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

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Abstract

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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Acknowledgments

We acknowledge funding from the Medical Research Council (project grant G0700073; CAJ), an Egyptian Government Scholarship (ZA) and the Sir Jules Thorn Charitable Trust (09/JTA). We thank Tamara Caspary, Jeremy Reiter, and Joe Gleeson for helpful discussions.

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  1. 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

    Clare V. Logan, Zakia Abdel-Hamed & Colin A. Johnson

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  1. Clare V. Logan
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Correspondence to Colin A. Johnson.

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Logan, C.V., Abdel-Hamed, Z. & Johnson, C.A. Molecular Genetics and Pathogenic Mechanisms for the Severe Ciliopathies: Insights into Neurodevelopment and Pathogenesis of Neural Tube Defects. Mol Neurobiol 43, 12–26 (2011). https://doi.org/10.1007/s12035-010-8154-0

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