Molecular genetics and pathogenic mechanisms for the severe ciliopathies: insights into neurodevelopment and pathogenesis of neural tube defects.
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.
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
CV
Logan
Zakia
Z
Abdel-Hamed
Colin A
CA
Johnson
D000015:Abnormalities, Multiple / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins; D002923:Cilia / Q000473:pathology / Q000502:physiology* / Q000648:ultrastructure; D002925:Ciliary Motility Disorders / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D003598:Cytoskeletal Proteins; D003937:Diagnosis, Differential; D004195:Disease Models, Animal; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D006666:History of Medicine; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008967:Molecular Biology; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009436:Neural Tube Defects / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013577:Syndrome
D048868:Adaptor Proteins, Signal Transducing; D000951:Antigens, Neoplasm; C528701:CC2D2A protein, human; D018797:Cell Cycle Proteins; C493903:Cep290 protein, human; D003598:Cytoskeletal Proteins; D053823:Hedgehog Proteins; C509165:MKS1 protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D011506:Proteins; C532826:RPGRIP1L protein, human; C551542:TMEM216 protein, human; C468846:TMEM67 protein, human