Search results for "ciliopathie"
showing 10 items of 34 documents
Mutations in LCA5, encoding the ciliary protein lebercilin, cause Leber congenital amaurosis
2007
Contains fulltext : 53618.pdf (Publisher’s version ) (Closed access) Leber congenital amaurosis (LCA) causes blindness or severe visual impairment at or within a few months of birth. Here we show, using homozygosity mapping, that the LCA5 gene on chromosome 6q14, which encodes the previously unknown ciliary protein lebercilin, is associated with this disease. We detected homozygous nonsense and frameshift mutations in LCA5 in five families affected with LCA. In a sixth family, the LCA5 transcript was completely absent. LCA5 is expressed widely throughout development, although the phenotype in affected individuals is limited to the eye. Lebercilin localizes to the connecting cilia of photore…
The oral-facial-digital syndrome gene C2CD3 encodes a positive regulator of centriole elongation
2014
Centrioles are microtubule-based, barrel-shaped structures that initiate the assembly of centrosomes and cilia(1,2). How centriole length is precisely set remains elusive. The microcephaly protein CPAP (also known as MCPH6) promotes procentriole growth(3-5), whereas the oral-facial-digital (OFD) syndrome protein OFD1 represses centriole elongation(6,7). Here we uncover a new subtype of OFD with severe microcephaly and cerebral malformations and identify distinct mutations in two affected families in the evolutionarily conserved C2CD3 gene. Concordant with the clinical overlap, C2CD3 colocalizes with OFD1 at the distal end of centrioles, and C2CD3 physically associates with OFD1. However, wh…
An siRNA-based functional genomics screen for the identification of regulators of ciliogenesis and ciliopathy genes
2015
Item does not contain fulltext Defects in primary cilium biogenesis underlie the ciliopathies, a growing group of genetic disorders. We describe a whole-genome siRNA-based reverse genetics screen for defects in biogenesis and/or maintenance of the primary cilium, obtaining a global resource. We identify 112 candidate ciliogenesis and ciliopathy genes, including 44 components of the ubiquitin-proteasome system, 12 G-protein-coupled receptors, and 3 pre-mRNA processing factors (PRPF6, PRPF8 and PRPF31) mutated in autosomal dominant retinitis pigmentosa. The PRPFs localize to the connecting cilium, and PRPF8- and PRPF31-mutated cells have ciliary defects. Combining the screen with exome sequen…
Primary ciliary dyskinesia. Ciliopathies
2008
Abstract Primary ciliary dyskinesia is a genetically inherited syndrome characterised by ciliary immotility or dysmotility. Deficiency in mucociliary clearance produces chronic respiratory infections from birth, male sterility by spermatozoid immotility and situs inversus in 40%–50% of patients (Kartagener's syndrome). Diagnosis is made by analysing ciliary motility with high-speed digital video and ciliary ultrastructure. The wide distribution and functions of the cilia in the body mean that this dysfunction can generate other ciliopathies apart from primary ciliary dyskinesia.
An organelle-specific protein landscape identifies novel diseases and molecular mechanisms.
2016
Cellular organelles provide opportunities to relate biological mechanisms to disease. Here we use affinity proteomics, genetics and cell biology to interrogate cilia: poorly understood organelles, where defects cause genetic diseases. Two hundred and seventeen tagged human ciliary proteins create a final landscape of 1,319 proteins, 4,905 interactions and 52 complexes. Reverse tagging, repetition of purifications and statistical analyses, produce a high-resolution network that reveals organelle-specific interactions and complexes not apparent in larger studies, and links vesicle transport, the cytoskeleton, signalling and ubiquitination to ciliary signalling and proteostasis. We observe sub…
CiliaCarta: An integrated and validated compendium of ciliary genes
2019
The cilium is an essential organelle at the surface of mammalian cells whose dysfunction causes a wide range of genetic diseases collectively called ciliopathies. The current rate at which new ciliopathy genes are identified suggests that many ciliary components remain undiscovered. We generated and rigorously analyzed genomic, proteomic, transcriptomic and evolutionary data and systematically integrated these using Bayesian statistics into a predictive score for ciliary function. This resulted in 285 candidate ciliary genes. We generated independent experimental evidence of ciliary associations for 24 out of 36 analyzed candidate proteins using multiple cell and animal model systems (mouse…
Primary Cilium Mediated Retinal Pigment Epithelium Maturation is Retarded in Ciliopathy Patient Cells
2018
Primary cilia are sensory organelles that protrude from the cell membrane. Cilia defects cause ciliopathy disorders with retinal degeneration as a prominent phenotype. Here, we demonstrate that the retinal pigment epithelium (RPE), essential for photoreceptor development and function, requires a functional primary cilium for complete maturation, and RPE maturation defects in ciliopathies precede photoreceptor development. Pharmacologically enhanced ciliogenesis in wildtype induced pluripotent stem cells (iPSCs)-RPE leads to fully-mature and functional cells. Whereas, ciliopathy patient-derived iPSCs-RPE and wildtype iPSC-RPE with a knockdown of ciliary-trafficking protein remain immature, w…
Usher Syndrome Protein Network Functions in the Retina and their Relation to Other Retinal Ciliopathies
2014
The human Usher syndrome (USH) is the most frequent cause of combined hereditary deaf-blindness. USH is genetically and clinically heterogeneous: 15 chromosomal loci assigned to 3 clinical types, USH1-3. All USH1 and 2 proteins are organized into protein networks by the scaffold proteins harmonin (USH1C), whirlin (USH2D) and SANS (USH1G). This has contributed essentially to our current understanding of the USH protein function in the eye and the ear and explains why defects in proteins of different families cause very similar phenotypes. Ongoing in depth analyses of USH protein networks in the eye indicated cytoskeletal functions as well as roles in molecular transport processes and ciliary…
Gene-based treatment options for Usher type 1C by translational read-through of a nonsense mutation
2012
The Usher syndrome (USH) is the most frequent cause of inherited combined deaf-blindness. The ciliopathy is clinically and genetically heterogeneous, assigned to three clinical USH types of which the most severe type is USH1. The USH1C gene encodes the PDZ containing scaffold protein harmonin which is expressed in form of numerous alternatively spliced variants. Hamonin binds directly to all USH1/2 proteins and is a key organizer of USH protein networks in photoreceptor cells. So far no effective treatment for the ophthalmic component of USH exists. Translational read-through was introduced as an innovative therapy option for several non-ocular diseases caused by nonsense mutations leading …
A Transition Zone Complex Regulates Mammalian Ciliogenesis and Ciliary Membrane Composition
2011
Mutations in genes encoding ciliary components cause ciliopathies, but how many of these mutations disrupt ciliary function is unclear. We investigated Tectonic1 (Tctn1), a regulator of mouse Hedgehog signaling, and found that it is essential for ciliogenesis in some, but not all, tissues. Cell types that do not require Tctn1 for ciliogenesis require it to localize select membrane-associated proteins to the cilium, including Arl13b, AC3, Smoothened and Pkd2. Tctn1 forms a complex with multiple ciliopathy proteins associated with Meckel (MKS) and Joubert (JBTS) syndromes, including Mks1, Tmem216, Tmem67, Cep290, B9d1, Tctn2, and Cc2d2a. Components of the Tectonic ciliopathy complex colocaliz…