DOCSLIB.ORG

Exome Sequencing Identifies Mutations in the Gene TTC7A In

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Exome Sequencing Identifies Mutations in the Gene TTC7A In Developmental defects J Med Genet: first published as 10.1136/jmedgenet-2012-101483 on 19 February 2013. Downloaded from ORIGINAL ARTICLE Exome sequencing identifies mutations in the gene TTC7A in French-Canadian cases with hereditary multiple intestinal atresia Mark E Samuels,1 Jacek Majewski,2 Najmeh Alirezaie,2 Isabel Fernandez,1,3 Ferran Casals,1 Natalie Patey,1,4 Hélène Decaluwe,1,5 Isabelle Gosselin,6 Elie Haddad,1,3,5 Alan Hodgkinson,1 Youssef Idaghdour,1 Valerie Marchand,1,5 1,5 6,7 6 6 Open Access Jacques L Michaud, Marc-André Rodrigue, Sylvie Desjardins, Stéphane Dubois, Scan to access more 1,3 1,5 6,7 8 free content Francoise Le Deist, Philip Awadalla, Vincent Raymond, Bruno Maranda ▸ Additional material is ABSTRACT attempted, outcomes are poor and the condition is published online only. To view Background Congenital multiple intestinal atresia usual fatal within the first month of life. To date, please visit the journal online (http://dx.doi.org/10.1136/ (MIA) is a severe, fatal neonatal disorder, involving the no primary aetiology has been proved for the con- jmedgenet-2012-101483). occurrence of obstructions in the small and large dition. Importantly, in some cases MIA is also asso- 1 intestines ultimately leading to organ failure. Surgical ciated with either mild or severe combined Centre de Recherche du CHU fi 2–5 Ste-Justine, University of interventions are palliative but do not provide long-term immunode ciency (SCID), raising the possibility Montreal, Montreal, Quebec, survival. Severe immunodeficiency may be associated that an abnormal immune response might be the Canada with the phenotype. A genetic basis for MIA is likely. We origin of the disease. However failure of normal 2 Department of Human had previously ascertained a cohort of patients of embryogenesis remains a possibility with inflamma- Genetics, McGill University, Montreal, Quebec, Canada French-Canadian origin, most of whom were deceased tion or immune dysfunction only secondary. Most 3Department of Microbiology as infants or in utero. The goal of the study was to MIA cases are sporadic, although a genetic basis for and Immunology, University of identify the molecular basis for the disease in the congenital cases is likely given some familial recur- Montreal, Montreal, Quebec, patients of this cohort. rences.26A cluster of cases from Quebec, ascertained Canada 4 Methods We performed whole exome sequencing on by us, is also consistent with a genetic cause, given Department of Pathology, fi University of Montreal, samples from ve patients of four families. Validation of frequent documented French-Canadian founder Montreal, Quebec, Canada mutations and familial segregation was performed using effects going back to the first immigrants and leading 5Department of Pediatrics, standard Sanger sequencing in these and three to increased incidences of specific recessive disor- University of Montreal, additional families with deceased cases. Exon skipping ders.7 Other neonatal conditions involving local atre- Montreal, Quebec, Canada 6Department of Neurosciences, was assessed by reverse transcription-PCR and Sanger sias within the small or large intestine are also Centre de recherche du CHU sequencing. known, but it remains unclear whether these repre- http://jmg.bmj.com/ de Québec, Université Laval, Results Five patients from four different families were sent fundamentally different disease entities from Québec City, Quebec, Canada 7 each homozygous for a four base intronic deletion in the MIA or simply less severe examples. Département de Médecine gene TTC7A, immediately adjacent to a consensus GT Through whole exome sequencing of patients of Moléculaire, Université Laval, fi Québec City, Quebec, Canada splice donor site. The deletion was demonstrated to have French-Canadian origin, we identi ed two muta- 8Medical Genetics Service, deleterious effects on splicing causing the skipping of tions in a single gene, the tetratricopeptide repeat University of Sherbrooke, the attendant upstream coding exon, thereby leading to (TPR) domain 7A gene TTC7A, that could explain Sherbrooke, Quebec, Canada a predicted severe protein truncation. Parents were the disease in the affected cases. Mouse mutations on September 23, 2021 by guest. Protected copyright. Correspondence to heterozygous carriers of the deletion in these families in the orthologous gene are known and while the Bruno Maranda, and in two additional families segregating affected mice exhibit some abnormalities in their immune – Medical Genetics Service, cases. In a seventh family, an affected case was system, they lack a gastrointestinal phenotype.8 10 University of Sherbrooke, compound heterozygous for the same 4bp deletion and Sherbrooke, Quebec, Canada a second missense mutation p.L823P, also predicted as J1K 2R1; Bruno.Maranda@ METHODS USherbrooke.ca pathogenic. No other sequenced genes possessed Clinical ascertainment and patient descriptions deleterious variants explanatory for all patients in the In the course of clinical practice over many Received 14 December 2012 cohort. Neither mutation was seen in a large set of years, more than 20 patients with MIA have Accepted 22 January 2013 control chromosomes. been identified at the Centre Hospitalier de Published Online First ’ 19 February 2013 Conclusions Based on our genetic results, TTC7A is l Université Laval (CHUL) in Québec City, some the likely causal gene for MIA. previously described.2 All cases were reportedly of French-Canadian origin, though not formally related by known genealogy up to their great- INTRODUCTION grandparents. DNA suitable for genome-wide ana- Hereditary multiple intestinal atresia (MIA) (MIM lysis was obtained from these cases as well as three (243150)) is a severe congenital disorder, first for- newly ascertained cases. DNA from three add- fi 1 fi To cite: Samuels ME, mally de ned in 1973. MIA typically involves itional deceased cases was obtained from paraf n Majewski J, Alirezaie N, multiple lesions which occur at various levels blocks (F2, F4 and F5). We also had intestinal et al. J Med Genet throughout the small and large intestines.2 tissues embedded in plastic for two deceased cases – 2013;50:324 329. Although surgical intervention is sometimes (F3, F5) but DNA extracted from these blocks was 324 Samuels ME, et al. J Med Genet 2013;50:324–329. doi:10.1136/jmedgenet-2012-101483 Developmental defects J Med Genet: first published as 10.1136/jmedgenet-2012-101483 on 19 February 2013. Downloaded from degraded and could not be amplified. DNA from the sampled 100 bp paired end reads was carried out on Illumina HiSeq patient in F2 was also degraded. DNA for segregation studies 2000. Capture and sequencing was performed at the McGill was obtained for parents and/or unaffected siblings from all University and Genome Quebec Centre for Innovation. seven families (F1 to F7). Sequence reads were aligned to the human reference genome The three cases which underwent exome sequencing are hg19 using Burrows-Wheeler Alignment (BWA 0.5.9).11 described. The first case was born at term. The baby was imme- Genome Analysis Toolkit (GATK) was used for realignment diately brought to medical attention because of intestinal around suspected indels,12 and Picard was employed to mark obstruction and omphalocoele. He died the following day of duplicate reads and exclude them from downstream analyses.13 bowel obstruction. Autopsy revealed MIA. The second case is a Single nucleotide variants (SNVs) and short insertions and dele- fetus aborted at 23 weeks of gestation. Fetal ultrasound showed tions (indels) were called using Samtools mpileup.13 Mutations significant bowel distension at 22 weeks. Since the parents had a were annotated using Annovar14 and custom scripts. Filtering of child who died at 2 days of MIA the previous year, a recurrence common variants and recurrent technical artefacts of sequencing was highly suspected. Fetal autopsy showed MIA. The third case chemistry and/or read misalignment was performed using was born after a 35 weeks pregnancy, characterised by polyhy- dbSNP132, Exome Variant Server (EVS), the 1000 Genomes dramnios. Intestinal obstruction was suspected at birth on clin- variant dataset and a custom database of approximately 700 ical grounds. Imaging findings were consistent with a diagnosis exomes previously sequenced at our centre for unrelated pro- of MIA. Considering the invariably fatal outcome of this condi- jects. Variants seen in more than 20 control exomes, SNVs with tion in our centre, palliative care was given to the infant. a ratio of variant reads less than 0.2 and insertion/deletions with Autopsy was declined by the parents and the baby died at home a ratio of variant reads less than 0.15, were excluded from during the 1st week. further analysis. Only variants predicted to change protein Patients with MIA have also been identified at the Centre sequence (exonic non-synonymous SNVs, short indels, splice Hospitalier Ste-Justine (CHU Ste-Justine) in Montreal.1 In one site SNVs) were considered. Private variants were defined as family (F7) two newly ascertained male siblings (P11 and P14), those absent from dbSNP, 1000 Genomes, Exome Variant not previously described, were diagnosed with MIA. DNA was Server and our internal exome databases. Variants were visua- obtained from peripheral blood of one sibling, and from pre- lised using Integrative Genomics Viewer (IGV), or with served tissue of the other. The family is reportedly of NextGene (Soft Genetics, Inc.) French-Canadian origin on the maternal side, though not Sequences of primers for amplification and sequencing of known to be related to the CHUL and partial English ancestry TTC7A exons are given in online supplementary materials. on the paternal side. Genomic DNA was extracted using the Puregene DNA isolation The first sibling was born after 32 weeks of pregnancy compli- protocol from 28 ml of whole blood drawn by venipuncture. cated by polyhydramnios. Prenatal diagnosis of intestinal atresia PCRs were performed on a Hybaid Omnigene Temperature was highly suspected because bowel distension was observed on Cycling System in a total volume of 50 ml containing 100 ng of fetal ultrasound at 25 weeks of gestation.
Load more

Recommended publications
  • Primepcr™Assay Validation Report
    PrimePCR™Assay Validation Report Gene Information Gene Name long intergenic non-protein coding RNA 1119 Ensembl Gene Symbol LINC01119 LNCipedia Gene Symbol lnc-AC016722.2.1-1 Organism Human Ensembl Gene Aliases Not Available LCNipedia Gene Aliases XLOC_001459, linc-TTC7A-3, XLOC_001458, linc-TTC7A-2, ENSG00000239332, LINC01119, ENSG00000222005, LINC01118 UniGene ID Hs.114449 Ensembl Gene ID ENSG00000239332 Entrez Gene ID 100134259 Assay Information Unique Assay ID qhsaLEP0139233 Assay Type Probe - Validation information is for the primer pair using SYBR® Green detection Detected Ensembl Transcript(s) ENST00000422294,ENST00000490950,ENST00000495449,ENST00000468141 Detected LncPedia Transcript(s) lnc-AC016722.2.1-1_3,lnc-AC016722.2.1-1_15,lnc-AC016722.2.1-1_2,lnc-AC016722 .2.1-1_14,lnc-AC016722.2.1-1_9,lnc-AC016722.2.1-1_12,lnc-AC016722.2.1-1_13 Detected RefSeq Transcript(s) NR_024452 Amplicon Context Sequence GGGCCATTTTATACCAGTTGTAGGATGTTACACAGAAATGCCTGAAAAGCAAGG AGCAGCTATCAGAATGTTTGGTGACACAGCTCCTCCTGTCGTGGTTCCTTCGGC ATGGACTTCACATTCAGCAGATCCATGAGGTGTTC Amplicon Length (bp) 113 Chromosome Location chr2:46855974-46858205 Assay Design Exonic Validation Results Efficiency (%) 99.5 R2 0.9986 cDNA Cq 27.2537 cDNA Tm (Celsius) 83 gDNA Cq 24.0682 Page 1/5 PrimePCR™Assay Validation Report Specificity (%) 100 Information to assist with data interpretation is provided at the end of this report. Page 2/5 PrimePCR™Assay Validation Report LINC01119, Human Amplification Plot Amplification of cDNA generated from 25 ng of universal reference RNA Melt Peak
    [Show full text]
  • The Capacity of Long-Term in Vitro Proliferation of Acute Myeloid
    The Capacity of Long-Term in Vitro Proliferation of Acute Myeloid Leukemia Cells Supported Only by Exogenous Cytokines Is Associated with a Patient Subset with Adverse Outcome Annette K. Brenner, Elise Aasebø, Maria Hernandez-Valladares, Frode Selheim, Frode Berven, Ida-Sofie Grønningsæter, Sushma Bartaula-Brevik and Øystein Bruserud Supplementary Material S2 of S31 Table S1. Detailed information about the 68 AML patients included in the study. # of blasts Viability Proliferation Cytokine Viable cells Change in ID Gender Age Etiology FAB Cytogenetics Mutations CD34 Colonies (109/L) (%) 48 h (cpm) secretion (106) 5 weeks phenotype 1 M 42 de novo 241 M2 normal Flt3 pos 31.0 3848 low 0.24 7 yes 2 M 82 MF 12.4 M2 t(9;22) wt pos 81.6 74,686 low 1.43 969 yes 3 F 49 CML/relapse 149 M2 complex n.d. pos 26.2 3472 low 0.08 n.d. no 4 M 33 de novo 62.0 M2 normal wt pos 67.5 6206 low 0.08 6.5 no 5 M 71 relapse 91.0 M4 normal NPM1 pos 63.5 21,331 low 0.17 n.d. yes 6 M 83 de novo 109 M1 n.d. wt pos 19.1 8764 low 1.65 693 no 7 F 77 MDS 26.4 M1 normal wt pos 89.4 53,799 high 3.43 2746 no 8 M 46 de novo 26.9 M1 normal NPM1 n.d. n.d. 3472 low 1.56 n.d. no 9 M 68 MF 50.8 M4 normal D835 pos 69.4 1640 low 0.08 n.d.
    [Show full text]
  • TTC7A Mutations Disrupt Intestinal Epithelial Apicobasal Polarity
    TTC7A mutations disrupt intestinal epithelial apicobasal polarity Amélie E. Bigorgne, … , Hans Clevers, Geneviève de Saint Basile J Clin Invest. 2014;124(1):328-337. https://doi.org/10.1172/JCI71471. Research Article Gastroenterology Multiple intestinal atresia (MIA) is a rare cause of bowel obstruction that is sometimes associated with a combined immunodeficiency (CID), leading to increased susceptibility to infections. The factors underlying this rare disease are poorly understood. We characterized the immunological and intestinal features of 6 unrelated MIA-CID patients. All patients displayed a profound, generalized lymphocytopenia, with few lymphocytes present in the lymph nodes. The thymus was hypoplastic and exhibited an abnormal distribution of epithelial cells. Patients also had profound disruption of the epithelial barrier along the entire gastrointestinal tract. Using linkage analysis and whole-exome sequencing, we identified 10 mutations in tetratricopeptide repeat domain–7A (TTC7A), all of which potentially abrogate TTC7A expression. Intestinal organoid cultures from patient biopsies displayed an inversion of apicobasal polarity of the epithelial cells that was normalized by pharmacological inhibition of Rho kinase. Our data indicate that TTC7A deficiency results in increased Rho kinase activity, which disrupts polarity, growth, and differentiation of intestinal epithelial cells, and which impairs immune cell homeostasis, thereby promoting MIA-CID development. Find the latest version: https://jci.me/71471/pdf Research article TTC7A mutations disrupt intestinal epithelial apicobasal polarity Amélie E. Bigorgne,1,2,3 Henner F. Farin,4 Roxane Lemoine,1,2,3 Nizar Mahlaoui,2,3 Nathalie Lambert,5 Marine Gil,5 Ansgar Schulz,6 Pierre Philippet,7 Patrick Schlesser,7 Tore G. Abrahamsen,8 Knut Oymar,9 E.
    [Show full text]
  • CD98 [19] Among Others [5][23]
    bioRxiv preprint doi: https://doi.org/10.1101/2021.04.15.439921; this version posted April 18, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Physiological Substrates and Ontogeny-Specific Expression of the Ubiquitin Ligases 2 MARCH1 and MARCH8 3 4 Patrick Schriek1, Haiyin Liu1, Alan C. Ching1, Pauline Huang1, Nishma Gupta1, Kayla R. 5 Wilson1, MinHsuang Tsai1, Yuting Yan2, Christophe F. Macri1, Laura F. Dagley3,4, Giuseppe 6 Infusini3,4, Andrew I. Webb3,4, Hamish McWilliam1,2, Satoshi Ishido5, Justine D. Mintern1 and 7 Jose A. Villadangos1,2 8 9 1Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology 10 Institute, The University of Melbourne, Parkville, VIC 3010, Australia. 11 2Department of Microbiology and Immunology, Peter Doherty Institute for Infection and 12 Immunity, The University of Melbourne, Parkville, VIC 3010, Australia. 13 3Advanced Technology and Biology Division, The Walter and Eliza Hall Institute of Medical 14 Research, Parkville, VIC 3052, Australia. 15 4Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia. 16 5Department of Microbiology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya 17 17 663-8501, Japan 18 19 20 21 Correspondence to Justine D. Mintern ([email protected]) or 22 Jose A. Villadangos ([email protected]) 1 bioRxiv preprint doi: https://doi.org/10.1101/2021.04.15.439921; this version posted April 18, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder.
    [Show full text]
  • Tetratricopeptide Repeat Domain 7A Is a Nuclear Factor That Modulates
    El-Daher et al. Cell Discovery (2018) 4:61 Cell Discovery DOI 10.1038/s41421-018-0061-y www.nature.com/celldisc ARTICLE Open Access Tetratricopeptide repeat domain 7A is a nuclear factor that modulates transcription and chromatin structure Marie-Therese El-Daher1,2,NicolasCagnard2,3,4, Marine Gil1, Marie Chansel Da Cruz2,5, Claire Leveau1,2, Fernando Sepulveda 1,2, Mohammed Zarhrate6, Frédéric Tores3,PatriciaLegoix7, Sylvain Baulande 7, Jean Pierre de Villartay 2,5, Geneviève Almouzni8,9, Jean-Pierre Quivy8,9, Alain Fischer2,10,11,12 and GenevièvedeSaintBasile1,2,13 Abstract A loss-of-function mutation in tetratricopeptide repeat domain 7A (TTC7A) is a recently identified cause of human intestinal and immune disorders. However, clues to related underlying molecular dysfunctions remain elusive. It is now shown based on the study of TTC7A-deficient and wild-type cells that TTC7A is an essential nuclear protein. It binds to chromatin, preferentially at actively transcribed regions. Its depletion results in broad range of epigenomic changes at proximal and distal transcriptional regulatory elements and in altered control of the transcriptional program. Loss of WT_TTC7A induces general decrease in chromatin compaction, unbalanced cellular distribution of histones, higher nucleosome accessibility to nuclease digestion along with genome instability, and reduced cell viability. Our observations characterize for the first time unreported functions for TTC7A in the nucleus that exert a critical role in chromatin organization and gene regulation to safeguard healthy immune and intestinal status. 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; Introduction protein is critical for fine-tuning of the balance between The analysis of rare inherited diseases helps to identify cells’ proliferation, differentiation, and survival.
    [Show full text]
  • De Novo and Rare Mutations in the HSPA1L Heat
    Takahashi et al. Genome Medicine (2017) 9:8 DOI 10.1186/s13073-016-0394-9 RESEARCH Open Access De novo and rare mutations in the HSPA1L heat shock gene associated with inflammatory bowel disease Shinichi Takahashi1,2†, Gaia Andreoletti3†, Rui Chen1, Yoichi Munehira4,5, Akshay Batra6, Nadeem A. Afzal6, R. Mark Beattie6, Jonathan A. Bernstein7, Sarah Ennis3* and Michael Snyder1* Abstract Background: Inflammatory bowel disease (IBD) is a chronic, relapsing inflammatory disease of the gastrointestinal tract which includes ulcerative colitis and Crohn's disease. Genetic risk factors for IBD are not well understood. Methods: We performed a family-based whole exome sequencing (WES) analysis on a core family (Family A) to identify potential causal mutations and then analyzed exome data from a Caucasian pediatric cohort (136 patients and 106 controls) to validate the presence of mutations in the candidate gene, heat shock 70 kDa protein 1-like (HSPA1L). Biochemical assays of the de novo and rare (minor allele frequency, MAF < 0.01) mutation variant proteins further validated the predicted deleterious effects of the identified alleles. Results: In the proband of Family A, we found a heterozygous de novo mutation (c.830C > T; p.Ser277Leu) in HSPA1L. Through analysis of WES data of 136 patients, we identified five additional rare HSPA1L mutations (p.Gly77Ser, p.Leu172del, p.Thr267Ile, p.Ala268Thr, p.Glu558Asp) in six patients. In contrast, rare HSPA1L mutations were not observed in controls, and were significantly enriched in patients (P = 0.02). Interestingly, we did not find non-synonymous rare mutations in the HSP70 isoforms HSPA1A and HSPA1B. Biochemical assays revealed that all six rare HSPA1L variant proteins showed decreased chaperone activity in vitro.
    [Show full text]
  • Novel Mutations of the Tetratricopeptide Repeat Domain 7A Gene and Phenotype/Genotype Comparison
    ORIGINAL RESEARCH published: 07 September 2017 doi: 10.3389/fimmu.2017.01066 Novel Mutations of the Tetratricopeptide Repeat Domain 7A Gene and Phenotype/Genotype Comparison Reyin Lien 1, Yung-Feng Lin 2, Min-Wei Lai 3, Hui-Ying Weng 4, Ren-Chin Wu 5, Tang-Her Jaing 6,7, Jing-Long Huang 6,8, Shih-Feng Tsai 2 and Wen-I Lee 6,8* 1 Division of Neonatology, Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan, Taiwan, 2 Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Taiwan, 3 Division of Gastroenterology, Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan, Taiwan, 4 VYM Genome Research Center, National Yang-Ming University, Taipei, Taiwan, 5 Department of Pathology, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan, 6 Division of Allergy, Asthma and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan, Taiwan, 7 Division of Hematology/Oncology, Department Pediatrics, Chang Gung Memorial Hospital, Taoyuan, Taiwan, 8 Primary Immunodeficiency Care and Research (PICAR) Institute, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan The gastrointestinal tract contains the largest lymphoid organ to react with pathogenic microorganisms and suppress excess inflammation. Patients with primary immunodefi- Edited by: ciency diseases (PIDs) can suffer from refractory diarrhea. In this study, we present two Isabelle Meyts, KU Leuven, Belgium siblings who began to suffer from refractory diarrhea with a poor response to aggressive Reviewed by: antibiotic and immunosuppressive treatment after surgical release of neonatal intestinal Luigi Daniele Notarangelo, obstruction. Their lymphocyte proliferation was low, but superoxide production and Harvard Medical School, IL-10 signaling were normal.
    [Show full text]
  • Protein Tyrosine Phosphorylation in Haematopoietic Cancers and the Functional Significance of Phospho- Lyn SH2 Domain
    Protein Tyrosine Phosphorylation in Haematopoietic Cancers and the Functional Significance of Phospho- Lyn SH2 Domain By Lily Li Jin A thesis submitted in conformity with the requirements for the degree of Ph.D. in Molecular Genetics, Graduate Department of Molecular Genetics, in the University of Toronto © Copyright by Lily Li Jin (2015) Protein Tyrosine Phosphorylation in Haematopoietic Cancers and the Functional Significance of Phospho-Lyn SH2 Domain Lily Li Jin 2015 Ph.D. in Molecular Genetics Graduate Department of Molecular Genetics University of Toronto Abstract Protein-tyrosine phosphorylation (pY) is a minor but important protein post-translational modification that modulates a wide range of cellular functions and is involved in cancer. Dysregulation of tyrosine kinases (TKs) and protein-tyrosine phosphatases (PTPs) have been observed in multiple myeloma (MM) and acute myeloid leukemia (AML) and is a subject of study. Using recently developed mass spectrometry-based proteomics techniques, quantitative PTP expression and cellular pY profiles were generated for MM cell lines and mouse xenograft tumors, as well as primary AML samples. Integrated comprehensive analyses on these data implicated a subset of TKs and PTPs in MM and AML, with valuable insights gained on the dynamic regulation of pY in biological systems. In particular, I propose a model that describes the cellular pY state as a functional output of the total activated TKs and PTPs in the cell. My results show that the global pY profile in the cancer models is quantitatively related to the cellular levels of activated TKs and PTPs. Furthermore, the identity of the implicated TK/PTPs is system- ii dependent, demonstrating context-dependent regulation of pY.
    [Show full text]
  • A CASE of TTC7A DEFICIENCY Presented by Dr Bella Shadur Case
    APID2016 Case Summary: A CASE OF TTC7A DEFICIENCY Presented by Dr Bella Shadur Case summary 4/12 male Non-consanguineous, Anglo-Saxon heritage Presented with severe failure to thrive and diarrhoea o Initially worked up for cow’s milk protein intolerance o No improvement with various HA formulas Colonoscopy: severe inflammation of the entire colon Referred to immunology: could this be IPEX or IL10/IL10R deficiency? Baseline immune work-up demonstrated: o IgG 0.29 (↓), IgA 0.29 (normal), IgM 0.08 (↓), IgE < 5 o Normal lymphocyte subsets o T cell phenotype: normal proliferation to PHA and anti-CD3, STAT5p, TRECs, naïve T cells o Neutrophils: normal NBT and DHR o IPEX: normal FoxP3, CD25 staining, endocrine autoantibodies NAD o HLH: ferritin 50, SAP, XIAP, perforin, NK cell degranulation normal Enrolled in NEOPICS study (Inter-National Early Onset Paediatric IBD Cohort Study) o WES: compound heterozygous for two novel mutations in the TTC7A gene o Segregated in parents (both of whom asymptomatic) o Both predicted to be pathogenic, although one required confirmation via the creation of a DNA ladder Patient stabilised on subcutaneous immunoglobulin and total parenteral nutrition Ongoing monitoring of immune parameters, particularly T cell function For consideration of bone marrow transplant Learning points TTC7A deficiency = Tetratricopeptide repeat domain 7A Located on chromosome 2p21, autosomal recessive Deficiency leads to severe pathology of the gut and the immune system o Gut disease can range from inflammatory bowel disease
    [Show full text]
  • Chronic Intestinal Pseudo-Obstruction and Lymphoproliferative Syndrome
    Chronic Intestinal Pseudo-Obstruction and Lymphoproliferative Syndrome as a Novel Phenotype Associated With Tetratricopeptide Repeat Domain 7A Deficiency Marie-Thérèse El-Daher, Julie Lemale, Julie Bruneau, Claire Leveau, Frédéric Guerin, Nathalie Lambert, Jean-Sébastien Diana, Bénédicte Neven, Fernando Sepulveda Garrido, Aurore Coulomb-l’Hermine, et al. To cite this version: Marie-Thérèse El-Daher, Julie Lemale, Julie Bruneau, Claire Leveau, Frédéric Guerin, et al.. Chronic Intestinal Pseudo-Obstruction and Lymphoproliferative Syndrome as a Novel Phenotype Associated With Tetratricopeptide Repeat Domain 7A Deficiency. Frontiers in Immunology, Frontiers, 2019, 10, 10.3389/fimmu.2019.02592. hal-02365908 HAL Id: hal-02365908 https://hal.archives-ouvertes.fr/hal-02365908 Submitted on 9 Dec 2019 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Distributed under a Creative Commons Attribution| 4.0 International License CASE REPORT published: 07 November 2019 doi: 10.3389/fimmu.2019.02592 Chronic Intestinal Pseudo-Obstruction and Lymphoproliferative Syndrome as a Novel Phenotype Associated With Tetratricopeptide Repeat Domain 7A Deficiency Edited by: Marie-Thérèse El-Daher 1,2*, Julie Lemale 3, Julie Bruneau 2,4, Claire Leveau 1,2, Silvia Danielian, Frédéric Guerin 1,2, Nathalie Lambert 5, Jean-Sébastien Diana 6, Bénédicte Neven 6, Garrahan Hospital, Argentina Fernando E.
    [Show full text]
  • Book Halim.Indb
    Congenital Diseases of the Intestine Danny Halim The research described in this thesis was financially supported by Erasmus University Medical Center. The studies presented in this thesis were performed at the department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands. ISBN : 978-94-6299-997-8 Author : Danny Halim Cover Design : Tom de Vries Lentsch, Danny Halim and Hedwika Advina Nastiti Layout : Tom de Vries Lentsch and Danny Halim Printed by : Ridderprint BV, Ridderkerk, The Netherlands Copyright © D. Halim, 2016 All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means, without prior written permission of the author. The copyright of the published papers remains with the publisher. Congenital Diseases of the Intestine Aangeboren afwijkingen van de darm Proefschrift ter verkrijging van de graad van doctor aan de Erasmus Universiteit Rotterdam op gezag van de rector magnificus Prof.dr. H.A.P. Pols en volgens besluit van het College voor Promoties. De openbare verdediging zal plaatsvinden op woensdag 07 december 2016 om 13.30 uur door Danny Halim geboren te Bandung, Indonesië Promotiecommissie Promotors Prof.dr. R.M.W. Hofstra Prof.dr. D. Tibboel Overige leden Prof.dr. R.M.H. Wijnen Prof.dr. P.D. Coppi Prof.dr. D.F.E. Huylebroeck Copromotor Dr. A.J. Burns Table of Contents List of abbreviations 6 Chapter 1 General introduction and outline of the thesis 9 Chapter 2 ACTG2 variants impair actin polymerization in sporadic 23 Megacystis
    [Show full text]
  • WO 2014/177699 Al 6 November 2014 (06.11.2014) P O P C T
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2014/177699 Al 6 November 2014 (06.11.2014) P O P C T (51) International Patent Classification: CT Utrecht (NL). FARIN, Henner; Hubrecht Institute, A61K 31/437 (2006.01) A61K 31/551 (2006.01) Uppsalalaan 8, NL-3584 CT Utrecht (NL). A61K 31/4409 (2006.01) A61P 1/04 (2006.01) (74) Agent: HIRSCH, Denise; Inserm Transfert, 7 rue Watt, F- (21) International Application Number: 75013 Paris (FR). PCT/EP2014/058997 (81) Designated States (unless otherwise indicated, for every (22) International Filing Date: kind of national protection available): AE, AG, AL, AM, 2 May 2014 (02.05.2014) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (25) Filing Language: English DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (26) Publication Language: English HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, (30) Priority Data: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, 13305582.2 3 May 2013 (03.05.2013) EP OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (71) Applicants: INSERM (INSTITUT NATIONAL DE LA SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, SANTE ET DE LA RECHERCHE MEDICALE) TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, [FR/FR]; 101, rue de Tolbiac, F-75013 Paris (FR).
    [Show full text]