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  1. Artikel ; Online: Author Correction: Possible association of 16p11.2 copy number variation with altered lymphocyte and neutrophil counts.

    Giannuzzi, Giuliana / Chatron, Nicolas / Mannik, Katrin / Auwerx, Chiara / Pradervand, Sylvain / Willemin, Gilles / Hoekzema, Kendra / Nuttle, Xander / Chrast, Jacqueline / Sadler, Marie C / Porcu, Eleonora / Herault, Yann / Isidor, Bertrand / Gilbert-Dussardier, Brigitte / Eichler, Evan E / Kutalik, Zoltan / Reymond, Alexandre

    NPJ genomic medicine

    2023  Band 8, Heft 1, Seite(n) 9

    Sprache Englisch
    Erscheinungsdatum 2023-05-24
    Erscheinungsland England
    Dokumenttyp Published Erratum
    ZDB-ID 2813848-X
    ISSN 2056-7944 ; 2056-7944
    ISSN (online) 2056-7944
    ISSN 2056-7944
    DOI 10.1038/s41525-023-00354-z
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel ; Online: Possible association of 16p11.2 copy number variation with altered lymphocyte and neutrophil counts.

    Giannuzzi, Giuliana / Chatron, Nicolas / Mannik, Katrin / Auwerx, Chiara / Pradervand, Sylvain / Willemin, Gilles / Hoekzema, Kendra / Nuttle, Xander / Chrast, Jacqueline / Sadler, Marie C / Porcu, Eleonora / Herault, Yann / Isidor, Bertrand / Gilbert-Dussardier, Brigitte / Eichler, Evan E / Kutalik, Zoltan / Reymond, Alexandre

    NPJ genomic medicine

    2022  Band 7, Heft 1, Seite(n) 38

    Abstract: Recurrent copy-number variations (CNVs) at chromosome 16p11.2 are associated with neurodevelopmental diseases, skeletal system abnormalities, anemia, and genitourinary defects. Among the 40 protein-coding genes encompassed within the rearrangement, some ... ...

    Abstract Recurrent copy-number variations (CNVs) at chromosome 16p11.2 are associated with neurodevelopmental diseases, skeletal system abnormalities, anemia, and genitourinary defects. Among the 40 protein-coding genes encompassed within the rearrangement, some have roles in leukocyte biology and immunodeficiency, like SPN and CORO1A. We therefore investigated leukocyte differential counts and disease in 16p11.2 CNV carriers. In our clinically-recruited cohort, we identified three deletion carriers from two families (out of 32 families assessed) with neutropenia and lymphopenia. They had no deleterious single-nucleotide or indel variant in known cytopenia genes, suggesting a possible causative role of the deletion. Noticeably, all three individuals had the lowest copy number of the human-specific BOLA2 duplicon (copy-number range: 3-8). Consistent with the lymphopenia and in contrast with the neutropenia associations, adult deletion carriers from UK biobank (n = 74) showed lower lymphocyte (Padj = 0.04) and increased neutrophil (Padj = 8.31e-05) counts. Mendelian randomization studies pinpointed to reduced CORO1A, KIF22, and BOLA2-SMG1P6 expressions being causative for the lower lymphocyte counts. In conclusion, our data suggest that 16p11.2 deletion, and possibly also the lowest dosage of the BOLA2 duplicon, are associated with low lymphocyte counts. There is a trend between 16p11.2 deletion with lower copy-number of the BOLA2 duplicon and higher susceptibility to moderate neutropenia. Higher numbers of cases are warranted to confirm the association with neutropenia and to resolve the involvement of the deletion coupled with deleterious variants in other genes and/or with the structure and copy number of segments in the CNV breakpoint regions.
    Sprache Englisch
    Erscheinungsdatum 2022-06-17
    Erscheinungsland England
    Dokumenttyp Journal Article
    ZDB-ID 2813848-X
    ISSN 2056-7944 ; 2056-7944
    ISSN (online) 2056-7944
    ISSN 2056-7944
    DOI 10.1038/s41525-022-00308-x
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  3. Artikel: Variant-specific pathophysiological mechanisms of AFF3 differently influence transcriptome profiles.

    Bassani, Sissy / Chrast, Jacqueline / Ambrosini, Giovanna / Voisin, Norine / Schütz, Frédéric / Brusco, Alfredo / Sirchia, Fabio / Turban, Lydia / Schubert, Susanna / Jamra, Rami Abou / Schlump, Jan-Ulrich / DeMille, Desiree / Bayrak-Toydemir, Pinar / Nelson, Gary Rex / Wong, Kristen Nicole / Duncan, Laura / Mosera, Mackenzie / Gilissen, Christian / Vissers, Lisenka E L M /
    Pfundt, Rolph / Kersseboom, Rogier / Yttervik, Hilde / Hansen, Geir Åsmund Myge / Falkenberg Smeland, Marie / Butler, Kameryn M / Lyons, Michael J / Carvalho, Claudia M B / Zhang, Chaofan / Lupski, James R / Potocki, Lorraine / Flores-Gallegos, Leticia / Morales-Toquero, Rodrigo / Petit, Florence / Yalcin, Binnaz / Tuttle, Annabelle / Elloumi, Houda Zghal / Mccormick, Lane / Kukolich, Mary / Klaas, Oliver / Horvath, Judit / Scala, Marcello / Iacomino, Michele / Operto, Francesca / Zara, Federico / Writzl, Karin / Maver, Ales / Haanpää, Maria K / Pohjola, Pia / Arikka, Harri / Iseli, Christian / Guex, Nicolas / Reymond, Alexandre

    medRxiv : the preprint server for health sciences

    2024  

    Abstract: Background: We previously described the KINSSHIP syndrome, an autosomal dominant disorder associated with intellectual disability (ID), mesomelic dysplasia and horseshoe kidney,caused by : Methods: Evolutionary constraints suggest that other mode-of- ... ...

    Abstract Background: We previously described the KINSSHIP syndrome, an autosomal dominant disorder associated with intellectual disability (ID), mesomelic dysplasia and horseshoe kidney,caused by
    Methods: Evolutionary constraints suggest that other mode-of-inheritance could be at play. We challenged this hypothesis by screening ID cohorts for individuals with predicted-to-be deleterious variants in
    Results: We identified an individual with a KINSSHIP-like phenotype carrying a
    Conclusions: Our results and the high pleiotropy shown by variation at this locus suggest that minute changes in
    Sprache Englisch
    Erscheinungsdatum 2024-01-17
    Erscheinungsland United States
    Dokumenttyp Preprint
    DOI 10.1101/2024.01.14.24301100
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  4. Artikel ; Online: Variant-specific pathophysiological mechanisms of AFF3 differently influence transcriptome profiles.

    Bassani, Sissy / Chrast, Jacqueline / Ambrosini, Giovanna / Voisin, Norine / Schütz, Frédéric / Brusco, Alfredo / Sirchia, Fabio / Turban, Lydia / Schubert, Susanna / Abou Jamra, Rami / Schlump, Jan-Ulrich / DeMille, Desiree / Bayrak-Toydemir, Pinar / Nelson, Gary Rex / Wong, Kristen Nicole / Duncan, Laura / Mosera, Mackenzie / Gilissen, Christian / Vissers, Lisenka E L M /
    Pfundt, Rolph / Kersseboom, Rogier / Yttervik, Hilde / Hansen, Geir Åsmund Myge / Smeland, Marie Falkenberg / Butler, Kameryn M / Lyons, Michael J / Carvalho, Claudia M B / Zhang, Chaofan / Lupski, James R / Potocki, Lorraine / Flores-Gallegos, Leticia / Morales-Toquero, Rodrigo / Petit, Florence / Yalcin, Binnaz / Tuttle, Annabelle / Elloumi, Houda Zghal / McCormick, Lane / Kukolich, Mary / Klaas, Oliver / Horvath, Judit / Scala, Marcello / Iacomino, Michele / Operto, Francesca / Zara, Federico / Writzl, Karin / Maver, Aleš / Haanpää, Maria K / Pohjola, Pia / Arikka, Harri / Kievit, Anneke J A / Calandrini, Camilla / Iseli, Christian / Guex, Nicolas / Reymond, Alexandre

    Genome medicine

    2024  Band 16, Heft 1, Seite(n) 72

    Abstract: Background: We previously described the KINSSHIP syndrome, an autosomal dominant disorder associated with intellectual disability (ID), mesomelic dysplasia and horseshoe kidney, caused by de novo variants in the degron of AFF3. Mouse knock-ins and ... ...

    Abstract Background: We previously described the KINSSHIP syndrome, an autosomal dominant disorder associated with intellectual disability (ID), mesomelic dysplasia and horseshoe kidney, caused by de novo variants in the degron of AFF3. Mouse knock-ins and overexpression in zebrafish provided evidence for a dominant-negative mode of action, wherein an increased level of AFF3 resulted in pathological effects.
    Methods: Evolutionary constraints suggest that other modes-of-inheritance could be at play. We challenged this hypothesis by screening ID cohorts for individuals with predicted-to-be damaging variants in AFF3. We used both animal and cellular models to assess the deleteriousness of the identified variants.
    Results: We identified an individual with a KINSSHIP-like phenotype carrying a de novo partial duplication of AFF3 further strengthening the hypothesis that an increased level of AFF3 is pathological. We also detected seventeen individuals displaying a milder syndrome with either heterozygous Loss-of-Function (LoF) or biallelic missense variants in AFF3. Consistent with semi-dominance, we discovered three patients with homozygous LoF and one compound heterozygote for a LoF and a missense variant, who presented more severe phenotypes than their heterozygous parents. Matching zebrafish knockdowns exhibit neurological defects that could be rescued by expressing human AFF3 mRNA, confirming their association with the ablation of aff3. Conversely, some of the human AFF3 mRNAs carrying missense variants identified in affected individuals did not rescue these phenotypes. Overexpression of mutated AFF3 mRNAs in zebrafish embryos produced a significant increase of abnormal larvae compared to wild-type overexpression further demonstrating deleteriousness. To further assess the effect of AFF3 variation, we profiled the transcriptome of fibroblasts from affected individuals and engineered isogenic cells harboring + / + , KINSSHIP/KINSSHIP, LoF/ + , LoF/LoF or KINSSHIP/LoF AFF3 genotypes. The expression of more than a third of the AFF3 bound loci is modified in either the KINSSHIP/KINSSHIP or the LoF/LoF lines. While the same pathways are affected, only about one third of the differentially expressed genes are common to the homozygote datasets, indicating that AFF3 LoF and KINSSHIP variants largely modulate transcriptomes differently, e.g. the DNA repair pathway displayed opposite modulation.
    Conclusions: Our results and the high pleiotropy shown by variation at this locus suggest that minute changes in AFF3 function are deleterious.
    Mesh-Begriff(e) Animals ; Female ; Humans ; Male ; Intellectual Disability/genetics ; Loss of Function Mutation ; Mutation, Missense ; Phenotype ; Transcriptome ; Zebrafish/genetics
    Chemische Substanzen AFF3 protein, human
    Sprache Englisch
    Erscheinungsdatum 2024-05-30
    Erscheinungsland England
    Dokumenttyp Journal Article
    ZDB-ID 2484394-5
    ISSN 1756-994X ; 1756-994X
    ISSN (online) 1756-994X
    ISSN 1756-994X
    DOI 10.1186/s13073-024-01339-y
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  5. Artikel ; Online: Variants in USP48 encoding ubiquitin hydrolase are associated with autosomal dominant non-syndromic hereditary hearing loss.

    Bassani, Sissy / van Beelen, Edward / Rossel, Mireille / Voisin, Norine / Morgan, Anna / Arribat, Yoan / Chatron, Nicolas / Chrast, Jacqueline / Cocca, Massimiliano / Delprat, Benjamin / Faletra, Flavio / Giannuzzi, Giuliana / Guex, Nicolas / Machavoine, Roxane / Pradervand, Sylvain / Smits, Jeroen J / van de Kamp, Jiddeke M / Ziegler, Alban / Amati, Francesca /
    Marlin, Sandrine / Kremer, Hannie / Locher, Heiko / Maurice, Tangui / Gasparini, Paolo / Girotto, Giorgia / Reymond, Alexandre

    Human molecular genetics

    2021  Band 30, Heft 19, Seite(n) 1785–1796

    Abstract: Non-Syndromic Hereditary Hearing Loss (NSHHL) is a genetically heterogeneous sensory disorder with about 120 genes already associated. Through exome sequencing (ES) and data aggregation, we identified a family with six affected individuals and one ... ...

    Abstract Non-Syndromic Hereditary Hearing Loss (NSHHL) is a genetically heterogeneous sensory disorder with about 120 genes already associated. Through exome sequencing (ES) and data aggregation, we identified a family with six affected individuals and one unrelated NSHHL patient with predicted-to-be deleterious missense variants in USP48. We also uncovered an eighth patient presenting unilateral cochlear nerve aplasia and a de novo splice variant in the same gene. USP48 encodes a ubiquitin carboxyl-terminal hydrolase under evolutionary constraint. Pathogenicity of the variants is supported by in vitro assays that showed that the mutated proteins are unable to hydrolyze tetra-ubiquitin. Correspondingly, three-dimensional representation of the protein containing the familial missense variant is situated in a loop that might influence the binding to ubiquitin. Consistent with a contribution of USP48 to auditory function, immunohistology showed that the encoded protein is expressed in the developing human inner ear, specifically in the spiral ganglion neurons, outer sulcus, interdental cells of the spiral limbus, stria vascularis, Reissner's membrane and in the transient Kolliker's organ that is essential for auditory development. Engineered zebrafish knocked-down for usp48, the USP48 ortholog, presented with a delayed development of primary motor neurons, less developed statoacoustic neurons innervating the ears, decreased swimming velocity and circling swimming behavior indicative of vestibular dysfunction and hearing impairment. Corroboratingly, acoustic startle response assays revealed a significant decrease of auditory response of zebrafish lacking usp48 at 600 and 800 Hz wavelengths. In conclusion, we describe a novel autosomal dominant NSHHL gene through a multipronged approach combining ES, animal modeling, immunohistology and molecular assays.
    Mesh-Begriff(e) Animals ; Hearing Loss/genetics ; Humans ; Hydrolases ; Reflex, Startle ; Ubiquitin ; Ubiquitin-Specific Proteases ; Zebrafish/genetics
    Chemische Substanzen Ubiquitin ; Hydrolases (EC 3.-) ; USP48 protein, human (EC 3.4.19.12) ; Ubiquitin-Specific Proteases (EC 3.4.19.12)
    Sprache Englisch
    Erscheinungsdatum 2021-05-12
    Erscheinungsland England
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1108742-0
    ISSN 1460-2083 ; 0964-6906
    ISSN (online) 1460-2083
    ISSN 0964-6906
    DOI 10.1093/hmg/ddab145
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  6. Artikel ; Online: The Human-Specific BOLA2 Duplication Modifies Iron Homeostasis and Anemia Predisposition in Chromosome 16p11.2 Autism Individuals.

    Giannuzzi, Giuliana / Schmidt, Paul J / Porcu, Eleonora / Willemin, Gilles / Munson, Katherine M / Nuttle, Xander / Earl, Rachel / Chrast, Jacqueline / Hoekzema, Kendra / Risso, Davide / Männik, Katrin / De Nittis, Pasquelena / Baratz, Ethan D / Herault, Yann / Gao, Xiang / Philpott, Caroline C / Bernier, Raphael A / Kutalik, Zoltan / Fleming, Mark D /
    Eichler, Evan E / Reymond, Alexandre

    American journal of human genetics

    2019  Band 105, Heft 5, Seite(n) 947–958

    Abstract: Human-specific duplications at chromosome 16p11.2 mediate recurrent pathogenic 600 kbp BP4-BP5 copy-number variations, which are among the most common genetic causes of autism. These copy-number polymorphic duplications are under positive selection and ... ...

    Abstract Human-specific duplications at chromosome 16p11.2 mediate recurrent pathogenic 600 kbp BP4-BP5 copy-number variations, which are among the most common genetic causes of autism. These copy-number polymorphic duplications are under positive selection and include three to eight copies of BOLA2, a gene involved in the maturation of cytosolic iron-sulfur proteins. To investigate the potential advantage provided by the rapid expansion of BOLA2, we assessed hematological traits and anemia prevalence in 379,385 controls and individuals who have lost or gained copies of BOLA2: 89 chromosome 16p11.2 BP4-BP5 deletion carriers and 56 reciprocal duplication carriers in the UK Biobank. We found that the 16p11.2 deletion is associated with anemia (18/89 carriers, 20%, p = 4e-7, OR = 5), particularly iron-deficiency anemia. We observed similar enrichments in two clinical 16p11.2 deletion cohorts, which included 6/63 (10%) and 7/20 (35%) unrelated individuals with anemia, microcytosis, low serum iron, or low blood hemoglobin. Upon stratification by BOLA2 copy number, our data showed an association between low BOLA2 dosage and the above phenotypes (8/15 individuals with three copies, 53%, p = 1e-4). In parallel, we analyzed hematological traits in mice carrying the 16p11.2 orthologous deletion or duplication, as well as Bola2
    Mesh-Begriff(e) Anemia/genetics ; Animals ; Autistic Disorder/genetics ; Chromosome Deletion ; Chromosome Disorders/genetics ; Chromosome Duplication/genetics ; Chromosomes, Human, Pair 16/genetics ; DNA Copy Number Variations/genetics ; Female ; Genotype ; Heterozygote ; Homeostasis/genetics ; Humans ; Iron ; Male ; Phenotype ; Proteins/genetics
    Chemische Substanzen BOLA2 protein, human ; Proteins ; Iron (E1UOL152H7)
    Sprache Englisch
    Erscheinungsdatum 2019-10-24
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 219384-x
    ISSN 1537-6605 ; 0002-9297
    ISSN (online) 1537-6605
    ISSN 0002-9297
    DOI 10.1016/j.ajhg.2019.09.023
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  7. Artikel ; Online: Inhibition of G-protein signalling in cardiac dysfunction of intellectual developmental disorder with cardiac arrhythmia (IDDCA) syndrome.

    De Nittis, Pasquelena / Efthymiou, Stephanie / Sarre, Alexandre / Guex, Nicolas / Chrast, Jacqueline / Putoux, Audrey / Sultan, Tipu / Raza Alvi, Javeria / Ur Rahman, Zia / Zafar, Faisal / Rana, Nuzhat / Rahman, Fatima / Anwar, Najwa / Maqbool, Shazia / Zaki, Maha S / Gleeson, Joseph G / Murphy, David / Galehdari, Hamid / Shariati, Gholamreza /
    Mazaheri, Neda / Sedaghat, Alireza / Lesca, Gaetan / Chatron, Nicolas / Salpietro, Vincenzo / Christoforou, Marilena / Houlden, Henry / Simonds, William F / Pedrazzini, Thierry / Maroofian, Reza / Reymond, Alexandre

    Journal of medical genetics

    2020  Band 58, Heft 12, Seite(n) 815–831

    Abstract: Background: Pathogenic variants of : Methods: We used echocardiography and telemetric ECG recordings to investigate consequences of : Results: We delineated a key role of : Conclusions: Our data demonstrate that loss of negative regulation of ... ...

    Abstract Background: Pathogenic variants of
    Methods: We used echocardiography and telemetric ECG recordings to investigate consequences of
    Results: We delineated a key role of
    Conclusions: Our data demonstrate that loss of negative regulation of the inhibitory G-protein signalling causes HR perturbations in
    Mesh-Begriff(e) Adolescent ; Animals ; Arrhythmias, Cardiac/genetics ; Arrhythmias, Cardiac/physiopathology ; Child ; Child, Preschool ; Developmental Disabilities/genetics ; Developmental Disabilities/physiopathology ; Female ; GTP-Binding Protein beta Subunits/genetics ; GTP-Binding Protein beta Subunits/metabolism ; Gene Expression Profiling/methods ; Heart/physiopathology ; Heart Rate/genetics ; Heart Rate/physiology ; Humans ; Male ; Mice, Inbred C57BL ; Mice, Knockout ; Mutation ; Pedigree ; Signal Transduction/genetics ; Syndrome ; Exome Sequencing/methods ; Young Adult ; Mice
    Chemische Substanzen GNB5 protein, human ; GTP-Binding Protein beta Subunits
    Sprache Englisch
    Erscheinungsdatum 2020-11-10
    Erscheinungsland England
    Dokumenttyp Journal Article ; Multicenter Study ; Research Support, Non-U.S. Gov't
    ZDB-ID 220881-7
    ISSN 1468-6244 ; 0022-2593
    ISSN (online) 1468-6244
    ISSN 0022-2593
    DOI 10.1136/jmedgenet-2020-107015
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  8. Artikel: Spatial distributions of Kv4 channels and KChip2 isoforms in the murine heart based on laser capture microdissection.

    Teutsch, Christine / Kondo, Richard P / Dederko, Dorothy A / Chrast, Jacqueline / Chien, Kenneth R / Giles, Wayne R

    Cardiovascular research

    2007  Band 73, Heft 4, Seite(n) 739–749

    Abstract: Objective: Regional differences in repolarizing K(+) current densities and expression levels of their molecular components are important for coordinating the pattern of electrical excitation and repolarization of the heart. The small size of hearts from ...

    Abstract Objective: Regional differences in repolarizing K(+) current densities and expression levels of their molecular components are important for coordinating the pattern of electrical excitation and repolarization of the heart. The small size of hearts from mice may obscure these interventricular and/or transmural expression differences of K(+) channels. We have examined this possibility in adult mouse ventricle using a technology that provides very high spatial resolution of tissue collection.
    Methods: Conventional manual dissection and laser capture microdissection (LCM) were utilized to dissect tissue from distinct ventricular regions. RNA was isolated from epicardial, mid-myocardial and endocardial layers of both the right and left ventricles. Real-time RT-PCR was used to quantify the transcript expression in these different regions.
    Results: LCM revealed significant interventricular and transmural gradients for both Kv4.2 and the alpha-subunit of KChIP2. The expression profile of a second K(+) channel transcript, Kir2.1, which is responsible for the inwardly rectifying K(+) current I(k1), showed no interventricular or transmural gradients and therefore served as a negative control.
    Conclusions: Our findings are in contrast to previous reports of a relatively uniform left ventricular transmural pattern of expression of Kv4.2, Kv4.3 and KChIP2 in adult mouse heart, which appear to be different than that in larger mammals. Specifically, our results demonstrate significant epi- to endocardial differences in the patterns of expression of both Kv4.2 and KChIP2.
    Mesh-Begriff(e) Animals ; Endocardium/metabolism ; Gene Expression ; Heart Ventricles/chemistry ; Kv Channel-Interacting Proteins/genetics ; Laser Scanning Cytometry ; Male ; Mice ; Mice, Inbred C57BL ; Microdissection/methods ; Myocardium/chemistry ; Pericardium/metabolism ; Potassium Channels, Inwardly Rectifying/genetics ; RNA, Messenger/analysis ; Reverse Transcriptase Polymerase Chain Reaction ; Shal Potassium Channels/genetics
    Chemische Substanzen Kir2.1 channel ; Kv Channel-Interacting Proteins ; Potassium Channels, Inwardly Rectifying ; RNA, Messenger ; Shal Potassium Channels
    Sprache Englisch
    Erscheinungsdatum 2007-03-01
    Erscheinungsland England
    Dokumenttyp Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80340-6
    ISSN 1755-3245 ; 0008-6363
    ISSN (online) 1755-3245
    ISSN 0008-6363
    DOI 10.1016/j.cardiores.2006.11.034
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  9. Artikel ; Online: TBC1D7 mutations are associated with intellectual disability, macrocrania, patellar dislocation, and celiac disease.

    Alfaiz, Ali Abdullah / Micale, Lucia / Mandriani, Barbara / Augello, Bartolomeo / Pellico, Maria Teresa / Chrast, Jacqueline / Xenarios, Ioannis / Zelante, Leopoldo / Merla, Giuseppe / Reymond, Alexandre

    Human mutation

    2014  Band 35, Heft 4, Seite(n) 447–451

    Abstract: TBC1D7 forms a complex with TSC1 and TSC2 that inhibits mTORC1 signaling and limits cell growth. Mutations in TBC1D7 were reported in a family with intellectual disability (ID) and macrocrania. Using exome sequencing, we identified two sisters homozygote ...

    Abstract TBC1D7 forms a complex with TSC1 and TSC2 that inhibits mTORC1 signaling and limits cell growth. Mutations in TBC1D7 were reported in a family with intellectual disability (ID) and macrocrania. Using exome sequencing, we identified two sisters homozygote for the novel c.17_20delAGAG, p.R7TfsX21 TBC1D7 truncating mutation. In addition to the already described macrocephaly and mild ID, they share osteoarticular defects, patella dislocation, behavioral abnormalities, psychosis, learning difficulties, celiac disease, prognathism, myopia, and astigmatism. Consistent with a loss-of-function of TBC1D7, the patient's cell lines show an increase in the phosphorylation of 4EBP1, a direct downstream target of mTORC1 and a delay in the initiation of the autophagy process. This second family allows enlarging the phenotypic spectrum associated with TBC1D7 mutations and defining a TBC1D7 syndrome. Our work reinforces the involvement of TBC1D7 in the regulation of mTORC1 pathways and suggests an altered control of autophagy as possible cause of this disease.
    Mesh-Begriff(e) Adaptor Proteins, Signal Transducing/metabolism ; Autophagy ; Carrier Proteins/genetics ; Carrier Proteins/metabolism ; Celiac Disease/genetics ; Celiac Disease/pathology ; Cell Cycle Proteins ; Cell Line ; Exome ; Female ; Genetic Predisposition to Disease ; Genetic Variation ; High-Throughput Nucleotide Sequencing ; Homozygote ; Humans ; Intellectual Disability/genetics ; Intellectual Disability/pathology ; Intracellular Signaling Peptides and Proteins ; Megalencephaly/genetics ; Megalencephaly/pathology ; Mutation ; Patellar Dislocation/genetics ; Patellar Dislocation/pathology ; Pedigree ; Phosphoproteins/metabolism
    Chemische Substanzen Adaptor Proteins, Signal Transducing ; Carrier Proteins ; Cell Cycle Proteins ; EIF4EBP1 protein, human ; Intracellular Signaling Peptides and Proteins ; Phosphoproteins ; TBC1D7 protein, human
    Sprache Englisch
    Erscheinungsdatum 2014-02-04
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1126646-6
    ISSN 1098-1004 ; 1059-7794
    ISSN (online) 1098-1004
    ISSN 1059-7794
    DOI 10.1002/humu.22529
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  10. Artikel ; Online: Copy number variation modifies expression time courses.

    Chaignat, Evelyne / Yahya-Graison, Emilie Aït / Henrichsen, Charlotte N / Chrast, Jacqueline / Schütz, Frédéric / Pradervand, Sylvain / Reymond, Alexandre

    Genome research

    2010  Band 21, Heft 1, Seite(n) 106–113

    Abstract: A preliminary understanding into the phenotypic effect of DNA segment copy number variation (CNV) is emerging. These rearrangements were demonstrated to influence, in a somewhat dose-dependent manner, the expression of genes that map within them. They ... ...

    Abstract A preliminary understanding into the phenotypic effect of DNA segment copy number variation (CNV) is emerging. These rearrangements were demonstrated to influence, in a somewhat dose-dependent manner, the expression of genes that map within them. They were also shown to modify the expression of genes located on their flanks and sometimes those at a great distance from their boundary. Here we demonstrate, by monitoring these effects at multiple life stages, that these controls over expression are effective throughout mouse development. Similarly, we observe that the more specific spatial expression patterns of CNV genes are maintained through life. However, we find that some brain-expressed genes mapping within CNVs appear to be under compensatory loops only at specific time points, indicating that the effect of CNVs on these genes is modulated during development. Notably, we also observe that CNV genes are significantly enriched within transcripts that show variable time courses of expression between strains. Thus, modifying the copy number of a gene may potentially alter not only its expression level, but also the timing of its expression.
    Mesh-Begriff(e) Animals ; Brain/embryology ; Brain/metabolism ; DNA Copy Number Variations ; Gene Dosage ; Gene Expression Profiling ; Gene Expression Regulation, Developmental ; Liver/embryology ; Liver/metabolism ; Male ; Mice ; Mice, Inbred C3H ; Mice, Inbred C57BL ; Mice, Inbred DBA ; Time Factors
    Sprache Englisch
    Erscheinungsdatum 2010-11-17
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1284872-4
    ISSN 1549-5469 ; 1088-9051 ; 1054-9803
    ISSN (online) 1549-5469
    ISSN 1088-9051 ; 1054-9803
    DOI 10.1101/gr.112748.110
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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