Identification, Characterization, and Precise Mapping of a Human Gene Encoding a Novel Membrane-Spanning Protein from the 22q11 Region Deleted in Velo–Cardio–Facial Syndrome

Sirotkin, Howard I.; Morrow, Bernice E.; Saint-Jore, Bruno; Puech, Anne; Gupta, Ruchira Das; Patanjali, Sankhavaram R.; Skoultchi, Arthur I.; Weissman, Sherman M.; Kucherlapati, Raju

doi:10.1006/geno.1997.4734

Cited by 92 publications

(58 citation statements)

References 24 publications

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“…22 Interval 3 runs from the distal proximal breakpoint in patient JK to the proximal breakpoint in patient NA and contains the TMVCF locus. 23 Interval 4 runs from the proximal breakpoint in patient NA to the distal breakpoint in patient CTAF, and includes PNUTL1, Gp1B , TBX1, COMT, ARVCF, T10, LZTR1, ZNF74, and HCAT4 loci. 22,24 Interval 5 runs from the proximal breakpoint in patient III:3 to the distal breakpoint in patient JK, and contains the immunoglobulin light chain (IGLC) region.…”

Section: Resultsmentioning

confidence: 99%

Atypical deletions suggest five 22q11.2 critical regions related to the DiGeorge/velo-cardio-facial syndrome

et al. 1999

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Deletions of chromosome 22q11.2 have been associated with distinct phenotypes including DiGeorge syndrome (DGS) and velo-cardio-facial (VCFS) syndrome. These diseases result from a failure to form derivatives of the third and fourth branchial arches during development. DGS/VCFS deletions usually encompass about 3 Mb of genomic DNA in more than 90% of patients. However, deletion mapping studies have failed to demonstrate the existence of a single small region of overlap (SRO) and ruled out any obvious correlation between site or size of deletion and severity of clinical phenotype. We describe three patients carrying 'atypical' deletions presenting the DGS/VCFS phenotype. A comparative analysis of deletions in our patients and those previously published has suggested the existence of five distinct critical regions within the 22q11.2 locus. This observation argues that DGS/VCFS results from haploinsufficiency secondary to a complex and as yet unexplained molecular mechanism, probably involving chromatin effects in mediating gene expression throughout the entire region.

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Section: Resultsmentioning

confidence: 99%

Atypical deletions suggest five 22q11.2 critical regions related to the DiGeorge/velo-cardio-facial syndrome

et al. 1999

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“…Other syndromes with a similar cytogenetic lesion include Shprintzen syndrome, which is marked by the craniofacial and palatal abnormalities, and Takao syndrome, which has mostly cardiac anomalies. Several genes have been identified in the DGCR, including a putative transcription factor, a receptor for adhesion molecule, a serine-threonine kinase, and several proteins with unknown functions (25). The presence of a number of genes in the common deleted region and variability in the phenotypes raised the possibility that the phenotype may be attributed to more than one gene encompassed by a deletion.…”

Section: Discussionmentioning

confidence: 99%

“…DiGeorge syndrome is associated with congenital cardiac abnormalities, hypocalcemia arising from parathyroid hypoplasia, and primary immunodeficiency arising from thymic aplasia. The phenotype may arise from defects in the development of the pharyngeal arches and pouches during embryogenesis (23)(24)(25). Several genes have been identified in the minimal region (2 megabases) commonly deleted.…”

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confidence: 99%

The Human Homolog of Saccharomyces cerevisiae CDC45

Saha

Thome

Yamaguchi

et al. 1998

Journal of Biological Chemistry

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In budding yeast Saccharomyces cerevisiae CDC45 is an essential gene required for initiation of DNA replication. A structurally related protein Tsd2 is necessary for DNA replication in Ustilago maydis. We have identified and cloned the gene for a human protein homologous to the fungal proteins. The human gene CDC45L is 30 kilobases long and contains 15 introns. The 16 exons encode a protein of 566 amino acids. The human protein is 52 and 49.5% similar to CDC45p and Tsd2p, respectively. The level of CDC45L mRNA peaks at G 1 -S transition, but total protein amount remains constant throughout the cell cycle. Consistent with a role of CDC45L protein in the initiation of DNA replication it co-immunoprecipitates from cell extracts with a putative replication initiator protein, human ORC2L. In addition, subcellular fractionation indicates that the association of the protein with the nuclear fraction becomes labile as S phase progresses. The CDC45L gene is located to chromosome 22q11.2 region by cytogenetics and by fluorescence in situ hybridization. This region, known as DiGeorge syndrome critical region, is a minimal area of 2 megabases, which is consistently deleted in DiGeorge syndrome and related disorders. The syndrome is marked by parathyroid hypoplasia, thymic aplasia, or hypoplasia and congenital cardiac abnormalities. CDC45L is the first gene mapped to the DiGeorge syndrome critical region interval whose loss may negatively affect cell proliferation.Eukaryotic DNA replication is regulated during the cell cycle so that it occurs in S phase only once per cycle. This regulation occurs at the level of origin firing. In yeast Saccharomyces cerevisiae, origin recognition complex (ORC) 1 consisting of six subunits (ORC1-6) binds to specific cisacting DNA sequences(1, 2). In human, homologs of four of the ORC subunits (Orc1, Orc2, Orc4, and Orc5) have been identified (3, 4). Homologs of ORC proteins have been identified also in other eukaryotes (5). Although ORC subunits are essential for viability of yeast, their constant binding to replication origins throughout the cell cycle suggests that ORC alone cannot be responsible for the restriction of replication to once per cycle. Another protein, CDC6 in S. cerevisiae (6, 7) and Cdc18 in Schizosaccharomyces pombe (8), is essential for DNA replication and interacts with ORC and cyclin-Cdk. In yeast, CDC6/Cdc18 protein is degraded as the cell cycle progresses through S phase (9, 10). Overexpression of Cdc18 induces re-replication of DNA at S phase in S. pombe (11,12). Homologs of CDC6 have been found in human (13,14) and other eukaryotes (15). Studies with epitopetagged human CDC6Lp suggest that the human protein is regulated through the cell cycle by changes in subcellular localization (14). The epitope-tagged protein is nuclear in G 1 and cytoplasmic in S phase. Like Cdc6p, MCM (mini chromosome maintenance) family of proteins are also implicated in the regulation of initiation of DNA replication. There are six polypeptides in this family (MCM2-7) and homologs identified ...

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“…The identification of claudin-1 and claudin-2 led to the recognition that several genes that had already been cloned [e.g. TMVCF (Sirotkin et al, 1997); RVP.1 (Briehl and Miesfeld, 1991); SEMP1 (Swisshelm et al, 1999); Skulin (Turksen and Troy, 2001) and BCMP1 (Christophe-Hobertus et al, 2001)] also belong to the claudin family (Morita et al, 1999a). To date, 24 distinct claudin family genes have been identified in human (Peacock et al, 1997).…”

Section: The Claudinsmentioning

confidence: 99%

Barriers built on claudins

Turksen¹,

Troy²

2004

Journal of Cell Science

361

288

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We wish to correct some errors that we inadvertently introduced in revising and editing our recent Commentary. In the text, we incorrectly cited (Wolburg et al., 2003) in reference to the downregulation of claudin-23 in gastric cancer; the reference should be (Katoh and Katoh, 2003) as correctly cited in Table 3. (Peacock et al., 1997) was mistakenly inserted in relation to the discussion of the number of claudin genes. We also wrote the number of human claudin genes as 24, the number currently ascribed to the mouse claudin genes (GenBank). The correct number ascribed to human claudin genes by (Katoh and Katoh, 2003) is 23, up from the originally predicted 20 (Venter et al., 2001). In this regard, it is worth noting that, since our Commentary was published, (Loh et al., 2004) have annotated the claudins in the teleost Fugu rubripes genome and reported 56 claudin genes, of which only 35 can be assigned orthology to 17 mammalian claudin genes, with the remaining 21 being specific to the fish lineage and most of the 56 expressed in a more or less tissue-specific fashion, or at particular developmental stages. This, along with other issues we raised, suggests that additional annotation of multiple other genomes and other functional genomics approaches will be useful to advance our understanding of claudin biology and physiology. Finally, based on a Clustal analysis of full-length claudins, we reported that there is a highly conserved WWCC motif of unknown function within the first loop of the claudins analysed; a motif also reported in alignments of claudins carried out by (Katoh and Katoh, 2003). IntroductionIn multicellular organisms, certain tissues must be separated from each other and protected against the external environment. Epithelial and endothelial sheets achieve this by providing cellular borders that cover external and internal surfaces throughout the body. Complexes between adjacent cells in these sheets include gap junctions, desmosomes, adherence junctions and tight junctions (TJs) -also known as the zonula occludens. Early ultrastructural and morphological data revealed TJs as continuous circumferential intercellular contacts between epithelial cells (Farquhar and Palade, 1963) that create a barrier to the paracellular movement of water, solutes and immune cells (Madara, 1998;Nusrat et al., 2000). Later work showed that this epithelial barrier is heterogeneous in tightness and dynamics depending on the tissue. In addition it is physiologically regulated, and its disruption contributes to human disease. Numerous in-depth reviews on TJs exist (Begley and Brightman, 2003;Fanning et al., 1999; GonzalezMariscal et al., 2003;Heiskala et al., 2001;Madara, 1989;Mitic and Anderson, 1998;Stevenson, 1999;Tsukita and Furuse, 2000a;Tsukita and Furuse, 2000b;Tsukita et al., 2001;Zahraoui et al., 2000). Here we therefore only briefly summarize their essential features and then focus on the recent identification of claudins and our evolving understanding of their contribution to TJ structure and function. Tight...

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Identification, Characterization, and Precise Mapping of a Human Gene Encoding a Novel Membrane-Spanning Protein from the 22q11 Region Deleted in Velo–Cardio–Facial Syndrome

Cited by 92 publications

References 24 publications

Atypical deletions suggest five 22q11.2 critical regions related to the DiGeorge/velo-cardio-facial syndrome

Atypical deletions suggest five 22q11.2 critical regions related to the DiGeorge/velo-cardio-facial syndrome

The Human Homolog of Saccharomyces cerevisiae CDC45

Barriers built on claudins

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