UniProt release 2011_12
Published December 14, 2011
Between Charybdis and Cilia
A large number of genetic disorders, displaying a widely varying set of symptoms, are highly related in their root cause and can be grouped into a single category. This is the case for the ciliopathies in which the underlying cause is a cilium dysfunction. This emerging class of disease groups very different types of syndromes, including the Alstrom, Bardet-Biedl, Ellis-van Creveld, Joubert, Meckel, Sensenbrenner syndromes and many more.
Cilia are organelles found in almost all vertebrate cells. They contain a ciliary axoneme, i.e. a ring-shaped core of 9 microtubule doublets, which connects the base of the cilium to its tip. This axoneme is covered by the ciliary membrane and projects from a modified centriole, the basal body.
There are two types of cilia: motile cilia and non-motile (primary cilia). Motile cilia are found in certain types of highly specialized cells and are dedicated to a powerful motion of the extracellular fluid, for example, in the epithelial cells lining of the trachea, where they sweep mucus and dirt out of the lungs. By contrast, the majority of cells develop a single, non-motile primary cilium, which typically serves as a sensory organelle. The primary cilium membrane harbours receptors for crucial signaling cascades, most prominently Hedgehog, Wnt, planar cell polarity, FGF, Notch, mTor, PDGF or Hippo signaling. As a result, primary cilia play a role in cell proliferation, polarity, differentiation, tissue maintenance, and nerve growth.
The range of diseases due to cilia defects therefore include multiple phenotypes that affect different organs (predominantly kidney, eye, liver, bone and brain) and often show overlapping clinical features. Commonly observed clinical manifestations are renal cysts, retinal degeneration, polydactyly, mental retardation, and obesity.
The genetics of ciliopathies is complex. In some cases, identical phenotypes are caused by mutations in different genes. For example, over 15 genes have been shown to be involved in Bardet-Biedl syndrome, and close to 10 and 15 genes in Meckel and Joubert syndromes, respectively. On the other hand, multiple allelism at a single locus can lead to different phenotypes. For example, mutations in CEP290, a centrosomal protein involved in ciliogenesis, cause Bardet-Biedl syndrome type 14, Joubert syndrome type 5, Senior-Loken syndrome type 6, Leber congenital amaurosis type 10, Meckel syndrome type 4. Additionally, recent studies suggest that ciliopathy loci can be modulated by pathogenic lesions in other ciliary genes to either exacerbate overall severity or induce specific phenotypes.
Variations across multiple sites of the ciliary proteome may influence the clinical outcome and explain the variable penetrance and expressivity of ciliopathies. Examples are the TTC21B and KIF7 genes, which code for two ciliary proteins involved in the regulation of sonic hedgehog signaling. TTC21B mutations primarily cause nephronophthisis type 12 and asphyxiating thoracic dystrophy type 4, but have also been found in patients with Bardet-Biedl syndrome or Meckel-Gruber syndrome carrying disease causing mutations in other ciliopathy genes. KIF7 mutations are primarily responsible for acrocallosal syndrome, Joubert syndrome type 12, and hydrolethalus syndrome type 2, but may also genetically interact with Bardet-Biedl syndrome genes and contribute to disease manifestation and severity in Bardet-Biedl syndrome patients.
A number of ciliopathies have been annotated in UniProtKB/Swiss-Prot. The newly created keyword Ciliopathy allows users to retrieve all proteins involved in these diseases. More specific keywords can be used to restrict the set of proteins to those associated with special types of ciliopathies, such as Bardet-Biedl syndrome, Joubert syndrome, Kartagener syndrome, Meckel syndrome, Nephronophthisis, Primary ciliary dyskinesia, or Senior-Loken syndrome.
Proteins involved in cilia formation, organization, maintenance and degradation can be retrieved with the keyword Cilium biogenesis/degradation.
Cross-references to DMDM
Cross-references have been added to DMDM (Domain Mapping of Disease Mutations), a database in which each disease mutation can be displayed by its gene, protein or domain location. DMDM provides a unique domain-level view where all human coding mutations are mapped on the protein domain.
DMDM is available at http://bioinf.umbc.edu/dmdm/.
The format of the explicit links in the flat file is:
|Resource identifier||DMDM identifier|
DR DMDM; 44887889; -.
Cross-references to PATRIC
Cross-references have been added to PATRIC, a resource which integrates vital information on pathogens, provides key resources and tools to scientists, and helps researchers to analyze genomic, proteomic and other data arising from infectious disease research.
PATRIC is available at http://www.patricbrc.org/.
The format of the explicit links in the flat file is:
|Resource identifier||PATRIC identifier|
|Optional information 1||PATRIC locus tag|
DR PATRIC; 32118368; VBIEscCol129921_1604.
Changes in the controlled vocabulary for PTMs
New term for the feature key ‘Modified residue’ (‘MOD_RES’ in the flat file):
New terms for the feature key ‘Cross-link’ (‘CROSSLNK’ in the flat file):
- 2-(4-guanidinobutanoyl)-5-hydroxyimidazole-4-carbothionic acid (Arg-Cys)
- 5-methyloxazole-4-carboxylic acid (Cys-Thr)
- 5-methyloxazole-4-carboxylic acid (Thr-Thr)
- 5-methyloxazoline-4-carboxylic acid (Ser-Thr)
- Oxazole-4-carboxylic acid (Ile-Ser)
- Oxazole-4-carboxylic acid (Ser-Ser)
- Thiazole-4-carboxylic acid (Arg-Cys)
- Threonine 5-hydroxy-oxazole-4-carbonthionic acid (Thr-Cys)
Changes in subcellular location controlled vocabulary
New subcellular locations: