Abstract:
:Inactivating mutations in chromodomain helicase DNA binding protein 7 (CHD7) cause CHARGE syndrome, a severe multiorgan system disorder of which Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is a minor feature. Recent reports have described predominantly missense CHD7 alleles in IGD patients, but it is unclear if these alleles are relevant to causality or overall genetic burden of Kallmann syndrome (KS) and normosmic form of IGD. To address this question, we sequenced CHD7 in 783 well-phenotyped IGD patients lacking full CHARGE features; we identified nonsynonymous rare sequence variants in 5.2% of the IGD cohort (73% missense and 27% splice variants). Functional analyses in zebrafish using a surrogate otolith assay of a representative set of these CHD7 alleles showed that rare sequence variants observed in controls showed no altered function. In contrast, 75% of the IGD-associated alleles were deleterious and resulted in both KS and normosmic IGD. In two families, pathogenic mutations in CHD7 coexisted with mutations in other known IGD genes. Taken together, our data suggest that rare deleterious CHD7 alleles contribute to the mutational burden of patients with both KS and normosmic forms of IGD in the absence of full CHARGE syndrome. These findings (i) implicate a unique role or preferential sensitivity for CHD7 in the ontogeny of GnRH neurons, (ii) reiterate the emerging genetic complexity of this family of IGD disorders, and (iii) demonstrate how the coordinated use of well-phenotyped cohorts, families, and functional studies can inform genetic architecture and provide insights into the developmental biology of cellular systems.
journal_name
Proc Natl Acad Sci U S Aauthors
Balasubramanian R,Choi JH,Francescatto L,Willer J,Horton ER,Asimacopoulos EP,Stankovic KM,Plummer L,Buck CL,Quinton R,Nebesio TD,Mericq V,Merino PM,Meyer BF,Monies D,Gusella JF,Al Tassan N,Katsanis N,Crowley WF Jrdoi
10.1073/pnas.1417438111subject
Has Abstractpub_date
2014-12-16 00:00:00pages
17953-8issue
50eissn
0027-8424issn
1091-6490pii
1417438111journal_volume
111pub_type
杂志文章abstract::Wood-degrading brown rot fungi are essential recyclers of plant biomass in forest ecosystems. Their efficient cellulolytic systems, which have potential biotechnological applications, apparently depend on a combination of two mechanisms: lignocellulose oxidation (LOX) by reactive oxygen species (ROS) and polysaccharid...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1608454113
更新日期:2016-09-27 00:00:00
abstract::Electronic nematicity, a correlated state that spontaneously breaks rotational symmetry, is observed in several layered quantum materials. In contrast to their liquid-crystal counterparts, the nematic director cannot usually point in an arbitrary direction (XY nematics), but is locked by the crystal to discrete direct...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1909172117
更新日期:2020-03-24 00:00:00
abstract::The carboxy-terminal domain (CTD) code encrypted within the Y1S2P3T4S5P6S7 heptad repeats of RNA polymerase II (Pol2) is deeply rooted in eukaryal biology. Key steps to deciphering the code are identifying the events in gene expression that are governed by individual "letters" and then defining a vocabulary of multile...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1810711115
更新日期:2018-11-06 00:00:00
abstract::Although sexual selection theory has proved successful in explaining a wide array of male ornaments, the function of ornaments occurring in females is largely unknown. Traditionally, female ornaments have been considered nonfunctional, being merely a genetically correlated response to selection for male ornamentation....
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.211439298
更新日期:2001-11-06 00:00:00
abstract::We have devised a general strategy for gene mapping based upon the direct amplification of a target sequence within a single microdissected Giemsa-banded chromosomal segment using the polymerase chain reaction. The usefulness of this approach was demonstrated by mapping a cloned human brain sodium channel (alpha subun...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.88.2.335
更新日期:1991-01-15 00:00:00
abstract::O-GlcNAc is an intracellular posttranslational modification that governs myriad cell biological processes and is dysregulated in human diseases. Despite this broad pathophysiological significance, the biochemical effects of most O-GlcNAcylation events remain uncharacterized. One prevalent hypothesis is that O-GlcNAc m...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1722437115
更新日期:2018-06-05 00:00:00
abstract::Intracellular transport is based on molecular motors that pull cargos along cytoskeletal filaments. One motor species always moves in one direction, e.g., conventional kinesin moves to the microtubule plus end, whereas cytoplasmic dynein moves to the microtubule minus end. However, many cellular cargoes are observed t...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0706825105
更新日期:2008-03-25 00:00:00
abstract::The tendency for genetic architectures to exhibit epistasis among mutations plays a central role in the modern synthesis of evolutionary biology and in theoretical descriptions of many evolutionary processes. Nevertheless, few studies unquestionably show whether, and how, mutations typically interact. Beneficial mutat...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0404125101
更新日期:2004-10-26 00:00:00
abstract::A single animal group can display different types of collective motion at different times. For a one-dimensional individual-based model of self-organizing group formation, we show that repeated switching between distinct ordered collective states can occur entirely because of stochastic effects. We introduce a framewo...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0608270104
更新日期:2007-04-03 00:00:00
abstract::Although the apoptotic role of caspases has been largely understood, accumulating evidence in Drosophila suggests that caspases also control other processes than apoptotic cell death. However, how caspases contribute to the development of the mammalian nervous system remains obscure. Here, we provide unique evidence t...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0910488107
更新日期:2010-07-27 00:00:00
abstract::Elucidating the mechanism of folding of polynucleotides depends on accurate estimates of free energy surfaces and a quantitative description of the kinetics of structure formation. Here, the kinetics of hairpin formation in single-stranded DNA are measured after a laser temperature jump. The kinetics are modeled as co...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.131477798
更新日期:2001-07-03 00:00:00
abstract::Controlling the effects of proactive interference (PI), the deleterious effect of prior mental activity on current memory representations, is believed to be a key function of the prefrontal cortex. This view is supported by neuroimaging evidence for a correlation between the longer reaction times caused by high PI con...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0604509103
更新日期:2006-12-19 00:00:00
abstract::Promoter-proximal stalling, a general phenomenon observed during the expression of many RNA polymerase II transcribed genes, is dependent on transcription factor IIH (TFIIH). Reactions lacking TFIIH initiated transcription, but the transcription complex encountered a block to elongation proximal to the promoter. The a...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.95.17.9767
更新日期:1998-08-18 00:00:00
abstract::The neo (neomycin-resistance) gene of transposon Tn5 encodes the enzyme neomycin phosphotransferase II (EC 2.7.1.95), which confers resistance to various aminoglycoside antibiotics, including kanamycin and G418. The gene is widely used as a selectable marker in the transformation of organisms as diverse as bacteria, y...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.87.9.3435
更新日期:1990-05-01 00:00:00
abstract::Synthetic oligonucleotide probes can be easily obtained and used, in contrast to cDNA cloning to develop probes, and thus the present study was carried out to determine whether such probes could also be useful for in situ hybridization. A 24-base synthetic oligonucleotide complementary to part of the alpha-melanocyte-...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.83.15.5419
更新日期:1986-08-01 00:00:00
abstract::It was recently demonstrated that amyloid beta (Abeta) peptide vaccination was effective in reducing the Abeta burden in Alzheimer model mice. However, the clinical trial was halted because of the development of meningoencephalitis in some patients. To overcome this problem, anti-Abeta antibody therapy and other types...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0600966103
更新日期:2006-06-20 00:00:00
abstract::von Willebrand factor (VWF), a protein present in our circulatory system, is necessary to stop bleeding under high shear-stress conditions as found in small blood vessels. The results presented here help unravel how an increase in hydrodynamic shear stress activates VWF's adhesion potential, leading to the counterintu...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0608422104
更新日期:2007-05-08 00:00:00
abstract::A major challenge in interpreting genome sequences is understanding how the genome encodes the information that specifies when and where a gene will be expressed. The first step in this process is the identification of regions of the genome that contain regulatory information. In higher eukaryotes, this cis-regulatory...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.231608898
更新日期:2002-01-22 00:00:00
abstract::Underactivity of the glutamatergic system is an attractive model for the pathophysiology of several major mental illnesses. We previously described a chromosome abnormality disrupting the kainate class ionotropic glutamate receptor gene, GRIK4/KA1, in an individual with schizophrenia and learning disability (mental re...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0800643105
更新日期:2008-09-30 00:00:00
abstract::We have identified a cDNA from a human phytohemagglutinin-activated lymphoblast library encoding a protein that binds 125I-labeled human interleukin 12 (125I-huIL-12) with a Kd of about 5 nM when expressed in COS-7 cells. When coexpressed in COS-7 cells with the previously identified IL-12 beta receptor (IL-12R beta) ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.93.24.14002
更新日期:1996-11-26 00:00:00
abstract::The diversity of the T cell receptor (TCR) repertoire is limited, because of the processes of positive and negative T cell selection. To obtain T cells with specificities beyond the immune system's capacity, we have developed a strategy for retroviral TCR display. In this approach, a library of T cell variants is gene...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.97.26.14578
更新日期:2000-12-19 00:00:00
abstract::Although neural circuits mediating various simple behaviors have been delineated, those generating more complex behaviors are less well described. The discrete structure of avian song control nuclei promises that circuits controlling complex behaviors, such as birdsong, can also be understood. To this end, we develope...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.88.10.4075
更新日期:1991-05-15 00:00:00
abstract::sorLA (Sorting protein-related receptor) is a type-1 membrane protein of unknown function that is expressed in neurons. Its homology to sorting receptors that shuttle between the plasma membrane, endosomes, and the Golgi suggests a related function in neuronal trafficking processes. Because expression of sorLA is redu...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0503689102
更新日期:2005-09-20 00:00:00
abstract::The aim of the present study was to assess possible adverse effects of transgene expression in leaves of field-grown barley relative to the influence of genetic background and the effect of plant interaction with arbuscular mycorrhizal fungi. We conducted transcript profiling, metabolome profiling, and metabolic finge...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1001945107
更新日期:2010-04-06 00:00:00
abstract::Cloned DNA templates were used to direct the transcription of early and late simian virus 40 (SV40) genes by a cell-free RNA-synthesizing system. Transcription by RNA polymerase II was sensitive to low levels of alpha-amanitin and completely dependent on exogenously added DNA template. RNA products of discrete lengths...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.77.10.5706
更新日期:1980-10-01 00:00:00
abstract::Explaining the variation between human languages and the constraints on that variation is a core goal of linguistics. In the last 20 y, it has been claimed that many striking universals of cross-linguistic variation follow from a hypothetical principle that dependency length--the distance between syntactically related...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1502134112
更新日期:2015-08-18 00:00:00
abstract::Understanding mammalian spermatozoan development and the events surrounding fertilization has grown slowly, in part because of uncertainty about the number and identity of the cellular components involved. Determination of those transcripts expressed specifically by germ cells should provide an inclusive list of proba...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1635054100
更新日期:2003-10-14 00:00:00
abstract::Molecular junctions are essentially modified electrodes familiar to electrochemists where the electrolyte is replaced by a conducting "contact." It is generally hypothesized that changing molecular structure will alter system energy levels leading to a change in the transport barrier. Here, we show the conductance of ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1201557109
更新日期:2012-07-17 00:00:00
abstract::The endoplasmic reticulum (ER) plays an important role in peroxisome biogenesis; some peroxisomal membrane proteins are inserted into the ER and trafficked to peroxisomes in vesicles. These vesicles could also provide the phospholipids required for the growth of peroxisomal membranes, because peroxisomes lack phosphol...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0808321105
更新日期:2008-10-14 00:00:00
abstract::An enzymatic activity, having the properties expected of a B-specific host-controlled modification enzyme, has been purified from an extract of Escherichia coli strain B. This activity renders the unmodified replicative form of phage fd resistant to B-specific restriction and is only present in strains carrying intact...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.63.2.556
更新日期:1969-06-01 00:00:00