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Chien S.-C.,University of California at Berkeley | Brinkmann E.-M.,University of California at Berkeley | Brinkmann E.-M.,Institute of Human Genetics | Teuliere J.,University of California at Berkeley | Garriga G.,University of California at Berkeley
Genetics | Year: 2013

Asymmetric cell divisions produce daughter cells with distinct sizes and fates, a process important for generating cell diversity during development. Many Caenorhabditis elegans neuroblasts, including the posterior daughter of the Q cell (Q.p), divide to produce a larger neuron or neuronal precursor and a smaller cell that dies. These size and fate asymmetries require the gene pig-1, which encodes a protein orthologous to vertebrate MELK and belongs to the AMPK-related family of kinases. Members of this family can be phosphorylated and activated by the tumor suppressor kinase LKB1, a conserved polarity regulator of epithelial cells and neurons. In this study, we present evidence that the C. elegans orthologs of LKB1 (PAR-4) and its partners STRAD (STRD-1) and MO25 (MOP-25.2) regulate the asymmetry of the Q.p neuroblast division. We show that PAR-4 and STRD-1 act in the Q lineage and function genetically in the same pathway as PIG-1. A conserved threonine residue (T169) in the PIG-1 activation loop is essential for PIG-1 activity, consistent with the model that PAR-4 (or another PAR-4-regulated kinase) phosphorylates and activates PIG-1. We also demonstrate that PIG-1 localizes to centrosomes during cell divisions of the Q lineage, but this localization does not depend on T169 or PAR-4. We propose that a PAR-4-STRD-1 complex stimulates PIG-1 kinase activity to promote asymmetric neuroblast divisions and the generation of daughter cells with distinct fates. Changes in cell fate may underlie many of the abnormal behaviors exhibited by cells after loss of PAR-4 or LKB1. © 2013 by the Genetics Society of America.

Reutter H.,Institute of Human Genetics | Reutter H.,University of Bonn | Ludwig M.,University of Bonn
Molecular Syndromology | Year: 2013

The VATER/VACTERL association is typically defined by the presence of at least 3 of the following congenital malformations: Vertebral anomalies, Anal atresia, Cardiac malformations, Tracheo-Esophageal fistula, Renal anomalies, and Limb abnormalities. The involvement of genetic factors in the development of this rare association is suggested by reports of familial occurrence, the increased prevalence of component features among first-degree relatives of affected individuals, high concordance rates among monozygotic twins, chromosomal (micro-)aberrations or single gene mutations in individuals with the VATER/VACTERL phenotype, as well as murine knock-out models. Despite substantial efforts over the past decade, the genetic etiology of the VATER/VACTERL association in most instances remains elusive. The application of new genomic technologies such as high-resolution copy number variation studies or next-generation exome sequencing might lead to the identification of some of these causes. © 2012 S. Karger AG, Basel.

Wright M.J.,Institute of Human Genetics | Irving M.D.,Guys and St Thomas NHS Foundation Trust
Archives of Disease in Childhood | Year: 2012

Achondroplasia, o ne of the skeletal dysplasias and the commonest form of disproportionate short stature, has a different developmental and growth profi le compared to average stature children. In addition, a specifi c group of complications occur more frequently in children with achondroplasia. These include common but usually relatively minor complications such as recurrent otitis media, and rarer but more severe problems such as cervicomedullary compression. Knowledge of these complications, appropriate surveillance strategies and treatment options is essential for the paediatrician. The authors review the published literature in this area and provide a system based approach to the management of the healthcare needs of the child with achondroplasia.

Gavrilov A.,Institute of Gene Biology | Razin S.V.,Moscow State University | Cavalli G.,Institute of Human Genetics
Briefings in Functional Genomics | Year: 2015

Formaldehyde cross-linking is an important component of many technologies, including chromatin immunoprecipitation and chromosome conformation capture. The procedure remains empirical and poorly characterized, however, despite a long history of its use in research. Little is known about the specificity of in vivo cross-linking, its efficiency and chemical adducts induced by the procedure. It is time to search this black box. © The Author 2014. Published by Oxford University Press. All rights reserved.

Martin M.,Institute of Human Genetics | Martin M.,TU Dortmund | Masshofer L.,University of Duisburg - Essen | Temming P.,University of Duisburg - Essen | And 9 more authors.
Nature Genetics | Year: 2013

Gene expression profiles and chromosome 3 copy number divide uveal melanomas into two distinct classes correlating with prognosis. Using exome sequencing, we identified recurrent somatic mutations in EIF1AX and SF3B1, specifically occurring in uveal melanomas with disomy 3, which rarely metastasize. Targeted resequencing showed that 24 of 31 tumors with disomy 3 (77%) had mutations in either EIF1AX (15; 48%) or SF3B1 (9; 29%). Mutations were infrequent (2/35; 5.7%) in uveal melanomas with monosomy 3, which are associated with poor prognosis. Resequencing of 13 uveal melanomas with partial monosomy 3 identified 8 tumors with a mutation in either SF3B1 (7; 54%) or EIF1AX (1; 8%). All EIF1AX mutations caused in-frame changes affecting the N terminus of the protein, whereas 17 of 19 SF3B1 mutations encoded an alteration of Arg625. Resequencing of ten uveal melanomas with disomy 3 that developed metastases identified SF3B1 mutations in three tumors, none of which targeted Arg625. © 2013 Nature America, Inc. All rights reserved.

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