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  • 1
    Publication Date: 2011-07-22
    Description: 〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3638940/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3638940/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Oh, Edwin C -- Katsanis, Nicholas -- R01 DK072301/DK/NIDDK NIH HHS/ -- England -- Nature. 2011 Jul 20;475(7356):299-300. doi: 10.1038/475299a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21776070" target="_blank"〉PubMed〈/a〉
    Keywords: Aging/genetics/metabolism ; Animals ; Animals, Newborn/growth & development/*metabolism ; Astrocytes/*metabolism ; Embryo, Mammalian/metabolism ; Female ; *Genomic Imprinting ; Intercellular Signaling Peptides and Proteins/genetics/*metabolism ; Male ; Mice ; Neural Stem Cells/*metabolism ; *Neurogenesis ; Olfactory Bulb/cytology ; Stem Cell Niche/*cytology/secretion
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2012-01-28
    Description: Neighboring genes are often coordinately expressed within cis-regulatory modules, but evidence that nonparalogous genes share functions in mammals is lacking. Here, we report that mutation of either TMEM138 or TMEM216 causes a phenotypically indistinguishable human ciliopathy, Joubert syndrome. Despite a lack of sequence homology, the genes are aligned in a head-to-tail configuration and joined by chromosomal rearrangement at the amphibian-to-reptile evolutionary transition. Expression of the two genes is mediated by a conserved regulatory element in the noncoding intergenic region. Coordinated expression is important for their interdependent cellular role in vesicular transport to primary cilia. Hence, during vertebrate evolution of genes involved in ciliogenesis, nonparalogous genes were arranged to a functional gene cluster with shared regulatory elements.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3671610/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3671610/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lee, Jeong Ho -- Silhavy, Jennifer L -- Lee, Ji Eun -- Al-Gazali, Lihadh -- Thomas, Sophie -- Davis, Erica E -- Bielas, Stephanie L -- Hill, Kiley J -- Iannicelli, Miriam -- Brancati, Francesco -- Gabriel, Stacey B -- Russ, Carsten -- Logan, Clare V -- Sharif, Saghira Malik -- Bennett, Christopher P -- Abe, Masumi -- Hildebrandt, Friedhelm -- Diplas, Bill H -- Attie-Bitach, Tania -- Katsanis, Nicholas -- Rajab, Anna -- Koul, Roshan -- Sztriha, Laszlo -- Waters, Elizabeth R -- Ferro-Novick, Susan -- Woods, C Geoffrey -- Johnson, Colin A -- Valente, Enza Maria -- Zaki, Maha S -- Gleeson, Joseph G -- DK068306/DK/NIDDK NIH HHS/ -- DK072301/DK/NIDDK NIH HHS/ -- DK075972/DK/NIDDK NIH HHS/ -- DK090917/DK/NIDDK NIH HHS/ -- EY021872/EY/NEI NIH HHS/ -- G0700073/Medical Research Council/United Kingdom -- GGP08145/Telethon/Italy -- HD042601/HD/NICHD NIH HHS/ -- NS04843/NS/NINDS NIH HHS/ -- NS052455/NS/NINDS NIH HHS/ -- P30 CA023100/CA/NCI NIH HHS/ -- P30NS047101/NS/NINDS NIH HHS/ -- R01 DK068306/DK/NIDDK NIH HHS/ -- R01 DK072301/DK/NIDDK NIH HHS/ -- R01 DK075972/DK/NIDDK NIH HHS/ -- R01 EY021872/EY/NEI NIH HHS/ -- R01 HD042601/HD/NICHD NIH HHS/ -- R01 NS048453/NS/NINDS NIH HHS/ -- R01 NS052455/NS/NINDS NIH HHS/ -- U54 HG003067/HG/NHGRI NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2012 Feb 24;335(6071):966-9. doi: 10.1126/science.1213506. Epub 2012 Jan 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Neurogenetics Laboratory, Howard Hughes Medical Institute (HHMI), Department of Neurosciences, University of California, San Diego, CA, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22282472" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Cell Line ; Cerebellar Diseases/*genetics/metabolism/pathology ; Cilia/metabolism/*ultrastructure ; Conserved Sequence ; DNA, Intergenic ; *Evolution, Molecular ; Eye Abnormalities/*genetics/metabolism/pathology ; Gene Expression Profiling ; *Gene Expression Regulation ; Genetic Heterogeneity ; *Genetic Loci ; Humans ; Kidney Diseases, Cystic/*genetics/metabolism/pathology ; Membrane Proteins/chemistry/*genetics/metabolism ; Molecular Sequence Data ; Multigene Family ; Mutation ; Mutation, Missense ; Phenotype ; Protein Transport ; *Regulatory Sequences, Nucleic Acid ; Retina/abnormalities/metabolism/pathology ; Transport Vesicles/metabolism/ultrastructure
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2012-05-19
    Description: Copy number variants (CNVs) are major contributors to genetic disorders. We have dissected a region of the 16p11.2 chromosome--which encompasses 29 genes--that confers susceptibility to neurocognitive defects when deleted or duplicated. Overexpression of each human transcript in zebrafish embryos identified KCTD13 as the sole message capable of inducing the microcephaly phenotype associated with the 16p11.2 duplication, whereas suppression of the same locus yielded the macrocephalic phenotype associated with the 16p11.2 deletion, capturing the mirror phenotypes of humans. Analyses of zebrafish and mouse embryos suggest that microcephaly is caused by decreased proliferation of neuronal progenitors with concomitant increase in apoptosis in the developing brain, whereas macrocephaly arises by increased proliferation and no changes in apoptosis. A role for KCTD13 dosage changes is consistent with autism in both a recently reported family with a reduced 16p11.2 deletion and a subject reported here with a complex 16p11.2 rearrangement involving de novo structural alteration of KCTD13. Our data suggest that KCTD13 is a major driver for the neurodevelopmental phenotypes associated with the 16p11.2 CNV, reinforce the idea that one or a small number of transcripts within a CNV can underpin clinical phenotypes, and offer an efficient route to identifying dosage-sensitive loci.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3366115/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3366115/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Golzio, Christelle -- Willer, Jason -- Talkowski, Michael E -- Oh, Edwin C -- Taniguchi, Yu -- Jacquemont, Sebastien -- Reymond, Alexandre -- Sun, Mei -- Sawa, Akira -- Gusella, James F -- Kamiya, Atsushi -- Beckmann, Jacques S -- Katsanis, Nicholas -- F32MH087123/MH/NIMH NIH HHS/ -- HD06286/HD/NICHD NIH HHS/ -- MH-084018/MH/NIMH NIH HHS/ -- MH-091230/MH/NIMH NIH HHS/ -- P50 MH094268/MH/NIMH NIH HHS/ -- P50 MH094268-02/MH/NIMH NIH HHS/ -- R01 MH091230/MH/NIMH NIH HHS/ -- R01 MH092443/MH/NIMH NIH HHS/ -- England -- Nature. 2012 May 16;485(7398):363-7. doi: 10.1038/nature11091.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Human Disease Modeling and Department of Cell biology, Duke University, Durham, North Carolina 27710, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22596160" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apoptosis/genetics ; Cell Proliferation ; Chromosomes, Human, Pair 16/*genetics ; DNA Copy Number Variations/*genetics ; Gene Dosage/*genetics ; Gene Duplication/genetics ; Head/*abnormalities/embryology ; Humans ; Mice ; Microcephaly/*genetics ; Nuclear Proteins/*genetics/metabolism ; Organ Size/genetics ; *Phenotype ; RNA, Messenger/genetics/metabolism ; Sequence Deletion/genetics ; Transcription, Genetic ; Up-Regulation ; Zebrafish/abnormalities/embryology/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2011-04-08
    Description: Regulatory mechanisms governing the sequence from progenitor cell proliferation to neuronal migration during corticogenesis are poorly understood. Here we report that phosphorylation of DISC1, a major susceptibility factor for several mental disorders, acts as a molecular switch from maintaining proliferation of mitotic progenitor cells to activating migration of postmitotic neurons in mice. Unphosphorylated DISC1 regulates canonical Wnt signalling via an interaction with GSK3beta, whereas specific phosphorylation at serine 710 (S710) triggers the recruitment of Bardet-Biedl syndrome (BBS) proteins to the centrosome. In support of this model, loss of BBS1 leads to defects in migration, but not proliferation, whereas DISC1 knockdown leads to deficits in both. A phospho-dead mutant can only rescue proliferation, whereas a phospho-mimic mutant rescues exclusively migration defects. These data highlight a dual role for DISC1 in corticogenesis and indicate that phosphorylation of this protein at S710 activates a key developmental switch.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3088774/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3088774/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ishizuka, Koko -- Kamiya, Atsushi -- Oh, Edwin C -- Kanki, Hiroaki -- Seshadri, Saurav -- Robinson, Jon F -- Murdoch, Hannah -- Dunlop, Allan J -- Kubo, Ken-ichiro -- Furukori, Keiko -- Huang, Beverly -- Zeledon, Mariela -- Hayashi-Takagi, Akiko -- Okano, Hideyuki -- Nakajima, Kazunori -- Houslay, Miles D -- Katsanis, Nicholas -- Sawa, Akira -- DK-072301/DK/NIDDK NIH HHS/ -- DK-075972/DK/NIDDK NIH HHS/ -- G0600765/Medical Research Council/United Kingdom -- HD-04260/HD/NICHD NIH HHS/ -- MH-069853/MH/NIMH NIH HHS/ -- MH-084018/MH/NIMH NIH HHS/ -- MH-085226/MH/NIMH NIH HHS/ -- MH-088753/MH/NIMH NIH HHS/ -- MH-091230/MH/NIMH NIH HHS/ -- R01 DK072301/DK/NIDDK NIH HHS/ -- R01 DK075972/DK/NIDDK NIH HHS/ -- R01 DK075972-06/DK/NIDDK NIH HHS/ -- R01 HD042601/HD/NICHD NIH HHS/ -- R01 HD042601-10/HD/NICHD NIH HHS/ -- R01 MH091230/MH/NIMH NIH HHS/ -- R01 MH092443/MH/NIMH NIH HHS/ -- England -- Nature. 2011 May 5;473(7345):92-6. doi: 10.1038/nature09859. Epub 2011 Apr 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21471969" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; COS Cells ; Cell Movement/genetics ; Cell Proliferation ; Cercopithecus aethiops ; Cerebral Cortex/cytology/*embryology/physiology ; Gene Knockdown Techniques ; Glycogen Synthase Kinase 3/metabolism ; HEK293 Cells ; Humans ; Mice ; Microtubule-Associated Proteins/genetics/metabolism ; *Nerve Tissue Proteins/genetics/metabolism ; Neurons/*cytology/metabolism/*physiology ; PC12 Cells ; Phosphorylation ; Protein Binding ; Rats ; Signal Transduction ; Stem Cells/*cytology ; Wnt Proteins/metabolism ; beta Catenin/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
    Publication Date: 2015-07-01
    Description: Patterns of amino acid conservation have served as a tool for understanding protein evolution. The same principles have also found broad application in human genomics, driven by the need to interpret the pathogenic potential of variants in patients. Here we performed a systematic comparative genomics analysis of human disease-causing missense variants. We found that an appreciable fraction of disease-causing alleles are fixed in the genomes of other species, suggesting a role for genomic context. We developed a model of genetic interactions that predicts most of these to be simple pairwise compensations. Functional testing of this model on two known human disease genes revealed discrete cis amino acid residues that, although benign on their own, could rescue the human mutations in vivo. This approach was also applied to ab initio gene discovery to support the identification of a de novo disease driver in BTG2 that is subject to protective cis-modification in more than 50 species. Finally, on the basis of our data and models, we developed a computational tool to predict candidate residues subject to compensation. Taken together, our data highlight the importance of cis-genomic context as a contributor to protein evolution; they provide an insight into the complexity of allele effect on phenotype; and they are likely to assist methods for predicting allele pathogenicity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4537371/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4537371/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jordan, Daniel M -- Frangakis, Stephan G -- Golzio, Christelle -- Cassa, Christopher A -- Kurtzberg, Joanne -- Task Force for Neonatal Genomics -- Davis, Erica E -- Sunyaev, Shamil R -- Katsanis, Nicholas -- R01 DK072301/DK/NIDDK NIH HHS/ -- R01 DK075972/DK/NIDDK NIH HHS/ -- R01 DK095721/DK/NIDDK NIH HHS/ -- R01 EY021872/EY/NEI NIH HHS/ -- R01 GM078598/GM/NIGMS NIH HHS/ -- R01 HD042601/HD/NICHD NIH HHS/ -- R01 MH101244/MH/NIMH NIH HHS/ -- R01DK072301/DK/NIDDK NIH HHS/ -- R01DK075972/DK/NIDDK NIH HHS/ -- R01EY021872/EY/NEI NIH HHS/ -- R01HD04260/HD/NICHD NIH HHS/ -- U01 HG006500/HG/NHGRI NIH HHS/ -- England -- Nature. 2015 Aug 13;524(7564):225-9. doi: 10.1038/nature14497. Epub 2015 Jun 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. ; Center for Human Disease Modeling, Duke University, Durham, North Carolina 27701, USA. ; Department of Pediatrics, Division of Pediatric Blood and Marrow Transplantation, Duke University, Durham, North Carolina 27710, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26123021" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/genetics ; Alleles ; Animals ; Disease/*genetics ; Evolution, Molecular ; Genome, Human/genetics ; *Genomics ; Humans ; Immediate-Early Proteins/genetics ; Microcephaly/genetics ; Mutation, Missense/*genetics ; Phenotype ; Proteins/genetics ; Sequence Alignment ; Suppression, Genetic/*genetics ; Tumor Suppressor Proteins/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 6
    Publication Date: 2015-03-26
    Description: Autism is a multifactorial neurodevelopmental disorder affecting more males than females; consequently, under a multifactorial genetic hypothesis, females are affected only when they cross a higher biological threshold. We hypothesize that deleterious variants at conserved residues are enriched in severely affected patients arising from female-enriched multiplex families with severe disease, enhancing the detection of key autism genes in modest numbers of cases. Here we show the use of this strategy by identifying missense and dosage sequence variants in the gene encoding the adhesive junction-associated delta-catenin protein (CTNND2) in female-enriched multiplex families and demonstrating their loss-of-function effect by functional analyses in zebrafish embryos and cultured hippocampal neurons from wild-type and Ctnnd2 null mouse embryos. Finally, through gene expression and network analyses, we highlight a critical role for CTNND2 in neuronal development and an intimate connection to chromatin biology. Our data contribute to the understanding of the genetic architecture of autism and suggest that genetic analyses of phenotypic extremes, such as female-enriched multiplex families, are of innate value in multifactorial disorders.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4383723/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4383723/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Turner, Tychele N -- Sharma, Kamal -- Oh, Edwin C -- Liu, Yangfan P -- Collins, Ryan L -- Sosa, Maria X -- Auer, Dallas R -- Brand, Harrison -- Sanders, Stephan J -- Moreno-De-Luca, Daniel -- Pihur, Vasyl -- Plona, Teri -- Pike, Kristen -- Soppet, Daniel R -- Smith, Michael W -- Cheung, Sau Wai -- Martin, Christa Lese -- State, Matthew W -- Talkowski, Michael E -- Cook, Edwin -- Huganir, Richard -- Katsanis, Nicholas -- Chakravarti, Aravinda -- 1U24MH081810/MH/NIMH NIH HHS/ -- 5R25MH071584-07/MH/NIMH NIH HHS/ -- MH095867/MH/NIMH NIH HHS/ -- MH19961-14/MH/NIMH NIH HHS/ -- R00 MH095867/MH/NIMH NIH HHS/ -- R01 DK075972/DK/NIDDK NIH HHS/ -- R01 MH060007/MH/NIMH NIH HHS/ -- R01 MH074090/MH/NIMH NIH HHS/ -- R01MH074090/MH/NIMH NIH HHS/ -- R01MH081754/MH/NIMH NIH HHS/ -- England -- Nature. 2015 Apr 2;520(7545):51-6. doi: 10.1038/nature14186. Epub 2015 Mar 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Center for Complex Disease Genomics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Predoctoral Training Program in Human Genetics and Molecular Biology, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [3] National Institute of Mental Health (NIMH) Autism Centers of Excellence (ACE) Genetics Consortium at the University of California, Los Angeles, Los Angeles, California 90095, USA. ; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; Center for Human Disease Modeling, Duke University, Durham, North Carolina 27710, USA. ; Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. ; 1] Center for Complex Disease Genomics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] National Institute of Mental Health (NIMH) Autism Centers of Excellence (ACE) Genetics Consortium at the University of California, Los Angeles, Los Angeles, California 90095, USA. ; 1] Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA [2] Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114 USA. ; 1] National Institute of Mental Health (NIMH) Autism Centers of Excellence (ACE) Genetics Consortium at the University of California, Los Angeles, Los Angeles, California 90095, USA [2] Department of Psychiatry, University of California, San Francisco, San Francisco, California 94158, USA. ; 1] National Institute of Mental Health (NIMH) Autism Centers of Excellence (ACE) Genetics Consortium at the University of California, Los Angeles, Los Angeles, California 90095, USA [2] Department of Psychiatry, Yale University, New Haven, Connecticut 06511, USA. ; Leidos Biomedical Research, Inc., Frederick, Maryland 21702, USA. ; National Human Genome Research Institute, Bethesda, Maryland 20892, USA. ; Baylor College of Medicine, Houston, Texas 77030, USA. ; 1] National Institute of Mental Health (NIMH) Autism Centers of Excellence (ACE) Genetics Consortium at the University of California, Los Angeles, Los Angeles, California 90095, USA [2] Autism &Developmental Medicine Institute, Geisinger Health System, Lewisburg, Pennsylvania 17837, USA. ; University of Illinois at Chicago, Chicago, Illinois 60608, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25807484" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Autistic Disorder/*genetics/*metabolism ; Brain/embryology/*metabolism ; Catenins/*deficiency/*genetics/metabolism ; Cells, Cultured ; Chromatin/genetics/metabolism ; DNA Copy Number Variations/genetics ; Embryo, Mammalian/cytology/metabolism ; Exome/genetics ; Female ; Gene Expression ; Gene Expression Regulation, Developmental ; Hippocampus/pathology ; Humans ; Male ; Mice ; Models, Genetic ; Multifactorial Inheritance/genetics ; Mutation, Missense ; Nerve Net ; Neurons/cytology/metabolism ; Sex Characteristics ; Zebrafish/embryology/genetics/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 7
    Keywords: HEART ; MOUSE ; MUTATIONS ; HOMOLOG ; DEFECTS ; DYSKINESIA ; CHLAMYDOMONAS ; DNAH5 ; FLAGELLA
    Abstract: Primary ciliary dyskinesia (PCD) is an inherited disorder characterized by recurrent infections of the upper and lower respiratory tract, reduced fertility in males and situs inversus in about 50% of affected individuals (Kartagener syndrome). It is caused by motility defects in the respiratory cilia that are responsible for airway clearance, the flagella that propel sperm cells and the nodal monocilia that determine left-right asymmetry(1). Recessive mutations that cause PCD have been identified in genes encoding components of the outer dynein arms, radial spokes and cytoplasmic pre-assembly factors of axonemal dyneins, but these mutations account for only about 50% of cases of PCD. We exploited the unique properties of dog populations to positionally clone a new PCD gene, CCDC39. We found that loss-of-function mutations in the human ortholog underlie a substantial fraction of PCD cases with axonemal disorganization and abnormal ciliary beating. Functional analyses indicated that CCDC39 localizes to ciliary axonemes and is essential for assembly of inner dynein arms and the dynein regulatory complex
    Type of Publication: Journal article published
    PubMed ID: 21131972
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  • 8
    ISSN: 1432-1203
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract. A large number of extracellular matrix proteins have been found to contain variations of the epidermal growth factor (EGF) domain and have been implicated in functions as diverse as blood coagulation, activation of complement, and determination of cell fate during development. The gene for one such protein, S1–5, was identified from a subtractively enriched cDNA library from a patient with Werner syndrome and was shown to be preferentially expressed in senescent and quiescent fibroblasts. We have cloned and characterized, in human and mouse, a novel gene that shows significant homology to the gene for S1–5. We have determined that the encoded protein contains four EGF domains and six calcium-binding EGF domains. On the basis of its homology to known proteins, we have designated this gene EFEMP2 (Egf-containing fibulin-like extracellular matrix protein 2) and the gene for the S1–5 protein EFEMP1. Like EFEMP1, this novel gene is expressed in a wide range of adult and fetal tissues. In contrast to EFEMP1, however, EFEMP2 is not significantly overexpressed in senescent or quiescent fibroblasts, suggesting a diversity of function within this new EGF-like domain subfamily. We have mapped EFEMP2 to 11q13, in an area where several retinopathies have been genetically linked. Given that mutations in EFEMP1 have been recently described in patients with Doyne honeycomb retinal dystrophy, EFEMP2 becomes a good candidate for such disorders.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1432-1777
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Type of Medium: Electronic Resource
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  • 10
    Publication Date: 2018-07-03
    Description: Trisomy for human chromosome 21 (Hsa21) results in Down syndrome (DS), one of the most genetically complex conditions compatible with human survival. Assessment of the physiological consequences of dosage-driven overexpression of individual Hsa21 genes during early embryogenesis and the resulting contributions to DS pathology in mammals are not tractable in a systematic way. A recent study looked at loss-of-function of a subset of Caenorhabditis elegans orthologs of Hsa21 genes and identified ten candidates with behavioral phenotypes, but the equivalent over-expression experiment has not been done. We turned to zebrafish as a developmental model and, using a number of surrogate phenotypes, we screened Hsa21 genes for effects on early embyrogenesis. We prepared a library of 164 cDNAs of conserved protein coding genes, injected mRNA into early embryos and evaluated up to 5 days post-fertilization (dpf). Twenty-four genes produced a gross morphological phenotype, 11 of which could be reproduced reliably. Seven of these gave a phenotype consistent with down regulation of the sonic hedgehog (Shh) pathway; two showed defects indicative of defective neural crest migration; one resulted consistently in pericardial edema; and one was embryonic lethal. Combinatorial injections of multiple Hsa21 genes revealed both additive and compensatory effects, supporting the notion that complex genetic relationships underlie end phenotypes of trisomy that produce DS. Together, our data suggest that this system is useful in the genetic dissection of dosage-sensitive gene effects on early development and can inform the contribution of both individual loci and their combinatorial effects to phenotypes relevant to the etiopathology of DS.
    Electronic ISSN: 2160-1836
    Topics: Biology
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