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.
"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. "
[Show abstract][Hide abstract] 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.
"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 . MKS is a lethal autosomal recessive disorder and known to be a genetically heterogenous disease with seven causative genes : MKS1 (OMIM 249000), 17q23, MKS1 gene (OMIM 609883); MKS2 (OMIM 603194), 11q13, TMEM216 gene (OMIM 613277); MKS3 (OMIM 607361), 8q21.13-q22.1, "
[Show abstract][Hide abstract] 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.
PLoS ONE 09/2013; 8(9):e73245. DOI:10.1371/journal.pone.0073245 · 3.23 Impact Factor
"The sequence of the DHCR7 gene ruled out Smith-Lemli-Opitz syndrome (SLO). We did not sequence the gene responsible for Hydrolethalus syndrome (HYLS1), as this syndrome almost invariably includes polyhydramnios, a 'key-hole shaped' foramen magnum, severe hydrocephalus and pre-axial (rather than post-axial) polydactyly of the lower limbs (Honkala et al., 2009); likewise the pathognomonic features of Meckel syndrome, which include occipital encephalocele, bilateral renal cystic dysplasia, hepatic duct proliferation, fibrosis and cysts, were not present (Chen, 2007; Logan et al., 2011). Pallister-Hall syndrome, caused by mutations in the GLI3 gene, was excluded as the foetus did not have a hypothalamic hamartoma, bifid epiglottis, imperforate anus, or the renal abnormalities that are characteristic of this syndrome, and the family history was indicative of autosomal recessive rather than autosomal dominant inheritance. "
[Show abstract][Hide abstract] ABSTRACT: Pseudotrisomy 13 syndrome is characterised by holoprosencephaly with or without polydactyly, but with a normal karyotype. The genetic cause of this syndrome remains unclear, but it is thought to be autosomal recessive. In order to identify possible candidate genes, we identified regions of homozygosity in the DNA of an affected foetus, which was the seventh pregnancy of a healthy non-consanguineous Cook Island Maori couple; this ethnic group derives from a small founder population. Several large regions of homozygosity were identified using a high density array. We excluded two candidate genes that lay within these regions, and suggest that Pseudotrisomy 13 syndrome might not be monogenic and that a larger cohort of patients should be analysed using high density dosage/SNP arrays as well as whole exome sequencing in order to clarify the genetic underpinning of this rare syndrome.
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