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1.
Reiners J van Wijk E Märker T Zimmermann U Jürgens K te Brinke H Overlack N Roepman R Knipper M Kremer H Wolfrum U 《Human molecular genetics》2005,14(24):3933-3943
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 and this USH1-protein network. We show a molecular interaction between the scaffold protein harmonin (USH1C) and the USH2A protein, VLGR1 (USH2C) and the candidate for USH2B, NBC3. We pinpoint these interactions to interactions between the PDZ1 domain of harmonin and the PDZ-binding motifs at the C-termini of the USH2 proteins and NBC3. We demonstrate that USH2A, VLGR1 and NBC3 are co-expressed with the USH1-protein harmonin in the synaptic terminals of both retinal photoreceptors and inner ear hair cells. In hair cells, these USH proteins are also localized in the signal uptaking stereocilia. Our data indicate that the USH2 proteins and NBC3 are further partners in the supramolecular USH-protein network in the retina and inner ear which shed new light on the function of USH2 proteins and the entire USH-protein network. These findings provide first evidence for a molecular linkage between the pathophysiology in USH1 and USH2. The organization of USH molecules in a mutual 'interactome' related to the disease can explain the common phenotype in USH. 相似文献
2.
Identification of a gene disrupted by a microdeletion in a patient with X-linked retinitis pigmentosa (XLRP) 总被引:2,自引:2,他引:2
Roepman R; Bauer D; Rosenberg T; van Duijnhoven G; van de Vosse E; Platzer M; Rosenthal A; Ropers HH; Cremers FP; Berger W 《Human molecular genetics》1996,5(6):827-833
The gene for the most frequent from of X-linked retinitis pigmentosa
(XLRP), RP3, has been assigned by genetic and physical mapping to a segment
of less than 1000 kbp, which is flanked by the marker DXS1110 and the
ornithine transcarbamylase (OTC) gene. In search of microdeletions, we have
screened the DNA of 30 unrelated patients with XLRP by employing a
representative set of YAC-derived DNA fragments that were generated by
restriction enzyme digestion and PCR amplification. In one of these
patients, a 6.4 kbp microdeletion was detected which was not present in the
DNA of 444 male controls. A cosmid contig spanning the deletion was
constructed and used to isolate cDNAs from retina-specific libraries. Exons
corresponding to these expressed sequences as well as other putative exons
were identified by sequencing more than 30 kbp of the critical region. So
far, no point mutations in these putative exon sequences have been
identified.
相似文献
3.
Positional cloning of the gene for X-linked retinitis pigmentosa 3: homology with the guanine-nucleotide-exchange factor RCC1 总被引:6,自引:7,他引:6
Roepman R; van Duijnhoven G; Rosenberg T; Pinckers AJ; Bleeker-Wagemakers LM; Bergen AA; Post J; Beck A; Reinhardt R; Ropers HH; Cremers FP; Berger W 《Human molecular genetics》1996,5(7):1035-1041
The gene for retinitis pigmentosa 3 (RP3), the most frequent form of X-
linked RP (XLRP), has been mapped previously to a chromosome interval of
less than 1000 kbp between the DXS1110 marker and the OTC locus at
Xp21.1-p11.4. Employing a novel technique, YAC Representation Hybridization
(YRH)', we have recently identified a small XLRP associated microdeletion
in this interval, as well as several putative exons including the 3' end of
a gene that was truncated by the deletion. cDNA library screening and
sequencing of a cosmid centromeric to the deletion has now enabled us to
identify numerous additional exons and to detect several point mutations in
patients with XLRP. The predicted gene product shows homology to RCC1, the
guanine-nucleotide- exchange factor (GEF) of the Ras-like GTPase Ran. Our
findings suggest that we have cloned the long-sought RP3 gene, and that it
may encode the GEF of a retina-specific GTP-binding protein.
相似文献
4.
Ji Yun Song Puya Aravand Sergei Nikonov Lanfranco Leo Arkady Lyubarsky Jeannette L. Bennicelli Jieyan Pan Zhangyong Wei Ivan Shpylchak Pamela Herrera Daniel J. Bennett Nicoletta Commins Albert M. Maguire Jennifer Pham Anneke I. den Hollander Frans P.M. Cremers Robert K. Koenekoop Ronald Roepman Jean Bennett 《Molecular therapy》2018,26(6):1581-1593
5.
Ian J Majewski Lorenza Mittempergher Nadia M Davidson Astrid Bosma Stefan M Willems Hugo M Horlings Iris de Rink Liliana Greger Gerrit KJ Hooijer Dennis Peters Petra M Nederlof Ingrid Hofland Jeroen de Jong Jelle Wesseling Roelof JC Kluin Wim Brugman Ron Kerkhoven Frank Nieboer Paul Roepman Annegien Broeks Thomas R Muley Jacek Jassem Jacek Niklinski Nico van Zandwijk Alvis Brazma Alicia Oshlack Michel van den Heuvel René Bernards 《The Journal of pathology》2013,230(3):270-276
6.
Oral Diseases (2012) 18 , 178–183 Objective: A small subset of patients with head and neck squamous cell carcinoma are non‐smoking and non‐drinking and have distinct clinical characteristics. We aimed to identify a possible different genetic profile for these patients when compared with their smoking and drinking counterparts. Materials and Methods: The gene expression data previously detected from primary tumors located in the oral cavity and oropharynx, using DNA microarray was analyzed for their differential expression between non‐smoking and non‐drinking patients (n = 15) and smoking and drinking patients (n = 89). Student’s T‐test (P < 0.05) and 10‐fold cross‐validation procedure (100 times repeated) were performed to determine differentially expressed genes. Results: Non‐smoking and non‐drinking patients were older, mostly female and had oral cavity‐localized tumors, whereas smoking and drinking patients were younger male patients with 81% oral cavity and 19% oropharynx tumors. A set of 49 differentially expressed genes were detected. Among others, seven genes related to interferon‐γ were upregulated and two genes linked to NFKB pathway were downregulated. Conclusions: Differentially expressed genes in non‐smoking and non‐drinking patients possibly indicate the presence of a different cellular response to carcinogenic events in these patients. Further studies are warranted to validate this gene set and explore possible therapeutic implications to improve prognosis for these patients. 相似文献
7.
Interaction of nephrocystin-4 and RPGRIP1 is disrupted by nephronophthisis or Leber congenital amaurosis-associated mutations 下载免费PDF全文
Roepman R Letteboer SJ Arts HH van Beersum SE Lu X Krieger E Ferreira PA Cremers FP 《Proceedings of the National Academy of Sciences of the United States of America》2005,102(51):18520-18525
RPGR-interacting protein 1 (RPGRIP1) is a key component of cone and rod photoreceptor cells, where it interacts with RPGR (retinitis pigmentosa GTPase regulator). Mutations in RPGRIP1 lead to autosomal recessive congenital blindness [Leber congenital amaurosis (LCA)]. Most LCA-associated missense mutations in RPGRIP1 are located in a segment that encodes two C2 domains. Based on the C2 domain of novel protein kinase C epsilon (PKC epsilon), we built a 3D-homology model for the C-terminal C2 domain of RPGRIP1. This model revealed a potential Ca2+-binding site that was predicted to be disrupted by a missense mutation in RPGRIP1, which was previously identified in an LCA patient. Through yeast two-hybrid screening of a retinal cDNA library, we found this C2 domain to specifically bind to nephrocystin-4, encoded by NPHP4. Mutations in NPHP4 are associated with nephronophthisis and a combination of nephronophthisis and retinitis pigmentosa called Senior-L?ken syndrome (SLSN). We show that RPGRIP1 and nephrocystin-4 interact strongly in vitro and in vivo, and that they colocalize in the retina, matching the panretinal localization pattern of specific RPGRIP1 isoforms. Their interaction is disrupted by either mutations in RPGRIP1, found in patients with LCA, or by mutations in NPHP4, found in patients with nephronophthisis or SLSN. Thus, we provide evidence for the involvement of this disrupted interaction in the retinal dystrophy of both SLSN and LCA patients. 相似文献
8.
Coene KL Mans DA Boldt K Gloeckner CJ van Reeuwijk J Bolat E Roosing S Letteboer SJ Peters TA Cremers FP Ueffing M Roepman R 《Human molecular genetics》2011,20(18):3592-3605
Recent studies have established ciliary dysfunction as the underlying cause of a broad range of multi-organ phenotypes, known as 'ciliopathies'. Ciliopathy-associated proteins have a common site of action in the cilium, however, their overall importance for ciliary function differs, as implied by the extreme variability in ciliopathy phenotypes. The aim of this study was to gain more insight in the function of two ciliopathy-associated protein homologs, RPGR interacting protein 1 (RPGRIP1) and RPGRIP1-like protein (RPGRIP1L). Mutations in RPGRIP1 lead to the eye-restricted disease Leber congenital amaurosis, while mutations in RPGRIP1L are causative for Joubert and Meckel syndrome, which affect multiple organs and are at the severe end of the ciliopathy spectrum. Using tandem affinity purification in combination with mass spectrometry, we identified Nek4 serine/threonine kinase as a prominent component of both the RPGRIP1- as well as the RPGRIP1L-associated protein complex. In ciliated cells, this kinase localized to basal bodies, while in ciliated organs, the kinase was predominantly detected at the ciliary rootlet. Down-regulation of NEK4 in ciliated cells led to a significant decrease in cilium assembly, pointing to a role for Nek4 in cilium dynamics. We now hypothesize that RPGRIP1 and RPGRIP1L function as cilium-specific scaffolds that recruit a Nek4 signaling network which regulates cilium stability. Our data are in line with previously established roles in the cilium of other members of the Nek protein family and define NEK4 as a ciliopathy candidate gene. 相似文献
9.
A.K. Philips M. Pinelli C.I. de Bie A. Mustonen T. Määttä H.H. Arts K. Wu R. Roepman J.S. Moilanen S. Raza T. Varilo G. Scala S. Cocozza C. Gilissen K.L.I. van Gassen I. Järvelä 《Clinical genetics》2017,91(1):100-105
Intellectual disability (ID) is a major health problem in our society. Genetic causes of ID remain unknown because of its vast heterogeneity. Here we report two Finnish families and one Dutch family with affected individuals presenting with mild to moderate ID, neuropsychiatric symptoms and delayed speech development. By utilizing whole exome sequencing (WES), we identified a founder missense variant c.983T>C (p.Leu328Pro) in seven affected individuals from two Finnish consanguineous families and a deletion c.799_1034‐429delinsTTATGA (p.Gln267fs) in one affected individual from a consanguineous Dutch family in the C12orf4 gene on chromosome 12. Both the variants co‐segregated in the respective families as an autosomal recessive trait. Screening of the p.Leu328Pro variant showed enrichment in the North Eastern sub‐isolate of Finland among anonymous local blood donors with a carrier frequency of 1:53, similar to other disease mutations with a founder effect in that region. To date, only one Arab family with a three affected individuals with a frameshift insertion variant in C12orf4 has been reported. In summary, we expand and establish the clinical and mutational spectrum of C12orf4 variants. Our findings implicate C12orf4 as a causative gene for autosomal recessive ID. 相似文献
10.
Roepman P 《Bioanalysis》2010,2(2):249-262
During the last two decades, an increasing number of microarray studies have identified gene-expression profiles that link disease characteristics to patient outcome. However, despite improvements in technology and the clinical relevance of the identified profiles, only a handful of microarray tests are currently available for clinical use. So why have microarrays, regardless of the great application and success within a research setting, not yet been embraced for routine diagnostic use? Besides the strengths of microarray diagnostics, this perspective will outline the important challenges that need to be considered for successful translation of a gene profile into a routine diagnostic test. Finally, some new microarray technologies will be reviewed and an outlook for the future of diagnostic microarrays will be presented. 相似文献