Search

Your search keyword '"Huma Cheema"' showing total 2 results
Start Over Author "Huma Cheema" Topic humans
2 results on '"Huma Cheema"'

1. A disorder clinically resembling cystic fibrosis caused by biallelic variants in the AGR2 gene

Author

Aida Bertoli-Avella, Ronja Hotakainen, Maryam Al Shehhi, Alice Urzi, Catarina Pareira, Anett Marais, Khoula Al Shidhani, Sumaya Aloraimi, Galina Morales-Torres, Steffen Fisher, Laura Demuth, Laila Abdel Moteleb Selim, Nihal Al Menabawy, Maryam Busehail, Mohammed AlShaikh, Naser Gilani, Dler Nooruldeen Chalabi, Nasser S Alharbi, Majid Alfadhel, Mohammed Abdelrahman, Hanka Venselaar, Nadeem Anjum, Anjum Saeed, Malak Ali Alghamdi, Hamad Aljaedi, Hisham Arabi, Vasiliki Karageorgou, Suliman Khan, Zahra Hajjari, Mandy Radefeldt, Ruslan Al-Ali, Kornelia Tripolszki, Amer Jamhawi, Omid Paknia, Claudia Cozma, Huma Cheema, Najim Ameziane, Saleh Al-Muhsen, and Peter Bauer

Subjects
Oncogene Proteins, Mucoproteins, Phenotype, Cystic Fibrosis, Mutation, Genetics, Cystic Fibrosis Transmembrane Conductance Regulator, Humans, Exome, Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19], Genetics (clinical)
Abstract

PurposeWe sought to describe a disorder clinically mimicking cystic fibrosis (CF) and to elucidate its genetic cause.MethodsExome/genome sequencing and human phenotype ontology data of nearly 40 000 patients from our Bio/Databank were analysed. RNA sequencing of samples from the nasal mucosa from patients, carriers and controls followed by transcriptome analysis was performed.ResultsWe identified 13 patients from 9 families with a CF-like phenotype consisting of recurrent lower respiratory infections (13/13), failure to thrive (13/13) and chronic diarrhoea (8/13), with high morbidity and mortality. All patients had biallelic variants in AGR2, (1) two splice-site variants, (2) gene deletion and (3) three missense variants. We confirmed aberrant AGR2 transcripts caused by an intronic variant and complete absence of AGR2 transcripts caused by the large gene deletion, resulting in loss of function (LoF). Furthermore, transcriptome analysis identified significant downregulation of components of the mucociliary machinery (intraciliary transport, cilium organisation), as well as upregulation of immune processes.ConclusionWe describe a previously unrecognised autosomal recessive disorder caused by AGR2 variants. AGR2-related disease should be considered as a differential diagnosis in patients presenting a CF-like phenotype. This has implications for the molecular diagnosis and management of these patients. AGR2 LoF is likely the disease mechanism, with consequent impairment of the mucociliary defence machinery. Future studies should aim to establish a better understanding of the disease pathophysiology and to identify potential drug targets.

Published
2021

2. Bi-allelic loss-of-function variants in TMEM147 cause moderate to profound intellectual disability with facial dysmorphism and pseudo-Pelger-Huët anomaly

Author

Quentin Thomas, Marialetizia Motta, Thierry Gautier, Maha S. Zaki, Andrea Ciolfi, Julien Paccaud, François Girodon, Odile Boespflug-Tanguy, Thomas Besnard, Jennifer Kerkhof, Haley McConkey, Aymeric Masson, Anne-Sophie Denommé-Pichon, Benjamin Cogné, Eva Trochu, Virginie Vignard, Fatima El It, Lance H. Rodan, Mohammad Ayman Alkhateeb, Rami Abou Jamra, Laurence Duplomb, Emilie Tisserant, Yannis Duffourd, Ange-Line Bruel, Adam Jackson, Siddharth Banka, Meriel McEntagart, Anand Saggar, Joseph G. Gleeson, David Sievert, Hyunwoo Bae, Beom Hee Lee, Kisang Kwon, Go Hun Seo, Hane Lee, Anjum Saeed, Nadeem Anjum, Huma Cheema, Salem Alawbathani, Imran Khan, Jorge Pinto-Basto, Joyce Teoh, Jasmine Wong, Umar Bin Mohamad Sahari, Henry Houlden, Kristina Zhelcheska, Melanie Pannetier, Mona A. Awad, Marion Lesieur-Sebellin, Giulia Barcia, Jeanne Amiel, Julian Delanne, Christophe Philippe, Laurence Faivre, Sylvie Odent, Aida Bertoli-Avella, Christel Thauvin, Bekim Sadikovic, Bruno Reversade, Reza Maroofian, Jérôme Govin, Marco Tartaglia, Antonio Vitobello, Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), CHU Pontchaillou [Rennes], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de référence Maladies Rares CLAD-Ouest [Rennes], FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), and This work was supported by grants from Dijon University Hospital, the ISITE-BFC (PIA ANR), and the European Union through the FEDER programs, EJP-RD (NSEuroNET), AIRC (IG21614), and Italian Ministry of Health (5x1000). Sequencing for individual 15 was funded by the Institute for Information and Communications Technology Promotion (IITP) grant from the Korean government (MSIT) (2018-0-00861, Intelligent SW Technology Development for Medical Data Analysis). This study makes use of DECIPHER (http://decipher.sanger.ac.uk), which is funded by the Wellcome (www.ddduk.org/access.html).55 This research was made possible through access to the data and findings generated by the 100KGP. The 100KGP is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100KGP is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK, and the Medical Research Council have also funded research infrastructure. The 100KGP uses data provided by individuals and collected by the National Health Service as part of their care and support. Several authors of this publication are members of the European Reference Network for Developmental Anomalies and Intellectual Disability (ERN-ITHACA). The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement no. 779257.

Subjects
Cell Nucleus, [SDV.GEN]Life Sciences [q-bio]/Genetics, DNA methylation, Loss of Heterozygosity, facial dysmorphism, neurodevelopmental disorder, Chromatin, Musculoskeletal Abnormalities, transcriptomics, translocon dysfunction, Pelger-Huët anomaly, intellectual disability, Genetics, LBR, Humans, TMEM147, nuclear envelope instability, Child, Pelger-Huet Anomaly, Genetics (clinical)
Abstract

International audience; The transmembrane protein TMEM147 has a dual function: first at the nuclear envelope, where it anchors lamin B receptor (LBR) to the inner membrane, and second at the endoplasmic reticulum (ER), where it facilitates the translation of nascent polypeptides within the ribosome-bound TMCO1 translocon complex. Through international data sharing, we identified 23 individuals from 15 unrelated families with bi-allelic TMEM147 loss-of-function variants, including splice-site, nonsense, frameshift, and missense variants. These affected children displayed congruent clinical features including coarse facies, developmental delay, intellectual disability, and behavioral problems. In silico structural analyses predicted disruptive consequences of the identified amino acid substitutions on translocon complex assembly and/or function, and in vitro analyses documented accelerated protein degradation via the autophagy-lysosomal-mediated pathway. Furthermore, TMEM147-deficient cells showed CKAP4 (CLIMP-63) and RTN4 (NOGO) upregulation with a concomitant reorientation of the ER, which was also witnessed in primary fibroblast cell culture. LBR mislocalization and nuclear segmentation was observed in primary fibroblast cells. Abnormal nuclear segmentation and chromatin compaction were also observed in approximately 20% of neutrophils, indicating the presence of a pseudo-Pelger-Huët anomaly. Finally, co-expression analysis revealed significant correlation with neurodevelopmental genes in the brain, further supporting a role of TMEM147 in neurodevelopment. Our findings provide clinical, genetic, and functional evidence that bi-allelic loss-of-function variants in TMEM147 cause syndromic intellectual disability due to ER-translocon and nuclear organization dysfunction.

Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results