0000000000065902
AUTHOR
Tina Märker
Usher syndrome: molecular links of pathogenesis, proteins and pathways.
Contains fulltext : 50437.pdf (Publisher’s version ) (Closed access) Usher syndrome is the most common form of deaf-blindness. The syndrome is both clinically and genetically heterogeneous, and to date, eight causative genes have been identified. The proteins encoded by these genes are part of a dynamic protein complex that is present in hair cells of the inner ear and in photoreceptor cells of the retina. The localization of the Usher proteins and the phenotype in animal models indicate that the Usher protein complex is essential in the morphogenesis of the stereocilia bundle in hair cells and in the calycal processes of photoreceptor cells. In addition, the Usher proteins are important in…
Usher syndrome and Leber congenital amaurosis are molecularly linked via a novel isoform of the centrosomal ninein-like protein.
Contains fulltext : 80984.pdf (Publisher’s version ) (Closed access) Usher syndrome (USH) and Leber congenital amaurosis (LCA) are autosomal recessive disorders resulting in syndromic and non-syndromic forms of blindness. In order to gain insight into the pathogenic mechanisms underlying retinal degeneration, we searched for interacting proteins of USH2A isoform B (USH2A(isoB)) and the LCA5-encoded protein lebercilin. We identified a novel isoform of the centrosomal ninein-like protein, hereby named Nlp isoform B (Nlp(isoB)), as a common interactor. Although we identified the capacity of this protein to bind calcium with one of its three EF-hand domains, the interacton with USH2A(isoB) did …
Direct interaction of the Usher syndrome 1G protein SANS and myomegalin in the retina
Contains fulltext : 96822.pdf (Publisher’s version ) (Closed access) The human Usher syndrome (USH) is the most frequent cause of combined hereditary deaf-blindness. USH is genetically heterogeneous with at least 11 chromosomal loci assigned to 3 clinical types, USH1-3. We have previously demonstrated that all USH1 and 2 proteins in the eye and the inner ear are organized into protein networks by scaffold proteins. This has contributed essentially to our current understanding of the function of USH proteins and explains why defects in proteins of different families cause very similar phenotypes. We have previously shown that the USH1G protein SANS (scaffold protein containing ankyrin repeat…
MPP1 links the Usher protein network and the Crumbs protein complex in the retina.
Contains fulltext : 53571.pdf (Publisher’s version ) (Closed access) The highly ordered distribution of neurons is an essential feature of a functional mammalian retina. Disruptions in the apico-basal polarity complexes at the outer limiting membrane (OLM) of the retina are associated with retinal patterning defects in vertebrates. We have analyzed the binding repertoire of MPP5/Pals1, a key member of the apico-basal Crumbs polarity complex, that has functionally conserved counterparts in zebrafish (nagie oko) and Drosophila (Stardust). We show that MPP5 interacts with its MAGUK family member MPP1/p55 at the OLM. Mechanistically, this interaction involves heterodimerization of both MAGUK mo…
Mutations in the gene encoding the basal body protein RPGRIP1L, a nephrocystin-4 interactor, cause Joubert syndrome.
Peters, T.A./0000-0001-8443-5500; van Beersum, Sylvia E.C./0000-0002-4552-2908; Cremers, Frans/0000-0002-4954-5592; Roepman, Ronald/0000-0002-5178-8163 WOS: 000247619800019 PubMed: 17558407 Protein- protein interaction analyses have uncovered a ciliary and basal body protein network that, when disrupted, can result in nephronophthisis ( NPHP), Leber congenital amaurosis, Senior- Loken syndrome ( SLSN) or Joubert syndrome ( JBTS)(1-6). However, details of the molecular mechanisms underlying these disorders remain poorly understood. RPGRIP1- like protein ( RPGRIP1L) is a homolog of RPGRIP1 ( RPGR-interacting protein 1), a ciliary protein defective in Leber congenital amaurosis(7,8). We show t…
Association of Whirlin with Cav1.3 (α1D) Channels in Photoreceptors, Defining a Novel Member of the Usher Protein Network
Contains fulltext : 88383.pdf (Publisher’s version ) (Closed access) PURPOSE: Usher syndrome is the most common form of hereditary deaf-blindness. It is both clinically and genetically heterogeneous. The USH2D protein whirlin interacts via its PDZ domains with other Usher-associated proteins containing a C-terminal type I PDZ-binding motif. These proteins co-localize with whirlin at the region of the connecting cilium and at the synapse of photoreceptor cells. This study was undertaken to identify novel, Usher syndrome-associated, interacting partners of whirlin and thereby obtain more insights into the function of whirlin. METHODS: The database of ciliary proteins was searched for proteins…
Scaffold protein harmonin (USH1C) provides molecular links between Usher syndrome type 1 and type 2.
Contains fulltext : 48386.pdf (Publisher’s version ) (Closed access) Usher syndrome (USH) is the most frequent cause of combined deaf-blindness in man. USH is clinically and genetically heterogeneous with at least 11 chromosomal loci assigned to the three USH types (USH1A-G, USH2A-C, USH3A). Although the different USH types exhibit almost the same phenotype in human, the identified USH genes encode for proteins which belong to very different protein classes and families. We and others recently reported that the scaffold protein harmonin (USH1C-gene product) integrates all identified USH1 molecules in a USH1-protein network. Here, we investigated the relationship between the USH2 molecules a…
Phosphorylation of the Usher syndrome 1G protein SANS controls Magi2-mediated endocytosis.
Item does not contain fulltext The human Usher syndrome (USH) is a complex ciliopathy with at least 12 chromosomal loci assigned to three clinical subtypes, USH1-3. The heterogeneous USH proteins are organized into protein networks. Here, we identified Magi2 (membrane-associated guanylate kinase inverted-2) as a new component of the USH protein interactome, binding to the multifunctional scaffold protein SANS (USH1G). We showed that the SANS-Magi2 complex assembly is regulated by the phosphorylation of an internal PDZ-binding motif in the sterile alpha motif domain of SANS by the protein kinase CK2. We affirmed Magi2's role in receptor-mediated, clathrin-dependent endocytosis and showed tha…
Homozygous disruption of PDZD7 by reciprocal translocation in a consanguineous family: a new member of the Usher syndrome protein interactome causing congenital hearing impairment.
A homozygous reciprocal translocation, 46,XY,t(10;11),t(10;11), was detected in a boy with non-syndromic congenital sensorineural hearing impairment. Both parents and their four other children were heterozygous translocation carriers, 46,XX,t(10;11) and 46,XY,t(10;11), respectively. Fluorescence in situ hybridization of region-specific clones to patient chromosomes was used to localize the breakpoints within bacterial artificial chromosome (BAC) RP11-108L7 on chromosome 10q24.3 and within BAC CTD-2527F12 on chromosome 11q23.3. Junction fragments were cloned by vector ligation and sequenced. The chromosome 10 breakpoint was identified within the PDZ domain containing 7 (PDZD7) gene, disrupti…
Molecular basis of human Usher syndrome: deciphering the meshes of the Usher protein network provides insights into the pathomechanisms of the Usher disease.
Usher syndrome (USH) is the most frequent cause of combined deaf-blindness in man. It is clinically and genetically heterogeneous and at least 12 chromosomal loci are assigned to three clinical USH types, namely USH1A-G, USH2A-C, USH3A (Davenport, S.L.H., Omenn, G.S., 1977. The heterogeneity of Usher syndrome. Vth Int. Conf. Birth Defects, Montreal; Petit, C., 2001. Usher syndrome: from genetics to pathogenesis. Annu. Rev. Genomics Hum. Genet. 2, 271-297). Mutations in USH type 1 genes cause the most severe form of USH. In USH1 patients, congenital deafness is combined with a pre-pubertal onset of retinitis pigmentosa (RP) and severe vestibular dysfunctions. Those with USH2 have moderate to…