title: Mutations in IFT172 cause isolated retinal degeneration and Bardet-Biedl syndrome.
abstract: Primary cilia are sensory organelles present on most mammalian cells. The assembly and maintenance of primary cilia are facilitated by intraflagellar transport (IFT), a bidirectional protein trafficking along the cilium. Mutations in genes coding for IFT components have been associated with a group of diseases called ciliopathies. These genetic disorders can affect a variety of organs including the retina. Using whole exome sequencing in three families, we identified mutations in Intraflagellar Transport 172 Homolog [IFT172 (Chlamydomonas)] that underlie an isolated retinal degeneration and Bardet-Biedl syndrome. Extensive functional analyses of the identified mutations in cell culture, rat retina and in zebrafish demonstrated their hypomorphic or null nature. It has recently been reported that mutations in IFT172 cause a severe ciliopathy syndrome involving skeletal, renal, hepatic and retinal abnormalities (Jeune and Mainzer-Saldino syndromes). Here, we report for the first time that mutations in this gene can also lead to an isolated form of retinal degeneration. The functional data for the mutations can partially explain milder phenotypes; however, the involvement of modifying alleles in the IFT172-associated phenotypes cannot be excluded. These findings expand the spectrum of disease associated with mutations in IFT172 and suggest that mutations in genes originally reported to be associated with syndromic ciliopathies should also be considered in subjects with non-syndromic retinal dystrophy.
authors.affiliation: Ocular Genomics Institute, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114, USA Institut National de la Santé et de la Recherche Médicale U968, Paris 75012, France Sorbonne Universités, UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, Paris 75012, France Centre National de la Recherche Scientifique, UMR_7210, Paris 75012, France.
authors.forename: Kinga M
authors.initials: KM
authors.lastname: Bujakowska
authors.affiliation: Ocular Genomics Institute, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Human Genetics.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Siemiatkowska
authors.affiliation: Ocular Genomics Institute, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Qin
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Ocular Genomics Institute, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Place
authors.affiliation: Department of Pediatrics, Division of Human Genetics, The Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Marni J
authors.initials: MJ
authors.lastname: Falk
authors.affiliation: Ocular Genomics Institute, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Consugar
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U968, Paris 75012, France Sorbonne Universités, UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, Paris 75012, France Centre National de la Recherche Scientifique, UMR_7210, Paris 75012, France.
authors.forename: Marie-Elise
authors.initials: ME
authors.lastname: Lancelot
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U968, Paris 75012, France Sorbonne Universités, UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, Paris 75012, France Centre National de la Recherche Scientifique, UMR_7210, Paris 75012, France.
authors.forename: Aline
authors.initials: A
authors.lastname: Antonio
authors.affiliation: Plateforme Post-génomique P3S, Hôpital Pitié Salpêtrière, Paris 75013, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Lonjou
authors.affiliation: Plateforme Post-génomique P3S, Hôpital Pitié Salpêtrière, Paris 75013, France.
authors.forename: Wassila
authors.initials: W
authors.lastname: Carpentier
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U968, Paris 75012, France Sorbonne Universités, UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, Paris 75012, France Centre National de la Recherche Scientifique, UMR_7210, Paris 75012, France Institut National de la Santé et de la Recherche Médicale and Direction de L'Hospitalisation et de L'Organisation des Soins Centre D'Investigation Clinique 1423, Centre Hospitalier National D'Ophtalmologie des Quinze-Vingts, Paris 75012, France.
authors.forename: Saddek
authors.initials: S
authors.lastname: Mohand-Saïd
authors.affiliation: Department of Human Genetics Radboud Institute for Molecular Life Sciences, and Department of Ophthalmology, Radboud University Medical Center, Nijmegen 6500 HB, The Netherlands.
authors.forename: Anneke I
authors.initials: AI
authors.lastname: den Hollander
authors.affiliation: Department of Human Genetics Radboud Institute for Molecular Life Sciences, and.
authors.forename: Frans P M
authors.initials: FP
authors.lastname: Cremers
authors.affiliation: Department of Ophthalmology and Center for Medical Genetics, Ghent University Hospital and Ghent University, Ghent 9000, Belgium Ophthalmic Genetics and Visual Electrophysiology, Division of Ophthalmology, The Children's Hospital of Philadelphia, PA 19104, USA.
authors.forename: Bart P
authors.initials: BP
authors.lastname: Leroy
authors.affiliation: Ocular Genomics Institute, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Xiaowu
authors.initials: X
authors.lastname: Gai
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U968, Paris 75012, France Sorbonne Universités, UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, Paris 75012, France Centre National de la Recherche Scientifique, UMR_7210, Paris 75012, France Institut National de la Santé et de la Recherche Médicale and Direction de L'Hospitalisation et de L'Organisation des Soins Centre D'Investigation Clinique 1423, Centre Hospitalier National D'Ophtalmologie des Quinze-Vingts, Paris 75012, France Fondation Ophtalmologique Adolphe de Rothschild, Paris 75019, France Academie des Sciences, Institut de France, Paris 75006, France University College London, Institute of Ophthalmology, London EC1V 9EL, UK and.
authors.forename: José-Alain
authors.initials: JA
authors.lastname: Sahel
authors.affiliation: The Rotterdam Eye Hospital, Rotterdam 3000 LM, The Netherlands.
authors.forename: L Ingeborgh
authors.initials: LI
authors.lastname: van den Born
authors.affiliation: Department of Human Genetics Radboud Institute for Molecular Life Sciences, and.
authors.forename: Rob W J
authors.initials: RW
authors.lastname: Collin
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U968, Paris 75012, France Sorbonne Universités, UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, Paris 75012, France Centre National de la Recherche Scientifique, UMR_7210, Paris 75012, France.
authors.forename: Christina
authors.initials: C
authors.lastname: Zeitz
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U968, Paris 75012, France Sorbonne Universités, UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, Paris 75012, France Centre National de la Recherche Scientifique, UMR_7210, Paris 75012, France Institut National de la Santé et de la Recherche Médicale and Direction de L'Hospitalisation et de L'Organisation des Soins Centre D'Investigation Clinique 1423, Centre Hospitalier National D'Ophtalmologie des Quinze-Vingts, Paris 75012, France University College London, Institute of Ophthalmology, London EC1V 9EL, UK and.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Audo
authors.affiliation: Ocular Genomics Institute, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114, USA eric_pierce@meei.harvard.edu.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Pierce
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D000328:Adult; D000818:Animals; D020788:Bardet-Biedl Syndrome / Q000235:genetics* / Q000473:pathology*; D002352:Carrier Proteins / Q000235:genetics*; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins; D059472:Exome; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D051381:Rats; D012160:Retina / Q000378:metabolism / Q000473:pathology*; D012174:Retinitis Pigmentosa / Q000235:genetics* / Q000473:pathology*; D017422:Sequence Analysis, DNA; D055815:Young Adult; D015027:Zebrafish
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; C000599964:IFT172 protein, human