Cohen Syndrome Is Caused by Mutations in a Novel Gene, COH1, Encoding a Transmembrane Protein with a Presumed Role in Vesicle-Mediated Sorting and Intracellular Protein Transport

Kolehmainen, Juha; Black, Graeme C M; Saarinen, Anne; Chandler, Kate; Clayton‐Smith, Jill; Träskelin, Ann-Liz; Perveen, Rahat; Kivitie‐Kallio, Satu; Norio, Reijo; Warburg, Mette; Fryns, Jean‐Pierre; Chapelle, Albert de la; Lehesjoki, Anna‐Elina

doi:10.1086/375454

Cited by 328 publications

(308 citation statements)

References 37 publications

Supporting

Mentioning

294

Contrasting

Unclassified

Order By: Relevance

“…Regulation of cell fate by αSnap may affect other organs, but previous analysis has not shown hypoplasia of other organs 1 in hyh mice, perhaps because other tissues regulate size postnatally, whereas the postnatal brain contains largely postmitotic neurons. Other genes that affect the size of the central nervous system in humans commonly do not affect other organs, even when they are ubiquitously expressed 27,28 29 , analysis of the hyh mutant supports this role and provides an opportunity to examine the role of apical vesicle trafficking in other aspects of neural development. The hyh mutant has additional defects in cerebellar development, neuronal migration and axonal pathfinding (data not shown), suggesting roles for apical trafficking in these processes.…”

mentioning

confidence: 86%

The hyh mutation uncovers roles for αSnap in apical protein localization and control of neural cell fate

et al. 2004

View full text Add to dashboard Cite

The hyh (hydrocephalus with hop gait) mouse shows a markedly small cerebral cortex at birth and dies postnatally from progressive enlargement of the ventricular system 1,2 . Here we show that the small hyh cortex reflects altered cell fate. Neural progenitor cells withdraw prematurely from the cell cycle, producing more early-born, deep-layer cerebral cortical neurons but depleting the cortical progenitor pool, such that late-born, upper-layer cortical neurons are underproduced, creating a small cortex. hyh mice carry a hypomorphic missense mutation in the gene Napa encoding soluble N-ethylmaleimidesensitive factor (NSF) attachment protein alpha (αSnap), involved in SNAP receptor (SNARE)-mediated vesicle fusion in many cellular contexts. A targeted null Napa mutation is embryonically lethal. Altered neural cell fate is accompanied by abnormal localization of many apical proteins implicated in regulation of neural cell fate, including E-cadherin, β-catenin, atypical protein kinase C (aPKC) and INADL (inactivation-noafterpotential D-like, also known as protein associated with Lin7, or Pals1). Apical localization of the SNARE Vamp7 is also disrupted. Thus, αSnap is essential for apical protein localization and cell fate determination in neuroepithelial cells.

show abstract

mentioning

confidence: 86%

The hyh mutation uncovers roles for αSnap in apical protein localization and control of neural cell fate

et al. 2004

View full text Add to dashboard Cite

show abstract

“…More recently, Cohen syndrome was found to be associated with mutations in the COH1 gene in different populations with a broader clinical spectrum than the Finnish subtype (Falk et al 2004;Hennies et al 2004;Kolehmainen et al 2003;Mochida et al 2004;Seifert et al 2006). To clarify the clinical and molecular features associated with Cohen syndrome in the Italian population, we describe here 10 patients from nine Italian families in which COH1 mutations have been identified.…”

Section: Introductionmentioning

confidence: 99%

Clinical and molecular characterization of Italian patients affected by Cohen syndrome

et al. 2007

View full text Add to dashboard Cite

Cohen syndrome is an autosomal recessive disorder with variability in the clinical manifestations, characterized by developmental delay, visual disability, facial dysmorphisms and intermittent neutropenia. We described a cohort of 10 patients affected by Cohen syndrome from nine Italian families ranging from 5 to 52 years at assessment. Characteristic age related facial changes were well documented. Visual anomalies, namely retinopathy and myopia, were present in 9/10 patients (retinopathy in 9/10 and myopia in 8/10). Truncal obesity has been described in all patients older than 6 years (8/8). DNA samples from all patients were analyzed for mutations in COH1 by DHPLC. We detected 15 COH1 alterations most of them were truncating mutations, only one being a missense change. Partial gene deletions have been found in two families. Most mutations were private. Two were already reported in the literature just once. A single base deletion leading to p.T3708fs3769, never reported before, was found in three apparently unrelated families deriving from a restricted area of the Veneto's lowland, between Padova town and Tagliamento river, in heterozygous state. Given the geographical conformation of this region, which is neither geographically or culturally isolated, a recent origin of the mutation could be hypothesized.

show abstract

“…Genes located near these loci perform a broad range of functions including DNA synthesis and repair (REV3L [48] and PCNA [73]), transcription (XPMC2H [55], HNRPUL1 [45], BANP [67], ATF7 [64], ZNF215 [3], and MYC [21]), mitochondrial function (CA5A [58] and COX7A2L [79]), and mitotic spindle assembly (CDCA8) (16). One target has direct involvement in the secretory functions of the cell (COH1) (41), while another target has a direct link to the unfolded protein response (UPR) (SYVN1) (75). CGI ChIP-chip to identify p53 targets genes therefore identifies a broad range of potential target genes that may mediate direct effects on p53 function.…”

Section: Resultsmentioning

confidence: 99%

Functional Analysis of p53 Binding under Differential Stresses

Krieg

Hammond

Giaccia

2006

Molecular and Cellular Biology

View full text Add to dashboard Cite

Hypoxia and DNA damage stabilize the p53 protein, but the subsequent effect that each stress has on transcriptional regulation of known p53 target genes is variable. We have used chromatin immunoprecipitation followed by CpG island (CGI) microarray hybridization to identify promoters bound by p53 under both DNA-damaging and non-DNA-damaging conditions in HCT116 cells. Using gene-specific PCR analysis, we have verified an association with CGIs of the highest enrichment (>2.5-fold) (REV3L, XPMC2H, HNRPUL1, TOR1AIP1, glutathione peroxidase 1, and SCFD2), with CGIs of intermediate enrichment (>2.2-fold) (COX7A2L, SYVN1, and JAG2), and with CGIs of low enrichment (>2.0-fold) (MYC and PCNA). We found little difference in promoter binding when p53 is stabilized by these two distinctly different stresses. However, expression of these genes varies a great deal: while a few genes exhibit classical induction with adriamycin, the majority of the genes are unchanged or are mildly repressed by either hypoxia or adriamycin. Further analysis using p53 mutated in the core DNA binding domain revealed that the interaction of p53 with CGIs may be occurring through both sequence-dependent and -independent mechanisms. Taken together, these experiments describe the identification of novel p53 target genes and the subsequent discovery of distinctly different expression phenomena for p53 target genes under different stress scenarios.The tumor microenvironment is a major factor influencing tumor growth, metastatic potential, and response to chemotherapeutic drugs and radiation therapy (7). The hypoxia-inducible factor (HIF) family of transcription factors regulates the expression of key enzymes in anaerobic glycolysis and proangiogenic factors (i.e., vascular endothelial growth factor), aiding cells in adapting to a low-oxygen environment (15). Thus, a tumor adapts to hypoxia first by sustaining itself via anaerobic metabolism and then by stimulating angiogenesis to acquire more nutrients and oxygen. However, the resulting vasculature tends to have aberrant structures with irregular blood flow and leaky walls, paradoxically creating regions of transient hypoxia and reoxygenation (76). Reoxygenation after hypoxia causes DNA damage, exacerbating genomic instability (25). The porous structure of the tumor vasculature may also provide an escape route for metastasizing cells. Repeated cycles of hypoxia, vascular formation, and reoxygenation select for cells that are more likely to survive in a restrictive environment. The consequences of this process are cancer cells that are more aggressive, more likely to metastasize, and more likely to be resistant to radiation and chemotherapy. Intimately tied to this process is the selection for cells that have lost the expression of functional p53 (19).A variety of cellular stresses, including DNA damage, oncogenic transformation, and hypoxia, stabilize the p53 protein by activating a host of stress-inducible kinases that phosphorylate p53 and MDM2, resulting in increased levels of p53 (17). Stabilized ...

show abstract

Cohen Syndrome Is Caused by Mutations in a Novel Gene, COH1, Encoding a Transmembrane Protein with a Presumed Role in Vesicle-Mediated Sorting and Intracellular Protein Transport

Cited by 328 publications

References 37 publications

The hyh mutation uncovers roles for αSnap in apical protein localization and control of neural cell fate

The hyh mutation uncovers roles for αSnap in apical protein localization and control of neural cell fate

Clinical and molecular characterization of Italian patients affected by Cohen syndrome

Functional Analysis of p53 Binding under Differential Stresses

Contact Info

Product

Resources

About