title: TMEM231, mutated in orofaciodigital and Meckel syndromes, organizes the ciliary transition zone.
abstract: The Meckel syndrome (MKS) complex functions at the transition zone, located between the basal body and axoneme, to regulate the localization of ciliary membrane proteins. We investigated the role of Tmem231, a two-pass transmembrane protein, in MKS complex formation and function. Consistent with a role in transition zone function, mutation of mouse Tmem231 disrupts the localization of proteins including Arl13b and Inpp5e to cilia, resulting in phenotypes characteristic of MKS such as polydactyly and kidney cysts. Tmem231 and B9d1 are essential for each other and other complex components such as Mks1 to localize to the transition zone. As in mouse, the Caenorhabditis elegans orthologue of Tmem231 localizes to and controls transition zone formation and function, suggesting an evolutionarily conserved role for Tmem231. We identified TMEM231 mutations in orofaciodigital syndrome type 3 (OFD3) and MKS patients that compromise transition zone function. Thus, Tmem231 is critical for organizing the MKS complex and controlling ciliary composition, defects in which cause OFD3 and MKS.
authors: Department of Biochemistry and Biophysics and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158.
authors: Elle C
authors: EC
authors: Roberson
authors: Department of Biochemistry and Biophysics and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158.
authors: William E
authors: WE
authors: Dowdle
authors: Center for Human Disease Modeling, Department of Medicine, and Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC 22710.
authors: Aysegul
authors: A
authors: Ozanturk
authors: Department of Biochemistry and Biophysics and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158.
authors: Francesc R
authors: FR
authors: Garcia-Gonzalo
authors: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, V5A 1S6 Canada.
authors: Chunmei
authors: C
authors: Li
authors: Division of Nephrology, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115.
authors: Jan
authors: J
authors: Halbritter
authors: Département de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique/Hôpitaux de Paris, 75015 Paris, France.
authors: Nadia
authors: N
authors: Elkhartoufi
authors: Division of Nephrology, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115.
authors: Jonathan D
authors: JD
authors: Porath
authors: Center for Human Disease Modeling, Department of Medicine, and Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC 22710.
authors: Heidi
authors: H
authors: Cope
authors: Center for Human Disease Modeling, Department of Medicine, and Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC 22710 Center for Human Disease Modeling, Department of Medicine, and Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC 22710.
authors: Allison
authors: A
authors: Ashley-Koch
authors: Center for Human Disease Modeling, Department of Medicine, and Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC 22710.
authors: Simon
authors: S
authors: Gregory
authors: Institut National de la Santé et de la Recherche Médicale UMR1163, 75015 Paris, France Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France.
authors: Sophie
authors: S
authors: Thomas
authors: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, England, UK Newcastle Hospitals National Health Service Foundation Trust, Newcastle upon Tyne NE7 7DN, England, UK.
authors: John A
authors: JA
authors: Sayer
authors: Institut National de la Santé et de la Recherche Médicale UMR1163, 75015 Paris, France Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France.
authors: Sophie
authors: S
authors: Saunier
authors: Department of Pediatrics, University of Michigan, Ann Arbor, MI 48109.
authors: Edgar A
authors: EA
authors: Otto
authors: Center for Human Disease Modeling, Department of Medicine, and Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC 22710.
authors: Nicholas
authors: N
authors: Katsanis
authors: Center for Human Disease Modeling, Department of Medicine, and Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC 22710.
authors: Erica E
authors: EE
authors: Davis
authors: Institut National de la Santé et de la Recherche Médicale UMR1163, 75015 Paris, France Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France Département de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique/Hôpitaux de Paris, 75015 Paris, France.
authors: Tania
authors: T
authors: Attié-Bitach
authors: Division of Nephrology, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115 Howard Hughes Medical Institute, Chevy Chase, MD 20815.
authors: Friedhelm
authors: F
authors: Hildebrandt
authors: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, V5A 1S6 Canada.
authors: Michel R
authors: MR
authors: Leroux
authors: Department of Biochemistry and Biophysics and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158 jeremy.reiter@ucsf.edu.
authors: Jeremy F
authors: JF
authors: Reiter
mesh_terms: D000818:Animals; D019556:COS Cells; D017173:Caenorhabditis elegans; D002522:Chlorocebus aethiops; D002923:Cilia / Q000378:metabolism* / Q000473:pathology; D002925:Ciliary Motility Disorders / Q000235:genetics*; D003598:Cytoskeletal Proteins; D004677:Encephalocele / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020125:Mutation, Missense; D009958:Orofaciodigital Syndromes / Q000235:genetics*; D007690:Polycystic Kidney Diseases / Q000235:genetics*; D011506:Proteins / Q000378:metabolism; D012174:Retinitis Pigmentosa
chemical_list: C000592877:B9D1 protein, human; D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; D011506:Proteins; C578841:TMEM231 protein, human