Mutation analysis of NPHP6/CEP290 in patients with Joubert-Syndrome and Senior-Loken-Syndrome

Journal of Medical Genetics (Impact Factor: 6.34). 11/2007; 44(10):657-63. DOI: 10.1136/jmg.2007.052027
Source: PubMed


Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease that constitutes the most common genetic cause of renal failure in the first three decades of life. Using positional cloning, six genes (NPHP1-6) have been identified as mutated in NPHP. In Joubert syndrome (JBTS), NPHP may be associated with cerebellar vermis aplasia/hypoplasia, retinal degeneration and mental retardation. In Senior-Løken syndrome (SLSN), NPHP is associated with retinal degeneration. Recently, mutations in NPHP6/CEP290 were identified as a new cause of JBTS.
Mutational analysis was performed on a worldwide cohort of 75 families with SLSN, 99 families with JBTS and 21 families with isolated nephronophthisis.
Six novel and six known truncating mutations, one known missense mutation and one novel 3 bp pair in-frame deletion were identified in a total of seven families with JBTS, two families with SLSN and one family with isolated NPHP.

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Available from: Heymut Omran, Oct 04, 2015
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    • "Alstrom syndrome patients develop vision loss in young adulthood [122]. Like JBTS cases, patients with SLSN tend to exhibit early vision loss [34,123-125]. Visual impairment in a child can be the presenting feature of Jeune syndrome (Jeune asphyxiating thoracic dystrophy) [126]. "
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    ABSTRACT: Ciliopathies encompass a broad array of clinical findings associated with genetic defects in biogenesis and/or function of the primary cilium, a ubiquitous organelle involved in the transduction of diverse biological signals. Degeneration or dysfunction of retinal photoreceptors is frequently observed in diverse ciliopathies. The sensory cilium in a photoreceptor elaborates into unique outer segment discs that provide extensive surface area for maximal photon capture and efficient visual transduction. The daily renewal of approximately 10% of outer segments requires a precise control of ciliary transport. Here, we review the ciliopathies with associated retinal degeneration, describe the distinctive structure of the photoreceptor cilium, and discuss mouse models that allow investigations into molecular mechanisms of cilia biogenesis and defects. We have specifically focused on two ciliary proteins -- CEP290 and RPGR -- that underlie photoreceptor degeneration and syndromic ciliopathies. Mouse models of CEP290 and RPGR disease, and of their multiple interacting partners, have helped unravel new functional insights into cell type-specific phenotypic defects in distinct ciliary proteins. Elucidation of multifaceted ciliary functions and associated protein complexes will require concerted efforts to assimilate diverse datasets from in vivo and in vitro studies. We therefore discuss a possible framework for investigating genetic networks associated with photoreceptor cilia biogenesis and pathology.
    Cilia 12/2012; 1(1):22. DOI:10.1186/2046-2530-1-22
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    • "The most frequently mutated LCA gene is CEP290, accounting for ~15% of all cases.3,4,6,7 Severe mutations in CEP290 have been reported to cause a spectrum of systemic diseases that, besides retinal dystrophy, are characterized by brain defects, kidney malformations, polydactyly, and/or obesity.8,9,10,11 There is no clear-cut genotype–phenotype correlation between the combination of CEP290 mutations and the associated phenotypes, but individuals with LCA and early onset retinal dystrophy very often carry hypomorphic alleles.3,6,7,12,13 "
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    ABSTRACT: Leber congenital amaurosis (LCA) is the most severe form of inherited retinal degeneration, with an onset in the first year of life. The most frequent mutation that causes LCA, present in at least 10% of individuals with LCA from North-American and Northern-European descent, is an intronic mutation in CEP290 that results in the inclusion of an aberrant exon in the CEP290 mRNA. Here, we describe a genetic therapy approach that is based on antisense oligonucleotides (AONs), small RNA molecules that are able to redirect normal splicing of aberrantly processed pre-mRNA. Immortalized lymphoblastoid cells of individuals with LCA homozygously carrying the intronic CEP290 mutation were transfected with several AONs that target the aberrant exon that is incorporated in the mutant CEP290 mRNA. Subsequent RNA isolation and reverse transcription-PCR analysis revealed that a number of AONs were capable of almost fully redirecting normal CEP290 splicing, in a dose-dependent manner. Other AONs however, displayed no effect on CEP290 splicing at all, indicating that the rescue of aberrant CEP290 splicing shows a high degree of sequence specificity. Together, our data show that AON-based therapy is a promising therapeutic approach for CEP290-associated LCA that warrants future research in animal models to develop a cure for this blinding disease.
    Molecular Therapy - Nucleic Acids 03/2012; 1(3):e14. DOI:10.1038/mtna.2012.3 · 4.51 Impact Factor
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    • "The mutations in some known LCA disease genes can also cause syndromic diseases. For example, Centrosomal protein of 290 kDa (CEP290, also known as NPHP6), which represents the most common cause of LCA identified to date [15,16], is also associated with other diseases, such as retinitis pigmentosa [17], Meckel syndrome (MKS) [18,19], SLSN [20], Bardet-Biedl syndrome (BBS) [21] and JBTS [22,23]. Similarly, Bardet–Biedl syndrome protein-8 (BBS8), one of the genes involved in BBS, has been linked to retinitis pigmentosa [24]. "
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    ABSTRACT: Leber congenital amaurosis (LCA) is one of the most severe eye dystrophies characterized by severe vision loss at an early stage and accounts for approximately 5% of all retinal dystrophies. The purpose of this study was to identify a novel LCA disease allele or gene and to develop an approach combining genetic mapping with whole exome sequencing. Three patients from King Khaled Eye Specialist Hospital (KKESH205) underwent whole genome single nucleotide polymorphism genotyping, and a single candidate region was identified. Taking advantage of next-generation high-throughput DNA sequencing technologies, whole exome capture sequencing was performed on patient KKESH205#7. Sanger direct sequencing was used during the validation step. The zebrafish model was used to examine the function of the mutant allele. A novel missense mutation in Bardet-Biedl syndrome 4 protein (BBS4) was identified in a consanguineous family from Saudi Arabia. This missense mutation in the fifth exon (c.253G>C;p.E85Q) of BBS4 is likely a disease-causing mutation as it segregates with the disease. The mutation is not found in the single nucleotide polymorphism (SNP) database, the 1000 Genomes Project, or matching normal controls. Functional analysis of this mutation in zebrafish indicates that the G253C allele is pathogenic. Coinjection of the G253C allele cannot rescue the mislocalization of rhodopsin in the retina when BBS4 is knocked down by morpholino injection. Immunofluorescence analysis in cell culture shows that this missense mutation in BBS4 does not cause obvious defects in protein expression or pericentriolar localization. This mutation likely mainly reduces or abolishes BBS4 function in the retina. Further studies of this allele will provide important insights concerning the pleiotropic nature of BBS4 function.
    Molecular vision 12/2011; 17:3529-40. · 1.99 Impact Factor
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