CEP290, a Gene with Many Faces: Mutation Overview and Presentation of CEP290base

Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
Human Mutation (Impact Factor: 5.14). 10/2010; 31(10):1097-108. DOI: 10.1002/humu.21337
Source: PubMed


Ciliopathies are an emerging group of disorders, caused by mutations in ciliary genes. One of the most intriguing disease genes associated with ciliopathies is CEP290, in which mutations cause a wide variety of distinct phenotypes, ranging from isolated blindness over Senior-Loken syndrome (SLS), nephronophthisis (NPHP), Joubert syndrome (related disorders) (JS[RD]), Bardet-Biedl syndrome (BBS), to the lethal Meckel-Grüber syndrome (MKS). Despite the identification of over 100 unique CEP290 mutations, no clear genotype-phenotype correlations could yet be established, and consequently the predictive power of a CEP290-related genotype remains limited. One of the challenges is a better understanding of second-site modifiers. In this respect, there is a growing interest in the potential modifying effects of variations in genes encoding other members of the ciliary proteome that interact with CEP290. Here, we provide an overview of all CEP290 mutations identified so far, with their associated phenotypes. To this end, we developed CEP290base, a locus-specific mutation database that links mutations with patients and their phenotypes (medgen.ugent.be/cep290base).

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    • "Although most mutations underlying LCA are located in coding regions, there is accumulating evidence for genetic defects in non-coding regions such as deep intronic mutations or regulatory mutations in enhancers, promoters, or untranslated regions (UTRs). A striking example is a deep intronic mutation of CEP290, accounting for 15% of congenital blindness in Europe (Coppieters et al., 2010). "
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    ABSTRACT: Leber Congenital Amaurosis (LCA) is a severe autosomal recessive retinal dystrophy leading to congenital blindness. A recently identified LCA gene is NMNAT1, located in the LCA9 locus. Although most mutations in blindness genes are coding variations, there is accumulating evidence for hidden non-coding defects or structural variations (SVs). The starting point of this study was an LCA9-associated consanguineous family in which no coding mutations were found in the LCA9 region. Exploring the UTRs of NMNAT1 revealed a novel homozygous 5'UTR variant, c.-70A>T. Moreover, an adjacent 5'UTR variant, c.-69C>T, was identified in a second consanguineous family displaying a similar phenotype. Both 5'UTR variants resulted in decreased NMNAT1 mRNA abundance in patients' lymphocytes, and caused decreased luciferase activity in human retinal pigment epithelial RPE-1 cells. Second, we unraveled pseudohomozygosity of a coding NMNAT1 mutation in two unrelated LCA patients by the identification of two distinct heterozygous partial NMNAT1 deletions. Molecular characterization of the breakpoint junctions revealed a complex Alu-rich genomic architecture. Our study uncovered hidden genetic variation in NMNAT1-associated LCA and emphasized a shift from coding to non-coding regulatory mutations and repeat-mediated SVs in the molecular pathogenesis of heterogeneous recessive disorders such as hereditary blindness. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Human Mutation 08/2015; 36(12). DOI:10.1002/humu.22899 · 5.14 Impact Factor
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    • "Among ciliopathy genes, CEP290, whose mutations cause a wide variety of distinct phenotypes (namely, Senior-Loken syndrome, nephronophthisis, Joubert syndrome, Bardet-Biedl syndrome, and Meckel-Grüber syndrome) [26], shows the highest number of connections (http://ccci.tigem.it). "
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    ABSTRACT: Background Cilia are microtubule-based organelles protruding from almost all mammalian cells which, when dysfunctional, result in genetic disorders called “ciliopathies”. High-throughput studies have revealed that cilia are composed of thousands of proteins. However, despite many efforts, much remains to be determined regarding the biological functions of this increasingly important complex organelle. Results We have derived an online tool, from a systematic network-based approach to dissect the cilia/centrosome complex interactome (CCCI). The tool integrates all current available data into a model which provides an “interaction” perspective on ciliary function. We generated a network of interactions between human proteins organized into functionally relevant “communities”, which can be defined as groups of genes that are both highly inter-connected and strongly co-expressed. We then combined sequence and co-expression data in order to identify the transcription factors responsible for regulating genes within their respective communities. Our analyses have discovered communities significantly specialized for delegating specific biological functions such as mRNA processing, protein translation, folding and degradation processes that had never been associated with ciliary proteins until now. Conclusions CCCI will allow us to clarify the roles of previously unknown ciliary functions, elucidate the molecular mechanisms underlying ciliary-associated phenotypes, and apply our knowledge of the functional roles of relatively uncharacterized molecular entities to disease phenotypes and new clinical applications. Electronic supplementary material The online version of this article (doi:10.1186/1471-2164-15-658) contains supplementary material, which is available to authorized users.
    BMC Genomics 08/2014; 15(1):658. DOI:10.1186/1471-2164-15-658 · 3.99 Impact Factor
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    • "Alterations in CEP290 have been connected to ASDs and intellectual disability and were previously identified in patients diagnosed with a wide variety of ciliopathies including Bardet-Biedl, Joubert, Meckel-Gruber, and Senior-Løken syndromes (http://medgen.ugent.be/cep290base/) [39]. Along with being linked to ASDs, CSMD1 has been associated with schizophrenia and is a known target of mir-137, a microRNA that regulates neuronal maturation and adult neurogenesis [40-43]. "
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    ABSTRACT: Autism spectrum disorders (ASDs) comprise a range of neurodevelopmental conditions of varying severity, characterized by marked qualitative difficulties in social relatedness, communication, and behavior. Despite overwhelming evidence of high heritability, results from genetic studies to date show that ASD etiology is extremely heterogeneous and only a fraction of autism genes have been discovered. To help unravel this genetic complexity, we performed whole exome sequencing on 100 ASD individuals from 40 families with multiple distantly related affected individuals. All families contained a minimum of one pair of ASD cousins. Each individual was captured with the Agilent SureSelect Human All Exon kit, sequenced on the Illumina Hiseq 2000, and the resulting data processed and annotated with Burrows-Wheeler Aligner (BWA), Genome Analysis Toolkit (GATK), and SeattleSeq. Genotyping information on each family was utilized in order to determine genomic regions that were identical by descent (IBD). Variants identified by exome sequencing which occurred in IBD regions and present in all affected individuals within each family were then evaluated to determine which may potentially be disease related. Nucleotide alterations that were novel and rare (minor allele frequency, MAF, less than 0.05) and predicted to be detrimental, either by altering amino acids or splicing patterns, were prioritized. We identified numerous potentially damaging, ASD associated risk variants in genes previously unrelated to autism. A subset of these genes has been implicated in other neurobehavioral disorders including depression (SLIT3), epilepsy (CLCN2, PRICKLE1), intellectual disability (AP4M1), schizophrenia (WDR60), and Tourette syndrome (OFCC1). Additional alterations were found in previously reported autism candidate genes, including three genes with alterations in multiple families (CEP290, CSMD1, FAT1, and STXBP5). Compiling a list of ASD candidate genes from the literature, we determined that variants occurred in ASD candidate genes 1.65 times more frequently than in random genes captured by exome sequencing (P = 8.55 x 10-5). By studying these unique pedigrees, we have identified novel DNA variations related to ASD, demonstrated that exome sequencing in extended families is a powerful tool for ASD candidate gene discovery, and provided further evidence of an underlying genetic component to a wide range of neurodevelopmental and neuropsychiatric diseases.
    Molecular Autism 01/2014; 5(1):1. DOI:10.1186/2040-2392-5-1 · 5.41 Impact Factor
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