformations
Gene Components
Learning Disorders
Hydrocephalus
Exons
Central Nervous System
Fibroblasts
Kidney
Membranes
Ciliopathies
Nephronophthisis 2
Proteins

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Failler, Marion ; Gee, Heon Yung ; Krug, Pauline ; Joo, Kwangsic ; Halbritter, Jan ; Belkacem, Lilya ; Filhol, Emilie ; Porath, Jonathan D. ; Braun, Daniela A. ; Schueler, Markus ; Frigo, Amandine ; Alibeu, Olivier ; Masson, Cécile ; Brochard, Karine ; Hurault De Ligny, Bruno ; Novo, Robert ; Pietrement, Christine ; Kayserili, Hulya ; Salomon, Rémi ; Gubler, Marie Claire ; Otto, Edgar A. ; Antignac, Corinne ; Kim, Joon ; Benmerah, Alexandre ; Hildebrandt, Friedhelm ; Saunier, Sophie. / Mutations of CEP83 cause infantile nephronophthisis and intellectual disability. In: American Journal of Human Genetics. 2014 ; Vol. 94, No. 6. pp. 905-914.
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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",
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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

Mutations of CEP83 cause infantile nephronophthisis and intellectual disability. / Failler, Marion; Gee, Heon Yung; Krug, Pauline; Joo, Kwangsic; Halbritter, Jan; Belkacem, Lilya; Filhol, Emilie; Porath, Jonathan D.; Braun, Daniela A.; Schueler, Markus; Frigo, Amandine; Alibeu, Olivier; Masson, Cécile; Brochard, Karine; Hurault De Ligny, Bruno; Novo, Robert; Pietrement, Christine; Kayserili, Hulya; Salomon, Rémi; Gubler, Marie Claire; Otto, Edgar A.; Antignac, Corinne; Kim, Joon; Benmerah, Alexandre; Hildebrandt, Friedhelm; Saunier, Sophie.

In: American Journal of Human Genetics, Vol. 94, No. 6, 05.06.2014, p. 905-914.

Research output: Contribution to journalArticle

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

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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