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Search on : Holoprosencephaly [Words]
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  1 / 1925 MEDLINE  
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[PMID]: 29355528
[Au] Autor:Zhu J; Li S; Ramelot TA; Kennedy MA; Liu M; Yang Y
[Ad] Address:State Key Laboratory of Magnetic Resonance and Atomic Molecular Physics, Wuhan Center for Magnetic Resonance, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan 430071, China.
[Ti] Title:Structural insights into the impact of two holoprosencephaly-related mutations on human TGIF1 homeodomain.
[So] Source:Biochem Biophys Res Commun;496(2):575-581, 2018 02 05.
[Is] ISSN:1090-2104
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Human protein TGIF1 is an essential regulator of cell fate with broad roles in different tissues, and has been implicated in holoprosencephaly (HPE) and many cancers. The function of TGIF1 in transcriptional regulation depends on its three-amino acid loop extension (TALE) type of homeodomain (HD). Two missense mutations that led to P192A and R219C substitutions in TGIF1-HD were previously found in HPE patients and suggested to be the causes for these cases. However, how these mutations affected TGIF1 function has not been investigated from a structural view. Here, we investigated the roles of P192 and R219 in TGIF1-HD structure packing through determining the NMR structure of TGIF1-HD. Surprisingly, P192 and R219 were found to play roles in packing α1 and α2 to α3 together with A190 and F215 through side-chain interactions. Circular dichroism (CD) showed that P192A and R219C mutants displayed structural change and less folding compared with wild-type TGIF1-HD, and H- N HSQC spectrum of P192A mutant exhibited chemical shift perturbations in all three helices of TGIF1-HD. Thus, it is suggested that P192A and R219C mutations led to structure disturbances of TGIF1-HD, which subsequently reduced the DNA-binding affinity of TGIF1-HD by 23-fold and 10-fold respectively, as revealed by the isothermal titration calorimetry (ITC) experiments. Our study provides structural insights of the probable pathogenesis mechanism of two TGIF1-related HPE cases, and evidences for the roles of P192 and R219 in HD folding.
[Mh] MeSH terms primary: Holoprosencephaly/genetics
Homeodomain Proteins/chemistry
Homeodomain Proteins/genetics
Point Mutation
Repressor Proteins/chemistry
Repressor Proteins/genetics
[Mh] MeSH terms secundary: Amino Acid Sequence
DNA/metabolism
Holoprosencephaly/metabolism
Homeodomain Proteins/metabolism
Humans
Models, Molecular
Mutation, Missense
Nuclear Magnetic Resonance, Biomolecular
Protein Conformation
Protein Folding
Repressor Proteins/metabolism
[Pt] Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Name of substance:0 (Homeodomain Proteins); 0 (Repressor Proteins); 0 (TGIF1 protein, human); 9007-49-2 (DNA)
[Em] Entry month:1803
[Cu] Class update date: 180309
[Lr] Last revision date:180309
[Js] Journal subset:IM
[Da] Date of entry for processing:180123
[St] Status:MEDLINE

  2 / 1925 MEDLINE  
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[PMID]: 29490507
[Au] Autor:Anwar M; Turner M; Farrell N; Zomlefer WB; McDougal OM; Morgan BW
[Ad] Address:a Jackson Health System , Miami , FL , USA.
[Ti] Title:Hikers poisoned: Veratrum steroidal alkaloid toxicity following ingestion of foraged Veratrum parviflorum.
[So] Source:Clin Toxicol (Phila);:1-5, 2018 Feb 28.
[Is] ISSN:1556-9519
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:INTRODUCTION: Steroidal alkaloids are found in plants of the genus Veratrum. Their toxicity manifests as gastrointestinal symptoms followed by a Bezold-Jarisch reflex: hypopnea, hypotension, and bradycardia. Some Veratrum steroidal alkaloids are also teratogens interfering with the hedgehog-2 signaling pathway, which causes cyclopsia and holoprosencephaly. We present a case of accidental poisoning from Veratrum parviflorum mistaken for the edible Allium tricoccum (ramps, wild leek). CASE HISTORY: A 27-year-old man and his 25-year-old wife presented to the emergency department with nausea, vomiting, hypotension, and bradycardia after foraging and ingesting plants that they believed to be a local native species of wild leek. METHODS: We collected and analyzed the implicated fresh plant material and both patients' serum/plasma. We used liquid chromatography-mass spectroscopy and high-resolution electrospray ionization time of flight tandem mass spectrometry to extract and characterize steroidal alkaloids from the foraged plant and patients' serum. RESULTS: Our V. parviflorum samples contained verazine, veratramine, veratridine, and cyclopamine. DISCUSSION: Steroidal alkaloids have been previously isolated from Veratrum viride and Veratrum album and toxicity has been reported mainly from V. album species. CONCLUSION: V. parviflorum toxicity manifests with gastrointestinal and cardiac symptoms. Treatment is symptomatic and supportive as with previous case reports of toxicity with other Veratrum species.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1803
[Cu] Class update date: 180307
[Lr] Last revision date:180307
[St] Status:Publisher
[do] DOI:10.1080/15563650.2018.1442007

  3 / 1925 MEDLINE  
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[PMID]: 29492654
[Au] Autor:Memi F; Zecevic N; Radonjic N
[Ad] Address:Department of Neuroscience, University of Connecticut Health Center, Farmington, CT, 06030, USA. fani.memi@ucl.ac.uk.
[Ti] Title:Multiple roles of Sonic Hedgehog in the developing human cortex are suggested by its widespread distribution.
[So] Source:Brain Struct Funct;, 2018 Feb 28.
[Is] ISSN:1863-2661
[Cp] Country of publication:Germany
[La] Language:eng
[Ab] Abstract:Sonic Hedgehog (Shh) plays an instrumental role in brain development, fine-tuning processes such as cell proliferation, patterning, and fate specification. Although, mutations in the SHH pathway in humans are associated with various neurodevelopmental disorders, ranging from holoprosencephaly to schizophrenia, its expression pattern in the developing human brain is not well established. We now determined the previously not reported wide expression of SHH in the human fetal cerebral cortex during most of the gestation period (10-40 gestational weeks). This spatiotemporal distribution puts Shh in a position to influence the fundamental processes involved in corticogenesis. SHH expression increased during development, shifting from progenitor cells in the proliferative zones to neurons, both glutamatergic and GABAergic, and astrocytes in upper cortical compartments. Importantly, the expression of its downstream effectors and complementary receptors revealed evolutionary differences in SHH-pathway gene expression between humans and rodents.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1803
[Cu] Class update date: 180301
[Lr] Last revision date:180301
[St] Status:Publisher
[do] DOI:10.1007/s00429-018-1621-5

  4 / 1925 MEDLINE  
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[PMID]: 29321670
[Au] Autor:Asadollahi R; Strauss JE; Zenker M; Beuing O; Edvardson S; Elpeleg O; Strom TM; Joset P; Niedrist D; Otte C; Oneda B; Boonsawat P; Azzarello-Burri S; Bartholdi D; Papik M; Zweier M; Haas C; Ekici AB; Baumer A; Boltshauser E; Steindl K; Nothnagel M; Schinzel A; Stoeckli ET; Rauch A
[Ad] Address:Institute of Medical Genetics, University of Zurich, Schlieren-Zurich, Switzerland.
[Ti] Title:Clinical and experimental evidence suggest a link between KIF7 and C5orf42-related ciliopathies through Sonic Hedgehog signaling.
[So] Source:Eur J Hum Genet;26(2):197-209, 2018 Feb.
[Is] ISSN:1476-5438
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:Acrocallosal syndrome (ACLS) is an autosomal recessive neurodevelopmental disorder caused by KIF7 defects and belongs to the heterogeneous group of ciliopathies related to Joubert syndrome (JBTS). While ACLS is characterized by macrocephaly, prominent forehead, depressed nasal bridge, and hypertelorism, facial dysmorphism has not been emphasized in JBTS cohorts with molecular diagnosis. To evaluate the specificity and etiology of ACLS craniofacial features, we performed whole exome or targeted Sanger sequencing in patients with the aforementioned overlapping craniofacial appearance but variable additional ciliopathy features followed by functional studies. We found (likely) pathogenic variants of KIF7 in 5 out of 9 families, including the original ACLS patients, and delineated 1000 to 4000-year-old Swiss founder alleles. Three of the remaining families had (likely) pathogenic variants in the JBTS gene C5orf42, and one patient had a novel de novo frameshift variant in SHH known to cause autosomal dominant holoprosencephaly. In accordance with the patients' craniofacial anomalies, we showed facial midline widening after silencing of C5orf42 in chicken embryos. We further supported the link between KIF7, SHH, and C5orf42 by demonstrating abnormal primary cilia and diminished response to a SHH agonist in fibroblasts of C5orf42-mutated patients, as well as axonal pathfinding errors in C5orf42-silenced chicken embryos similar to those observed after perturbation of Shh signaling. Our findings, therefore, suggest that beside the neurodevelopmental features, macrocephaly and facial widening are likely more general signs of disturbed SHH signaling. Nevertheless, long-term follow-up revealed that C5orf42-mutated patients showed catch-up development and fainting of facial features contrary to KIF7-mutated patients.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1801
[Cu] Class update date: 180220
[Lr] Last revision date:180220
[St] Status:In-Data-Review
[do] DOI:10.1038/s41431-017-0019-9

  5 / 1925 MEDLINE  
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[PMID]: 29392406
[Au] Autor:Aarabi M; Sniezek O; Jiang H; Saller DN; Bellissimo D; Yatsenko SA; Rajkovic A
[Ad] Address:Medical Genetics and Genomics Laboratories, Magee-Womens Hospital of UPMC, Pittsburgh, PA, USA.
[Ti] Title:Importance of complete phenotyping in prenatal whole exome sequencing.
[So] Source:Hum Genet;137(2):175-181, 2018 Feb.
[Is] ISSN:1432-1203
[Cp] Country of publication:Germany
[La] Language:eng
[Ab] Abstract:Whole exome sequencing (WES) is an emerging technique in prenatal diagnosis. In this retrospective study, we examined diagnostic utility and limitations of WES in prenatal cases with structural birth defects. DNA from 20 trios (fetal and parental), with normal karyotype and microarray findings, underwent WES and variant interpretation at a reference laboratory. The WES results were later re-evaluated in our academic center utilizing prenatal and postnatal phenotyping. Initial analysis using only prenatal ultrasound findings revealed no pathogenic or likely pathogenic variants in 20 pregnancies with structural birth defects. Re-analysis of WES variants and combination of prenatal and postnatal phenotyping yielded pathogenic variants in at least 20% of cases including PORCN gene in a fetus with split-hand/foot malformation, as well as variants of uncertain significance in NEB and NOTCH1 in fetuses with postnatal muscle weakness and Adams-Oliver syndrome, respectively. Furthermore, Sanger sequencing in a patient with holoprosencephaly, elucidated by postnatal MRI, revealed a pathogenic 47-base pairs deletion in ZIC2 which was missed by prenatal WES. This study suggests that incomplete prenatal phenotyping and lack of prenatal ultrasound-genotype databases are the limiting factors for current interpretation of WES data in prenatal diagnosis. Development of prenatal phenotype-genotype databases would significantly help WES interpretation in this setting. Patients who underwent prenatal clinical WES may benefit from the re-analysis based on detailed postnatal findings.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1802
[Cu] Class update date: 180219
[Lr] Last revision date:180219
[St] Status:In-Data-Review
[do] DOI:10.1007/s00439-017-1860-1

  6 / 1925 MEDLINE  
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[PMID]: 29298325
[Au] Autor:Xu P; Morrison JP; Foley JF; Stumpo DJ; Ward T; Zeldin DC; Blackshear PJ
[Ad] Address:Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, Unites States of America.
[Ti] Title:Conditional ablation of the RFX4 isoform 1 transcription factor: Allele dosage effects on brain phenotype.
[So] Source:PLoS One;13(1):e0190561, 2018.
[Is] ISSN:1932-6203
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Regulatory factor X4 (RFX4) isoform 1 is a recently discovered isoform of the winged helix transcription factor RFX4, which can bind to X-box consensus sequences that are enriched in the promoters of cilia-related genes. Early insertional mutagenesis studies in mice first identified this isoform, and demonstrated that it was crucial for mouse brain development. RFX4 isoform 1 is the only RFX4 isoform significantly expressed in the mouse fetal and adult brain. In this study, we evaluated conditional knock-out (KO) mice in which one or two floxed alleles of Rfx4 were deleted early in development through the use of a Sox2-Cre transgene. Heterozygous deletion of Rfx4 resulted in severe, non-communicating congenital hydrocephalus associated with hypoplasia of the subcommissural organ. Homozygous deletion of Rfx4 resulted in formation of a single ventricle in the forebrain, and severe dorsoventral patterning defects in the telencephalon and midbrain at embryonic day 12.5, a collection of phenotypes that resembled human holoprosencephaly. No anatomical abnormalities were noted outside the brain in either case. At the molecular level, transcripts encoded by the cilia-related gene Foxj1 were significantly decreased, and Foxj1 was identified as a direct gene target of RFX4 isoform 1. The phenotypes were similar to those observed in the previous Rfx4 insertional mutagenesis studies. Thus, we provide a novel conditional KO animal model in which to investigate the downstream genes directly and/or indirectly regulated by RFX4 isoform 1. This model could provide new insights into the pathogenesis of obstructive hydrocephalus and holoprosencephaly in humans, both relatively common and disabling birth defects.
[Mh] MeSH terms primary: Alleles
Brain/metabolism
Regulatory Factor X Transcription Factors/genetics
[Mh] MeSH terms secundary: Animals
Body Patterning
Homozygote
Mice
Mice, Knockout
Phenotype
Real-Time Polymerase Chain Reaction
[Pt] Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Name of substance:0 (Regulatory Factor X Transcription Factors); 0 (Rfx4 protein, mouse)
[Em] Entry month:1802
[Cu] Class update date: 180215
[Lr] Last revision date:180215
[Js] Journal subset:IM
[Da] Date of entry for processing:180104
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0190561

  7 / 1925 MEDLINE  
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[PMID]: 29399953
[Au] Autor:Boer LL; Boek PLJ; van Dam AJ; Oostra RJ
[Ad] Address:Department of Anatomy and Museum for Anatomy and Pathology, Radboud University Medical Centre, Nijmegen, The Netherlands.
[Ti] Title:History and highlights of the teratological collection in the Museum Anatomicum of Leiden University, The Netherlands.
[So] Source:Am J Med Genet A;176(3):618-637, 2018 Mar.
[Is] ISSN:1552-4833
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:The anatomical collection of the Anatomical Museum of Leiden University Medical Center (historically referred to as Museum Anatomicum Academiae Lugduno-Batavae) houses and maintains more than 13,000 unique anatomical, pathological and zoological specimens, and include the oldest teratological specimens of The Netherlands. Throughout four centuries hundreds of teratological specimens were acquired by more than a dozen collectors. Due to the rich history of this vast collection, teratological specimens can be investigated in a unique retrospective sight going back almost four centuries. The entire 19th century collection was described in full detail by Eduard Sandifort (1742-1814) and his son Gerard Sandifort (1779-1848). Efforts were made to re-describe, re-diagnose and re-categorize all present human teratological specimens, and to match them with historical descriptions. In the extant collection a total of 642 human teratological specimens were identified, including exceptional conditions such as faciocranioschisis and conjoined twins discordant for cyclopia, and sirenomelia. Both father and son Sandifort differed in their opinion regarding the causative explanation of congenital anomalies. Whereas, their contemporaries Wouter Van Doeveren (1730-1783) and Andreas Bonn (1738-1817) both presented an interesting view on how congenital anomalies were perceived and explained during the 18th and 19th centuries; the golden age of descriptive teratology. Although this enormous collection is almost 400 years old, it still impresses scientists, (bio)medical students, and laymen visiting and exploring the collections of the Museum Anatomicum in Leiden, The Netherlands.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1802
[Cu] Class update date: 180215
[Lr] Last revision date:180215
[St] Status:In-Data-Review
[do] DOI:10.1002/ajmg.a.38617

  8 / 1925 MEDLINE  
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[PMID]: 29442327
[Au] Autor:Barratt KS; Arkell RM
[Ad] Address:Early Mammalian Development Laboratory, John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.
[Ti] Title:ZIC2 in Holoprosencephaly.
[So] Source:Adv Exp Med Biol;1046:269-299, 2018.
[Is] ISSN:0065-2598
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:The ZIC2 transcription factor is one of the most commonly mutated genes in Holoprosencephaly (HPE) probands. HPE is a severe congenital defect of forebrain development which occurs when the cerebral hemispheres fail to separate during the early stages of organogenesis and is typically associated with mispatterning of the embryonic midline. Recent study of genotype-phenotype correlations in HPE cases has defined distinctive features of ZIC2-associated HPE presentation and genetics, revealing that ZIC2 mutation does not produce the craniofacial abnormalities generally thought to characterise HPE but leads to a range of non-forebrain phenotypes. Furthermore, the studies confirm the extent of ZIC2 allelic heterogeneity and that pathogenic variants of ZIC2 are associated with both classic and middle interhemispheric variant (MIHV) HPE which arise from defective ventral and dorsal forebrain patterning, respectively. An allelic series of mouse mutants has helped to delineate the cellular and molecular mechanisms by which one gene leads to defects in these related but distinct embryological processes.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1802
[Cu] Class update date: 180214
[Lr] Last revision date:180214
[St] Status:In-Data-Review
[do] DOI:10.1007/978-981-10-7311-3_14

  9 / 1925 MEDLINE  
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[PMID]: 29391420
[Au] Autor:Ishiguro A; Hatayama M; Otsuka MI; Aruga J
[Ad] Address:Laboratory for Behavioral and Developmental Disorders, RIKEN Brain Science Institute (BSI), Wako-shi, Saitama, 351-0198, Japan.
[Ti] Title:Link between the causative genes of holoprosencephaly: Zic2 directly regulates Tgif1 expression.
[So] Source:Sci Rep;8(1):2140, 2018 Feb 01.
[Is] ISSN:2045-2322
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:One of the causal genes for holoprosencephaly (HPE) is ZIC2 (HPE5). It belongs to the zinc finger protein of the cerebellum (Zic) family of genes that share a C2H2-type zinc finger domain, similar to the GLI family of genes. In order to clarify the role of Zic2 in gene regulation, we searched for its direct target genes using chromatin immunoprecipitation (ChIP). We identified TGIF1 (HPE4), another holoprosencephaly-causative gene in humans. We identified Zic2-binding sites (ZBS) on the 5' flanking region of Tgif1 by in vitro DNA binding assays. ZBS were essential for Zic2-dependent transcriptional activation in reporter gene assays. Zic2 showed a higher affinity to ZBS than GLI-binding sequences. Zic2-binding to the cis-regulatory element near the Tgif1 promoter may be involved in the mechanism underlying forebrain development and incidences of HPE.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1802
[Cu] Class update date: 180214
[Lr] Last revision date:180214
[St] Status:In-Data-Review
[do] DOI:10.1038/s41598-018-20242-2

  10 / 1925 MEDLINE  
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[PMID]: 29203345
[Au] Autor:Kim JK; Kim SJ
[Ad] Address:Department of Pediatrics, Chonbuk National University School of Medicine, Jeonju, Republic of Korea.
[Ti] Title:Midline Facial Defects With Associated Brain Anomaly.
[So] Source:Pediatr Neurol;79:76-77, 2018 Feb.
[Is] ISSN:1873-5150
[Cp] Country of publication:United States
[La] Language:eng
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1712
[Cu] Class update date: 180207
[Lr] Last revision date:180207
[St] Status:In-Data-Review


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