Molecular Genetics and Pathogenic Mechanisms for the Severe Ciliopathies: Insights into Neurodevelopment and Pathogenesis of Neural Tube Defects

Section of Ophthalmology and Neurosciences, Wellcome Trust Brenner Building, Leeds Institute of Molecular Medicine, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK.
Molecular Neurobiology (Impact Factor: 5.14). 02/2011; 43(1):12-26. DOI: 10.1007/s12035-010-8154-0
Source: PubMed


Meckel-Gruber syndrome (MKS) is a severe autosomal recessively inherited disorder characterized by developmental defects of the central nervous system that comprise neural tube defects that most commonly present as occipital encephalocele. MKS is considered to be the most common syndromic form of neural tube defect. MKS is genetically heterogeneous with six known disease genes: MKS1, MKS2/TMEM216, MKS3/TMEM67, RPGRIP1L, CEP290, and CC2D2A with the encoded proteins all implicated in the correct function of primary cilia. Primary cilia are microtubule-based organelles that project from the apical surface of most epithelial cell types. Recent progress has implicated the involvement of cilia in the Wnt and Shh signaling pathways and has led to an understanding of their role in normal mammalian neurodevelopment. The aim of this review is to provide an overview of the molecular genetics of the human disorder, and to assess recent insights into the etiology and molecular cell biology of severe ciliopathies from mammalian animal models of MKS.

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    • "A number of centriolar satellite proteins such as PCM1 and the ciliopathy proteins Cep290 and Bardet-Biedl Syndrome protein 4 (BBS4) co-operate in the formation of the primary cilia (Kim et al., 2008; Lopes et al., 2011; Stowe et al., 2012), an organelle only recently appreciated as a crucial signalling hub for a number of pathways including Wnt and Sonic hedgehog (Logan et al., 2011). Recent work has demonstrated that a number of proteins involved in the DNA damage response (DDR) also function during ciliogenesis. "
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    ABSTRACT: Here we identify coiled-coil domain-containing protein 13 (Ccdc13) in a genome-wide RNA interference screen for regulators of genome stability. We establish that Ccdc13 is a novel centriolar satellite protein that interacts with PCM1, Cep290 and pericentrin, which prevents the accumulation of DNA damage during mitotic transit. Depletion of Ccdc13 results in loss of microtubule organisation in a manner similar to PCM1 and Cep290 depletion, although Ccdc13 is not required for satellite integrity. We show that microtubule regrowth is enhanced in Ccdc13-depleted cells, but slowed in cells overexpressing Ccdc13. Furthermore, in serum-starved cells, Ccdc13 localises to the basal body, is required for primary cilia formation, and promotes the localisation of the ciliopathy protein BBS4 to both centriolar satellites and cilia. These data highlight the emerging link between DDR factors, centriolar/peri-centriolar satellites and cilia-associated proteins and implicate Ccdc13 as a centriolar satellite protein that functions to promote both genome stability and cilia formation.
    Full-text · Article · May 2014 · Journal of Cell Science
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    • "Meckel-Gruber syndrome (MKS, MIM 249000) comprises a group of monogenic disorders that result in cystic dysplasia of the kidneys with fibrotic changes in the liver and occipital encephalocele or some other malformation of the central nervous system. Clinical diagnosis of MKS can be established by ultrasonography at the end of the first trimester,which shows encephalocele and distended stomach for the enlarged cystic kidneys [2]. MKS is a lethal autosomal recessive disorder and known to be a genetically heterogenous disease with seven causative genes [3]: MKS1 (OMIM 249000), 17q23, MKS1 gene (OMIM 609883); MKS2 (OMIM 603194), 11q13, TMEM216 gene (OMIM 613277); MKS3 (OMIM 607361), 8q21.13-q22.1, "
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    ABSTRACT: Meckel-Gruber syndrome type 3 is an autosomal recessive genetic defect caused by mutations in TMEM67 gene. In our previous study, we have identified a homozygous TMEM67 mutation in a Chinese family exhibiting clinical characteristics of MKS3, which provided a ground for further PGD procedure. Here we report the development and the first clinical application of the PGD for this MKS3 family. Molecular analysis protocol for clinical PGD procedure was established using 50 single cells in pre-clinical set-up. After whole genomic amplification by multiple displacement amplification with the DNA from single cells, three techniques were applied simultaneously to increase the accuracy and reliability of genetic diagnosis in single blastomere, including real-time PCR with Taq Man-MGB probe, haplotype analysis with polymorphic STR markers and Sanger sequencing. In the clinical PGD cycle, nine embryos at cleavage-stage were biopsied and subjected to genetic diagnosis. Two embryos diagnosed as free of TMEM67 mutation were transferred and one achieving normal pregnancy. Non-invasive prenatal assessment of trisomy 13, 18 and 21 by multiplex DNA sequencing at 18 weeks' gestation excluded the aneuploidy of the analyzed chromosomes. A healthy boy was delivered by cesarean section at 39 weeks' gestation. DNA sequencing from his cord blood confirmed the result of genetic analysis in the PGD cycle. The protocol developed in this study was proved to be rapid and safe for the detection of monogenic mutations in clinical PGD cycle.
    Full-text · Article · Sep 2013 · PLoS ONE
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    • "It is clear that cilia are remarkably diverse in their signaling capabilities, and that both sensory and motile functions can be separate or mixed in various proportions across the spectrum of cilia currently being studied (Bloodgood,2010). Basic ciliary structure can be considered to have evolved to serve hybridized functions (entirely for sensory reception, for active motility, or for a combination of these) leading to the variable and highly evolved specializations seen in different cell types and at different developmental stages (Golinska,1982; Fuchs and Schwark,2004; Götz and Striker,2006; Eggenschwiler and Anderson,2007; D'Angelo and Franco,2009,2010; Lehman et al.,2009; Gluenz et al.,2010; Rohatgi and Snell,2010; Satir et al., 2010; Logan et al.,2011). Analogously, it can be considered that the fundamental microtubular and membrane structure of cilia has the versatility to support a wide range of receptor/ signaling modifications, leading to the full spectrum of ciliary specializations seen (Reiter and Mostov,2006; McClintock et al.,2008; Reiter,2008; Scholey,2008; Thomas et al.,2010; Vincensini et al.,2011). "
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    ABSTRACT: Two positional characteristics of the ciliary axoneme--its location on the plasma membrane as it emerges from the cell, and its orientation in three-dimensional (3D) space--are known to be critical for optimal function of actively motile cilia (including nodal cilia), as well as for modified cilia associated with special senses. However, these positional characteristics have not been analyzed to any significant extent for primary cilia. This review briefly summarizes the history of knowledge of these two positional characteristics across a wide spectrum of cilia, emphasizing their importance for proper function. Then the review focuses what is known about these same positional characteristics for primary cilia in all major tissue types where they have been reported. The review emphasizes major areas that would be productive for future research for understanding how positioning and 3D orientation of primary cilia may be related to their hypothesized signaling roles within different cellular populations.
    Full-text · Article · Nov 2011 · Developmental Dynamics
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