--- _id: '14368' abstract: - lang: eng text: "Purpose: \r\nBiallelic variants in TARS2, encoding the mitochondrial threonyl-tRNA-synthetase, have been reported in a small group of individuals displaying a neurodevelopmental phenotype but with limited neuroradiological data and insufficient evidence for causality of the variants.\r\nMethods:\r\nExome or genome sequencing was carried out in 15 families. Clinical and neuroradiological evaluation was performed for all affected individuals, including review of 10 previously reported individuals. The pathogenicity of TARS2 variants was evaluated using in vitro assays and a zebrafish model.\r\nResults:\r\nWe report 18 new individuals harboring biallelic TARS2 variants. Phenotypically, these individuals show developmental delay/intellectual disability, regression, cerebellar and cerebral atrophy, basal ganglia signal alterations, hypotonia, cerebellar signs, and increased blood lactate. In vitro studies showed that variants within the TARS2301-381 region had decreased binding to Rag GTPases, likely impairing mTORC1 activity. The zebrafish model recapitulated key features of the human phenotype and unraveled dysregulation of downstream targets of mTORC1 signaling. Functional testing of the variants confirmed the pathogenicity in a zebrafish model.\r\nConclusion:\r\nWe define the clinico-radiological spectrum of TARS2-related mitochondrial disease, unveil the likely involvement of the mTORC1 signaling pathway as a distinct molecular mechanism, and establish a TARS2 zebrafish model as an important tool to study variant pathogenicity." article_number: '100938' article_processing_charge: No article_type: original author: - first_name: Andrea full_name: Accogli, Andrea last_name: Accogli - first_name: Sheng-Jia full_name: Lin, Sheng-Jia last_name: Lin - first_name: Mariasavina full_name: Severino, Mariasavina last_name: Severino - first_name: Sung-Hoon full_name: Kim, Sung-Hoon last_name: Kim - first_name: Kevin full_name: Huang, Kevin id: 3b3d2888-1ff6-11ee-9fa6-8f209ca91fe3 last_name: Huang orcid: 0000-0002-2512-7812 - first_name: Clarissa full_name: Rocca, Clarissa last_name: Rocca - first_name: Megan full_name: Landsverk, Megan last_name: Landsverk - first_name: Maha S. full_name: Zaki, Maha S. last_name: Zaki - first_name: Almundher full_name: Al-Maawali, Almundher last_name: Al-Maawali - first_name: Varunvenkat M. full_name: Srinivasan, Varunvenkat M. last_name: Srinivasan - first_name: Khalid full_name: Al-Thihli, Khalid last_name: Al-Thihli - first_name: G. Bradly full_name: Schaefer, G. Bradly last_name: Schaefer - first_name: Monica full_name: Davis, Monica last_name: Davis - first_name: Davide full_name: Tonduti, Davide last_name: Tonduti - first_name: Chiara full_name: Doneda, Chiara last_name: Doneda - first_name: Lara M. full_name: Marten, Lara M. last_name: Marten - first_name: Chris full_name: Mühlhausen, Chris last_name: Mühlhausen - first_name: Maria full_name: Gomez, Maria last_name: Gomez - first_name: Eleonora full_name: Lamantea, Eleonora last_name: Lamantea - first_name: Rafael full_name: Mena, Rafael last_name: Mena - first_name: Mathilde full_name: Nizon, Mathilde last_name: Nizon - first_name: Vincent full_name: Procaccio, Vincent last_name: Procaccio - first_name: Amber full_name: Begtrup, Amber last_name: Begtrup - first_name: Aida full_name: Telegrafi, Aida last_name: Telegrafi - first_name: Hong full_name: Cui, Hong last_name: Cui - first_name: Heidi L. full_name: Schulz, Heidi L. last_name: Schulz - first_name: Julia full_name: Mohr, Julia last_name: Mohr - first_name: Saskia full_name: Biskup, Saskia last_name: Biskup - first_name: Mariana Amina full_name: Loos, Mariana Amina last_name: Loos - first_name: Hilda Verónica full_name: Aráoz, Hilda Verónica last_name: Aráoz - first_name: Vincenzo full_name: Salpietro, Vincenzo last_name: Salpietro - first_name: Laura Davis full_name: Keppen, Laura Davis last_name: Keppen - first_name: Manali full_name: Chitre, Manali last_name: Chitre - first_name: Cassidy full_name: Petree, Cassidy last_name: Petree - first_name: Lucy full_name: Raymond, Lucy last_name: Raymond - first_name: Julie full_name: Vogt, Julie last_name: Vogt - first_name: Lindsey B. full_name: Sawyer, Lindsey B. last_name: Sawyer - first_name: Alice A. full_name: Basinger, Alice A. last_name: Basinger - first_name: Signe Vandal full_name: Pedersen, Signe Vandal last_name: Pedersen - first_name: Toni S. full_name: Pearson, Toni S. last_name: Pearson - first_name: Dorothy K. full_name: Grange, Dorothy K. last_name: Grange - first_name: Lokesh full_name: Lingappa, Lokesh last_name: Lingappa - first_name: Paige full_name: McDunnah, Paige last_name: McDunnah - first_name: Rita full_name: Horvath, Rita last_name: Horvath - first_name: Benjamin full_name: Cognè, Benjamin last_name: Cognè - first_name: Bertrand full_name: Isidor, Bertrand last_name: Isidor - first_name: Andreas full_name: Hahn, Andreas last_name: Hahn - first_name: Karen W. full_name: Gripp, Karen W. last_name: Gripp - first_name: Seyed Mehdi full_name: Jafarnejad, Seyed Mehdi last_name: Jafarnejad - first_name: Elsebet full_name: Østergaard, Elsebet last_name: Østergaard - first_name: Carlos E. full_name: Prada, Carlos E. last_name: Prada - first_name: Daniele full_name: Ghezzi, Daniele last_name: Ghezzi - first_name: Vykuntaraju K. full_name: Gowda, Vykuntaraju K. last_name: Gowda - first_name: Robert W. full_name: Taylor, Robert W. last_name: Taylor - first_name: Nahum full_name: Sonenberg, Nahum last_name: Sonenberg - first_name: Henry full_name: Houlden, Henry last_name: Houlden - first_name: Marie full_name: Sissler, Marie last_name: Sissler - first_name: Gaurav K. full_name: Varshney, Gaurav K. last_name: Varshney - first_name: Reza full_name: Maroofian, Reza last_name: Maroofian citation: ama: Accogli A, Lin S-J, Severino M, et al. Clinical, neuroradiological, and molecular characterization of mitochondrial threonyl-tRNA-synthetase (TARS2)-related disorder. Genetics in Medicine. 2023;25(11). doi:10.1016/j.gim.2023.100938 apa: Accogli, A., Lin, S.-J., Severino, M., Kim, S.-H., Huang, K., Rocca, C., … Maroofian, R. (2023). Clinical, neuroradiological, and molecular characterization of mitochondrial threonyl-tRNA-synthetase (TARS2)-related disorder. Genetics in Medicine. Elsevier. https://doi.org/10.1016/j.gim.2023.100938 chicago: Accogli, Andrea, Sheng-Jia Lin, Mariasavina Severino, Sung-Hoon Kim, Kevin Huang, Clarissa Rocca, Megan Landsverk, et al. “Clinical, Neuroradiological, and Molecular Characterization of Mitochondrial Threonyl-TRNA-Synthetase (TARS2)-Related Disorder.” Genetics in Medicine. Elsevier, 2023. https://doi.org/10.1016/j.gim.2023.100938. ieee: A. Accogli et al., “Clinical, neuroradiological, and molecular characterization of mitochondrial threonyl-tRNA-synthetase (TARS2)-related disorder,” Genetics in Medicine, vol. 25, no. 11. Elsevier, 2023. ista: Accogli A, Lin S-J, Severino M, Kim S-H, Huang K, Rocca C, Landsverk M, Zaki MS, Al-Maawali A, Srinivasan VM, Al-Thihli K, Schaefer GB, Davis M, Tonduti D, Doneda C, Marten LM, Mühlhausen C, Gomez M, Lamantea E, Mena R, Nizon M, Procaccio V, Begtrup A, Telegrafi A, Cui H, Schulz HL, Mohr J, Biskup S, Loos MA, Aráoz HV, Salpietro V, Keppen LD, Chitre M, Petree C, Raymond L, Vogt J, Sawyer LB, Basinger AA, Pedersen SV, Pearson TS, Grange DK, Lingappa L, McDunnah P, Horvath R, Cognè B, Isidor B, Hahn A, Gripp KW, Jafarnejad SM, Østergaard E, Prada CE, Ghezzi D, Gowda VK, Taylor RW, Sonenberg N, Houlden H, Sissler M, Varshney GK, Maroofian R. 2023. Clinical, neuroradiological, and molecular characterization of mitochondrial threonyl-tRNA-synthetase (TARS2)-related disorder. Genetics in Medicine. 25(11), 100938. mla: Accogli, Andrea, et al. “Clinical, Neuroradiological, and Molecular Characterization of Mitochondrial Threonyl-TRNA-Synthetase (TARS2)-Related Disorder.” Genetics in Medicine, vol. 25, no. 11, 100938, Elsevier, 2023, doi:10.1016/j.gim.2023.100938. short: A. Accogli, S.-J. Lin, M. Severino, S.-H. Kim, K. Huang, C. Rocca, M. Landsverk, M.S. Zaki, A. Al-Maawali, V.M. Srinivasan, K. Al-Thihli, G.B. Schaefer, M. Davis, D. Tonduti, C. Doneda, L.M. Marten, C. Mühlhausen, M. Gomez, E. Lamantea, R. Mena, M. Nizon, V. Procaccio, A. Begtrup, A. Telegrafi, H. Cui, H.L. Schulz, J. Mohr, S. Biskup, M.A. Loos, H.V. Aráoz, V. Salpietro, L.D. Keppen, M. Chitre, C. Petree, L. Raymond, J. Vogt, L.B. Sawyer, A.A. Basinger, S.V. Pedersen, T.S. Pearson, D.K. Grange, L. Lingappa, P. McDunnah, R. Horvath, B. Cognè, B. Isidor, A. Hahn, K.W. Gripp, S.M. Jafarnejad, E. Østergaard, C.E. Prada, D. Ghezzi, V.K. Gowda, R.W. Taylor, N. Sonenberg, H. Houlden, M. Sissler, G.K. Varshney, R. Maroofian, Genetics in Medicine 25 (2023). date_created: 2023-09-25T08:44:29Z date_published: 2023-11-01T00:00:00Z date_updated: 2023-09-25T08:50:10Z day: '01' ddc: - '570' doi: 10.1016/j.gim.2023.100938 extern: '1' file: - access_level: open_access checksum: 440f0cd8a2ffcbe03c015c1746728387 content_type: application/pdf creator: dernst date_created: 2023-09-25T08:48:54Z date_updated: 2023-09-25T08:48:54Z file_id: '14369' file_name: 2023_GeneticsMedicine_Accogli.pdf file_size: 4105513 relation: main_file success: 1 file_date_updated: 2023-09-25T08:48:54Z has_accepted_license: '1' intvolume: ' 25' issue: '11' keyword: - Genetics (clinical) language: - iso: eng month: '11' oa: 1 oa_version: Published Version publication: Genetics in Medicine publication_identifier: issn: - 1098-3600 publication_status: published publisher: Elsevier quality_controlled: '1' scopus_import: '1' status: public title: Clinical, neuroradiological, and molecular characterization of mitochondrial threonyl-tRNA-synthetase (TARS2)-related disorder tmp: image: /images/cc_by.png legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0) short: CC BY (4.0) type: journal_article user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87 volume: 25 year: '2023' ... --- _id: '14543' abstract: - lang: eng text: The acyl-CoA-binding domain-containing protein 6 (ACBD6) is ubiquitously expressed, plays a role in the acylation of lipids and proteins, and regulates the N-myristoylation of proteins via N-myristoyltransferase enzymes (NMTs). However, its precise function in cells is still unclear, as is the consequence of ACBD6 defects on human pathophysiology. Utilizing exome sequencing and extensive international data sharing efforts, we identified 45 affected individuals from 28 unrelated families (consanguinity 93%) with bi-allelic pathogenic, predominantly loss-of-function (18/20) variants in ACBD6. We generated zebrafish and Xenopus tropicalis acbd6 knockouts by CRISPR/Cas9 and characterized the role of ACBD6 on protein N-myristoylation with YnMyr chemical proteomics in the model organisms and human cells, with the latter also being subjected further to ACBD6 peroxisomal localization studies. The affected individuals (23 males and 22 females), with ages ranging from 1 to 50 years old, typically present with a complex and progressive disease involving moderate-to-severe global developmental delay/intellectual disability (100%) with significant expressive language impairment (98%), movement disorders (97%), facial dysmorphism (95%), and mild cerebellar ataxia (85%) associated with gait impairment (94%), limb spasticity/hypertonia (76%), oculomotor (71%) and behavioural abnormalities (65%), overweight (59%), microcephaly (39%) and epilepsy (33%). The most conspicuous and common movement disorder was dystonia (94%), frequently leading to early-onset progressive postural deformities (97%), limb dystonia (55%), and cervical dystonia (31%). A jerky tremor in the upper limbs (63%), a mild head tremor (59%), parkinsonism/hypokinesia developing with advancing age (32%), and simple motor and vocal tics were among other frequent movement disorders. Midline brain malformations including corpus callosum abnormalities (70%), hypoplasia/agenesis of the anterior commissure (66%), short midbrain and small inferior cerebellar vermis (38% each), as well as hypertrophy of the clava (24%) were common neuroimaging findings. acbd6-deficient zebrafish and Xenopus models effectively recapitulated many clinical phenotypes reported in patients including movement disorders, progressive neuromotor impairment, seizures, microcephaly, craniofacial dysmorphism, and midbrain defects accompanied by developmental delay with increased mortality over time. Unlike ACBD5, ACBD6 did not show a peroxisomal localisation and ACBD6-deficiency was not associated with altered peroxisomal parameters in patient fibroblasts. Significant differences in YnMyr-labelling were observed for 68 co- and 18 post-translationally N-myristoylated proteins in patient-derived fibroblasts. N-Myristoylation was similarly affected in acbd6-deficient zebrafish and Xenopus tropicalis models, including Fus, Marcks, and Chchd-related proteins implicated in neurological diseases. The present study provides evidence that bi-allelic pathogenic variants in ACBD6 lead to a distinct neurodevelopmental syndrome accompanied by complex and progressive cognitive and movement disorders. article_number: awad380 article_processing_charge: No article_type: original author: - first_name: Rauan full_name: Kaiyrzhanov, Rauan last_name: Kaiyrzhanov - first_name: Aboulfazl full_name: Rad, Aboulfazl last_name: Rad - first_name: Sheng-Jia full_name: Lin, Sheng-Jia last_name: Lin - first_name: Aida full_name: Bertoli-Avella, Aida last_name: Bertoli-Avella - first_name: Wouter W full_name: Kallemeijn, Wouter W last_name: Kallemeijn - first_name: Annie full_name: Godwin, Annie last_name: Godwin - first_name: Maha S full_name: Zaki, Maha S last_name: Zaki - first_name: Kevin full_name: Huang, Kevin id: 3b3d2888-1ff6-11ee-9fa6-8f209ca91fe3 last_name: Huang orcid: 0000-0002-2512-7812 - first_name: Tracy full_name: Lau, Tracy last_name: Lau - first_name: Cassidy full_name: Petree, Cassidy last_name: Petree - first_name: Stephanie full_name: Efthymiou, Stephanie last_name: Efthymiou - first_name: Ehsan full_name: Ghayoor Karimiani, Ehsan last_name: Ghayoor Karimiani - first_name: Maja full_name: Hempel, Maja last_name: Hempel - first_name: Elizabeth A full_name: Normand, Elizabeth A last_name: Normand - first_name: Sabine full_name: Rudnik-Schöneborn, Sabine last_name: Rudnik-Schöneborn - first_name: Ulrich A full_name: Schatz, Ulrich A last_name: Schatz - first_name: Marc P full_name: Baggelaar, Marc P last_name: Baggelaar - first_name: Muhammad full_name: Ilyas, Muhammad last_name: Ilyas - first_name: Tipu full_name: Sultan, Tipu last_name: Sultan - first_name: Javeria Raza full_name: Alvi, Javeria Raza last_name: Alvi - first_name: Manizha full_name: Ganieva, Manizha last_name: Ganieva - first_name: Ben full_name: Fowler, Ben last_name: Fowler - first_name: Ruxandra full_name: Aanicai, Ruxandra last_name: Aanicai - first_name: Gulsen full_name: Akay Tayfun, Gulsen last_name: Akay Tayfun - first_name: Abdulaziz full_name: Al Saman, Abdulaziz last_name: Al Saman - first_name: Abdulrahman full_name: Alswaid, Abdulrahman last_name: Alswaid - first_name: Nafise full_name: Amiri, Nafise last_name: Amiri - first_name: Nilufar full_name: Asilova, Nilufar last_name: Asilova - first_name: Vorasuk full_name: Shotelersuk, Vorasuk last_name: Shotelersuk - first_name: Patra full_name: Yeetong, Patra last_name: Yeetong - first_name: Matloob full_name: Azam, Matloob last_name: Azam - first_name: Meisam full_name: Babaei, Meisam last_name: Babaei - first_name: Gholamreza full_name: Bahrami Monajemi, Gholamreza last_name: Bahrami Monajemi - first_name: Pouria full_name: Mohammadi, Pouria last_name: Mohammadi - first_name: Saeed full_name: Samie, Saeed last_name: Samie - first_name: Selina Husna full_name: Banu, Selina Husna last_name: Banu - first_name: Jorge Pinto full_name: Basto, Jorge Pinto last_name: Basto - first_name: Fanny full_name: Kortüm, Fanny last_name: Kortüm - first_name: Mislen full_name: Bauer, Mislen last_name: Bauer - first_name: Peter full_name: Bauer, Peter last_name: Bauer - first_name: Christian full_name: Beetz, Christian last_name: Beetz - first_name: Masoud full_name: Garshasbi, Masoud last_name: Garshasbi - first_name: Awatif full_name: Hameed Issa, Awatif last_name: Hameed Issa - first_name: Wafaa full_name: Eyaid, Wafaa last_name: Eyaid - first_name: Hind full_name: Ahmed, Hind last_name: Ahmed - first_name: Narges full_name: Hashemi, Narges last_name: Hashemi - first_name: Kazem full_name: Hassanpour, Kazem last_name: Hassanpour - first_name: Isabella full_name: Herman, Isabella last_name: Herman - first_name: Sherozjon full_name: Ibrohimov, Sherozjon last_name: Ibrohimov - first_name: Ban A full_name: Abdul-Majeed, Ban A last_name: Abdul-Majeed - first_name: Maria full_name: Imdad, Maria last_name: Imdad - first_name: Maksudjon full_name: Isrofilov, Maksudjon last_name: Isrofilov - first_name: Qassem full_name: Kaiyal, Qassem last_name: Kaiyal - first_name: Suliman full_name: Khan, Suliman last_name: Khan - first_name: Brian full_name: Kirmse, Brian last_name: Kirmse - first_name: Janet full_name: Koster, Janet last_name: Koster - first_name: Charles Marques full_name: Lourenço, Charles Marques last_name: Lourenço - first_name: Tadahiro full_name: Mitani, Tadahiro last_name: Mitani - first_name: Oana full_name: Moldovan, Oana last_name: Moldovan - first_name: David full_name: Murphy, David last_name: Murphy - first_name: Maryam full_name: Najafi, Maryam last_name: Najafi - first_name: Davut full_name: Pehlivan, Davut last_name: Pehlivan - first_name: Maria Eugenia full_name: Rocha, Maria Eugenia last_name: Rocha - first_name: Vincenzo full_name: Salpietro, Vincenzo last_name: Salpietro - first_name: Miriam full_name: Schmidts, Miriam last_name: Schmidts - first_name: Adel full_name: Shalata, Adel last_name: Shalata - first_name: Mohammad full_name: Mahroum, Mohammad last_name: Mahroum - first_name: Jawabreh Kassem full_name: Talbeya, Jawabreh Kassem last_name: Talbeya - first_name: Robert W full_name: Taylor, Robert W last_name: Taylor - first_name: Dayana full_name: Vazquez, Dayana last_name: Vazquez - first_name: Annalisa full_name: Vetro, Annalisa last_name: Vetro - first_name: Hans R full_name: Waterham, Hans R last_name: Waterham - first_name: Mashaya full_name: Zaman, Mashaya last_name: Zaman - first_name: Tina A full_name: Schrader, Tina A last_name: Schrader - first_name: Wendy K full_name: Chung, Wendy K last_name: Chung - first_name: Renzo full_name: Guerrini, Renzo last_name: Guerrini - first_name: James R full_name: Lupski, James R last_name: Lupski - first_name: Joseph full_name: Gleeson, Joseph last_name: Gleeson - first_name: Mohnish full_name: Suri, Mohnish last_name: Suri - first_name: Yalda full_name: Jamshidi, Yalda last_name: Jamshidi - first_name: Kailash P full_name: Bhatia, Kailash P last_name: Bhatia - first_name: Barbara full_name: Vona, Barbara last_name: Vona - first_name: Michael full_name: Schrader, Michael last_name: Schrader - first_name: Mariasavina full_name: Severino, Mariasavina last_name: Severino - first_name: Matthew full_name: Guille, Matthew last_name: Guille - first_name: Edward W full_name: Tate, Edward W last_name: Tate - first_name: Gaurav K full_name: Varshney, Gaurav K last_name: Varshney - first_name: Henry full_name: Houlden, Henry last_name: Houlden - first_name: Reza full_name: Maroofian, Reza last_name: Maroofian citation: ama: Kaiyrzhanov R, Rad A, Lin S-J, et al. Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders. Brain. 2023. doi:10.1093/brain/awad380 apa: Kaiyrzhanov, R., Rad, A., Lin, S.-J., Bertoli-Avella, A., Kallemeijn, W. W., Godwin, A., … Maroofian, R. (2023). Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders. Brain. Oxford University Press. https://doi.org/10.1093/brain/awad380 chicago: Kaiyrzhanov, Rauan, Aboulfazl Rad, Sheng-Jia Lin, Aida Bertoli-Avella, Wouter W Kallemeijn, Annie Godwin, Maha S Zaki, et al. “Bi-Allelic ACBD6 Variants Lead to a Neurodevelopmental Syndrome with Progressive and Complex Movement Disorders.” Brain. Oxford University Press, 2023. https://doi.org/10.1093/brain/awad380. ieee: R. Kaiyrzhanov et al., “Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders,” Brain. Oxford University Press, 2023. ista: Kaiyrzhanov R, Rad A, Lin S-J, Bertoli-Avella A, Kallemeijn WW, Godwin A, Zaki MS, Huang K, Lau T, Petree C, Efthymiou S, Ghayoor Karimiani E, Hempel M, Normand EA, Rudnik-Schöneborn S, Schatz UA, Baggelaar MP, Ilyas M, Sultan T, Alvi JR, Ganieva M, Fowler B, Aanicai R, Akay Tayfun G, Al Saman A, Alswaid A, Amiri N, Asilova N, Shotelersuk V, Yeetong P, Azam M, Babaei M, Bahrami Monajemi G, Mohammadi P, Samie S, Banu SH, Basto JP, Kortüm F, Bauer M, Bauer P, Beetz C, Garshasbi M, Hameed Issa A, Eyaid W, Ahmed H, Hashemi N, Hassanpour K, Herman I, Ibrohimov S, Abdul-Majeed BA, Imdad M, Isrofilov M, Kaiyal Q, Khan S, Kirmse B, Koster J, Lourenço CM, Mitani T, Moldovan O, Murphy D, Najafi M, Pehlivan D, Rocha ME, Salpietro V, Schmidts M, Shalata A, Mahroum M, Talbeya JK, Taylor RW, Vazquez D, Vetro A, Waterham HR, Zaman M, Schrader TA, Chung WK, Guerrini R, Lupski JR, Gleeson J, Suri M, Jamshidi Y, Bhatia KP, Vona B, Schrader M, Severino M, Guille M, Tate EW, Varshney GK, Houlden H, Maroofian R. 2023. Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders. Brain., awad380. mla: Kaiyrzhanov, Rauan, et al. “Bi-Allelic ACBD6 Variants Lead to a Neurodevelopmental Syndrome with Progressive and Complex Movement Disorders.” Brain, awad380, Oxford University Press, 2023, doi:10.1093/brain/awad380. short: R. Kaiyrzhanov, A. Rad, S.-J. Lin, A. Bertoli-Avella, W.W. Kallemeijn, A. Godwin, M.S. Zaki, K. Huang, T. Lau, C. Petree, S. Efthymiou, E. Ghayoor Karimiani, M. Hempel, E.A. Normand, S. Rudnik-Schöneborn, U.A. Schatz, M.P. Baggelaar, M. Ilyas, T. Sultan, J.R. Alvi, M. Ganieva, B. Fowler, R. Aanicai, G. Akay Tayfun, A. Al Saman, A. Alswaid, N. Amiri, N. Asilova, V. Shotelersuk, P. Yeetong, M. Azam, M. Babaei, G. Bahrami Monajemi, P. Mohammadi, S. Samie, S.H. Banu, J.P. Basto, F. Kortüm, M. Bauer, P. Bauer, C. Beetz, M. Garshasbi, A. Hameed Issa, W. Eyaid, H. Ahmed, N. Hashemi, K. Hassanpour, I. Herman, S. Ibrohimov, B.A. Abdul-Majeed, M. Imdad, M. Isrofilov, Q. Kaiyal, S. Khan, B. Kirmse, J. Koster, C.M. Lourenço, T. Mitani, O. Moldovan, D. Murphy, M. Najafi, D. Pehlivan, M.E. Rocha, V. Salpietro, M. Schmidts, A. Shalata, M. Mahroum, J.K. Talbeya, R.W. Taylor, D. Vazquez, A. Vetro, H.R. Waterham, M. Zaman, T.A. Schrader, W.K. Chung, R. Guerrini, J.R. Lupski, J. Gleeson, M. Suri, Y. Jamshidi, K.P. Bhatia, B. Vona, M. Schrader, M. Severino, M. Guille, E.W. Tate, G.K. Varshney, H. Houlden, R. Maroofian, Brain (2023). date_created: 2023-11-16T12:36:51Z date_published: 2023-11-10T00:00:00Z date_updated: 2023-11-20T10:17:32Z day: '10' department: - _id: GradSch doi: 10.1093/brain/awad380 extern: '1' keyword: - Neurology (clinical) language: - iso: eng main_file_link: - open_access: '1' url: https://doi.org/10.1093/brain/awad380 month: '11' oa: 1 oa_version: Submitted Version publication: Brain publication_identifier: eissn: - 1460-2156 issn: - 0006-8950 publication_status: epub_ahead publisher: Oxford University Press quality_controlled: '1' scopus_import: '1' status: public title: Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders type: journal_article user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87 year: '2023' ... --- _id: '14639' abstract: - lang: eng text: "Background: Biallelic variants in OGDHL, encoding part of the α-ketoglutarate dehydrogenase complex, have been associated with highly heterogeneous neurological and neurodevelopmental disorders. However, the validity of this association remains to be confirmed. A second OGDHL patient cohort was recruited to carefully assess the gene-disease relationship.\r\nMethods: Using an unbiased genotype-first approach, we screened large, multiethnic aggregated sequencing datasets worldwide for biallelic OGDHL variants. We used CRISPR/Cas9 to generate zebrafish knockouts of ogdhl, ogdh paralogs, and dhtkd1 to investigate functional relationships and impact during development. Functional complementation with patient variant transcripts was conducted to systematically assess protein functionality as a readout for pathogenicity.\r\nResults: A cohort of 14 individuals from 12 unrelated families exhibited highly variable clinical phenotypes, with the majority of them presenting at least one additional variant, potentially accounting for a blended phenotype and complicating phenotypic understanding. We also uncovered extreme clinical heterogeneity and high allele frequencies, occasionally incompatible with a fully penetrant recessive disorder. Human cDNA of previously described and new variants were tested in an ogdhl zebrafish knockout model, adding functional evidence for variant reclassification. We disclosed evidence of hypomorphic alleles as well as a loss-of-function variant without deleterious effects in zebrafish variant testing also showing discordant familial segregation, challenging the relationship of OGDHL as a conventional Mendelian gene. Going further, we uncovered evidence for a complex compensatory relationship among OGDH, OGDHL, and DHTKD1 isoenzymes that are associated with neurodevelopmental disorders and exhibit complex transcriptional compensation patterns with partial functional redundancy.\r\nConclusions: Based on the results of genetic, clinical, and functional studies, we formed three hypotheses in which to frame observations: biallelic OGDHL variants lead to a highly variable monogenic disorder, variants in OGDHL are following a complex pattern of inheritance, or they may not be causative at all. Our study further highlights the continuing challenges of assessing the validity of reported disease-gene associations and effects of variants identified in these genes. This is particularly more complicated in making genetic diagnoses based on identification of variants in genes presenting a highly heterogenous phenotype such as “OGDHL-related disorders”." article_number: '102' article_processing_charge: Yes article_type: original author: - first_name: Sheng-Jia full_name: Lin, Sheng-Jia last_name: Lin - first_name: Barbara full_name: Vona, Barbara last_name: Vona - first_name: Tracy full_name: Lau, Tracy last_name: Lau - first_name: Kevin full_name: Huang, Kevin id: 3b3d2888-1ff6-11ee-9fa6-8f209ca91fe3 last_name: Huang orcid: 0000-0002-2512-7812 - first_name: Maha S. full_name: Zaki, Maha S. last_name: Zaki - first_name: Huda Shujaa full_name: Aldeen, Huda Shujaa last_name: Aldeen - first_name: Ehsan Ghayoor full_name: Karimiani, Ehsan Ghayoor last_name: Karimiani - first_name: Clarissa full_name: Rocca, Clarissa last_name: Rocca - first_name: Mahmoud M. full_name: Noureldeen, Mahmoud M. last_name: Noureldeen - first_name: Ahmed K. full_name: Saad, Ahmed K. last_name: Saad - first_name: Cassidy full_name: Petree, Cassidy last_name: Petree - first_name: Tobias full_name: Bartolomaeus, Tobias last_name: Bartolomaeus - first_name: Rami full_name: Abou Jamra, Rami last_name: Abou Jamra - first_name: Giovanni full_name: Zifarelli, Giovanni last_name: Zifarelli - first_name: Aditi full_name: Gotkhindikar, Aditi last_name: Gotkhindikar - first_name: Ingrid M. full_name: Wentzensen, Ingrid M. last_name: Wentzensen - first_name: Mingjuan full_name: Liao, Mingjuan last_name: Liao - first_name: Emalyn Elise full_name: Cork, Emalyn Elise last_name: Cork - first_name: Pratishtha full_name: Varshney, Pratishtha last_name: Varshney - first_name: Narges full_name: Hashemi, Narges last_name: Hashemi - first_name: Mohammad Hasan full_name: Mohammadi, Mohammad Hasan last_name: Mohammadi - first_name: Aboulfazl full_name: Rad, Aboulfazl last_name: Rad - first_name: Juanita full_name: Neira, Juanita last_name: Neira - first_name: Mehran Beiraghi full_name: Toosi, Mehran Beiraghi last_name: Toosi - first_name: Cordula full_name: Knopp, Cordula last_name: Knopp - first_name: Ingo full_name: Kurth, Ingo last_name: Kurth - first_name: Thomas D. full_name: Challman, Thomas D. last_name: Challman - first_name: Rebecca full_name: Smith, Rebecca last_name: Smith - first_name: Asmahan full_name: Abdalla, Asmahan last_name: Abdalla - first_name: Thomas full_name: Haaf, Thomas last_name: Haaf - first_name: Mohnish full_name: Suri, Mohnish last_name: Suri - first_name: Manali full_name: Joshi, Manali last_name: Joshi - first_name: Wendy K. full_name: Chung, Wendy K. last_name: Chung - first_name: Andres full_name: Moreno-De-Luca, Andres last_name: Moreno-De-Luca - first_name: Henry full_name: Houlden, Henry last_name: Houlden - first_name: Reza full_name: Maroofian, Reza last_name: Maroofian - first_name: Gaurav K. full_name: Varshney, Gaurav K. last_name: Varshney citation: ama: Lin S-J, Vona B, Lau T, et al. Evaluating the association of biallelic OGDHL variants with significant phenotypic heterogeneity. Genome Medicine. 2023;15. doi:10.1186/s13073-023-01258-4 apa: Lin, S.-J., Vona, B., Lau, T., Huang, K., Zaki, M. S., Aldeen, H. S., … Varshney, G. K. (2023). Evaluating the association of biallelic OGDHL variants with significant phenotypic heterogeneity. Genome Medicine. Springer Nature. https://doi.org/10.1186/s13073-023-01258-4 chicago: Lin, Sheng-Jia, Barbara Vona, Tracy Lau, Kevin Huang, Maha S. Zaki, Huda Shujaa Aldeen, Ehsan Ghayoor Karimiani, et al. “Evaluating the Association of Biallelic OGDHL Variants with Significant Phenotypic Heterogeneity.” Genome Medicine. Springer Nature, 2023. https://doi.org/10.1186/s13073-023-01258-4. ieee: S.-J. Lin et al., “Evaluating the association of biallelic OGDHL variants with significant phenotypic heterogeneity,” Genome Medicine, vol. 15. Springer Nature, 2023. ista: Lin S-J, Vona B, Lau T, Huang K, Zaki MS, Aldeen HS, Karimiani EG, Rocca C, Noureldeen MM, Saad AK, Petree C, Bartolomaeus T, Abou Jamra R, Zifarelli G, Gotkhindikar A, Wentzensen IM, Liao M, Cork EE, Varshney P, Hashemi N, Mohammadi MH, Rad A, Neira J, Toosi MB, Knopp C, Kurth I, Challman TD, Smith R, Abdalla A, Haaf T, Suri M, Joshi M, Chung WK, Moreno-De-Luca A, Houlden H, Maroofian R, Varshney GK. 2023. Evaluating the association of biallelic OGDHL variants with significant phenotypic heterogeneity. Genome Medicine. 15, 102. mla: Lin, Sheng-Jia, et al. “Evaluating the Association of Biallelic OGDHL Variants with Significant Phenotypic Heterogeneity.” Genome Medicine, vol. 15, 102, Springer Nature, 2023, doi:10.1186/s13073-023-01258-4. short: S.-J. Lin, B. Vona, T. Lau, K. Huang, M.S. Zaki, H.S. Aldeen, E.G. Karimiani, C. Rocca, M.M. Noureldeen, A.K. Saad, C. Petree, T. Bartolomaeus, R. Abou Jamra, G. Zifarelli, A. Gotkhindikar, I.M. Wentzensen, M. Liao, E.E. Cork, P. Varshney, N. Hashemi, M.H. Mohammadi, A. Rad, J. Neira, M.B. Toosi, C. Knopp, I. Kurth, T.D. Challman, R. Smith, A. Abdalla, T. Haaf, M. Suri, M. Joshi, W.K. Chung, A. Moreno-De-Luca, H. Houlden, R. Maroofian, G.K. Varshney, Genome Medicine 15 (2023). date_created: 2023-12-04T08:10:55Z date_published: 2023-11-23T00:00:00Z date_updated: 2023-12-04T08:17:22Z day: '23' ddc: - '570' doi: 10.1186/s13073-023-01258-4 extern: '1' file: - access_level: open_access checksum: 279efd212005549aba817a487d56d363 content_type: application/pdf creator: dernst date_created: 2023-12-04T08:15:43Z date_updated: 2023-12-04T08:15:43Z file_id: '14640' file_name: 2023_GenomeMed_Lin.pdf file_size: 14791081 relation: main_file success: 1 file_date_updated: 2023-12-04T08:15:43Z has_accepted_license: '1' intvolume: ' 15' keyword: - Genetics (clinical) - Genetics - Molecular Biology - Molecular Medicine language: - iso: eng month: '11' oa: 1 oa_version: Published Version publication: Genome Medicine publication_identifier: issn: - 1756-994X publication_status: published publisher: Springer Nature quality_controlled: '1' status: public title: Evaluating the association of biallelic OGDHL variants with significant phenotypic heterogeneity tmp: image: /images/cc_by.png legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0) short: CC BY (4.0) type: journal_article user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87 volume: 15 year: '2023' ... --- _id: '14355' abstract: - lang: eng text: 'Purpose: The mediator (MED) multisubunit-complex modulates the activity of the transcriptional machinery, and genetic defects in different MED subunits (17, 20, 27) have been implicated in neurologic diseases. In this study, we identified a recurrent homozygous variant in MED11 (c.325C>T; p.Arg109Ter) in 7 affected individuals from 5 unrelated families. Methods: To investigate the genetic cause of the disease, exome or genome sequencing were performed in 5 unrelated families identified via different research networks and Matchmaker Exchange. Deep clinical and brain imaging evaluations were performed by clinical pediatric neurologists and neuroradiologists. The functional effect of the candidate variant on both MED11 RNA and protein was assessed using reverse transcriptase polymerase chain reaction and western blotting using fibroblast cell lines derived from 1 affected individual and controls and through computational approaches. Knockouts in zebrafish were generated using clustered regularly interspaced short palindromic repeats/Cas9. Results: The disease was characterized by microcephaly, profound neurodevelopmental impairment, exaggerated startle response, myoclonic seizures, progressive widespread neurodegeneration, and premature death. Functional studies on patient-derived fibroblasts did not show a loss of protein function but rather disruption of the C-terminal of MED11, likely impairing binding to other MED subunits. A zebrafish knockout model recapitulates key clinical phenotypes. Conclusion: Loss of the C-terminal of MED subunit 11 may affect its binding efficiency to other MED subunits, thus implicating the MED-complex stability in brain development and neurodegeneration. (C) 2022 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics.' article_processing_charge: No article_type: original author: - first_name: Elisa full_name: Cali, Elisa last_name: Cali - first_name: Sheng-Jia full_name: Lin, Sheng-Jia last_name: Lin - first_name: Clarissa full_name: Rocca, Clarissa last_name: Rocca - first_name: Yavuz full_name: Sahin, Yavuz last_name: Sahin - first_name: Aisha full_name: Al Shamsi, Aisha last_name: Al Shamsi - first_name: Salima full_name: El Chehadeh, Salima last_name: El Chehadeh - first_name: Myriam full_name: Chaabouni, Myriam last_name: Chaabouni - first_name: Kshitij full_name: Mankad, Kshitij last_name: Mankad - first_name: Evangelia full_name: Galanaki, Evangelia last_name: Galanaki - first_name: Stephanie full_name: Efthymiou, Stephanie last_name: Efthymiou - first_name: Sniya full_name: Sudhakar, Sniya last_name: Sudhakar - first_name: Alkyoni full_name: Athanasiou-Fragkouli, Alkyoni last_name: Athanasiou-Fragkouli - first_name: Tamer full_name: Celik, Tamer last_name: Celik - first_name: Nejat full_name: Narli, Nejat last_name: Narli - first_name: Sebastiano full_name: Bianca, Sebastiano last_name: Bianca - first_name: David full_name: Murphy, David last_name: Murphy - first_name: Francisco Martins De Carvalho full_name: Moreira, Francisco Martins De Carvalho last_name: Moreira - first_name: Andrea full_name: Accogli, Andrea last_name: Accogli - first_name: Cassidy full_name: Petree, Cassidy last_name: Petree - first_name: Kevin full_name: Huang, Kevin id: 3b3d2888-1ff6-11ee-9fa6-8f209ca91fe3 last_name: Huang orcid: 0000-0002-2512-7812 - first_name: Kamel full_name: Monastiri, Kamel last_name: Monastiri - first_name: Masoud full_name: Edizadeh, Masoud last_name: Edizadeh - first_name: Rosaria full_name: Nardello, Rosaria last_name: Nardello - first_name: Marzia full_name: Ognibene, Marzia last_name: Ognibene - first_name: Patrizia full_name: De Marco, Patrizia last_name: De Marco - first_name: Martino full_name: Ruggieri, Martino last_name: Ruggieri - first_name: Federico full_name: Zara, Federico last_name: Zara - first_name: Pasquale full_name: Striano, Pasquale last_name: Striano - first_name: Yavuz full_name: Sahin, Yavuz last_name: Sahin - first_name: Lihadh full_name: Al-Gazali, Lihadh last_name: Al-Gazali - first_name: Marie Therese Abi full_name: Warde, Marie Therese Abi last_name: Warde - first_name: Benedicte full_name: Gerard, Benedicte last_name: Gerard - first_name: Giovanni full_name: Zifarelli, Giovanni last_name: Zifarelli - first_name: Christian full_name: Beetz, Christian last_name: Beetz - first_name: Sara full_name: Fortuna, Sara last_name: Fortuna - first_name: Miguel full_name: Soler, Miguel last_name: Soler - first_name: Enza Maria full_name: Valente, Enza Maria last_name: Valente - first_name: Gaurav full_name: Varshney, Gaurav last_name: Varshney - first_name: Reza full_name: Maroofian, Reza last_name: Maroofian - first_name: Vincenzo full_name: Salpietro, Vincenzo last_name: Salpietro - first_name: Henry full_name: Houlden, Henry last_name: Houlden - first_name: SYNaPS Study full_name: Grp, SYNaPS Study last_name: Grp citation: ama: Cali E, Lin S-J, Rocca C, et al. A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease. Genetics in Medicine. 2022;24(10):2194-2203. doi:10.1016/j.gim.2022.07.013 apa: Cali, E., Lin, S.-J., Rocca, C., Sahin, Y., Al Shamsi, A., El Chehadeh, S., … Grp, Syn. S. (2022). A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease. Genetics in Medicine. Elsevier. https://doi.org/10.1016/j.gim.2022.07.013 chicago: Cali, Elisa, Sheng-Jia Lin, Clarissa Rocca, Yavuz Sahin, Aisha Al Shamsi, Salima El Chehadeh, Myriam Chaabouni, et al. “A Homozygous MED11 C-Terminal Variant Causes a Lethal Neurodegenerative Disease.” Genetics in Medicine. Elsevier, 2022. https://doi.org/10.1016/j.gim.2022.07.013. ieee: E. Cali et al., “A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease,” Genetics in Medicine, vol. 24, no. 10. Elsevier, pp. 2194–2203, 2022. ista: Cali E, Lin S-J, Rocca C, Sahin Y, Al Shamsi A, El Chehadeh S, Chaabouni M, Mankad K, Galanaki E, Efthymiou S, Sudhakar S, Athanasiou-Fragkouli A, Celik T, Narli N, Bianca S, Murphy D, Moreira FMDC, Accogli A, Petree C, Huang K, Monastiri K, Edizadeh M, Nardello R, Ognibene M, De Marco P, Ruggieri M, Zara F, Striano P, Sahin Y, Al-Gazali L, Warde MTA, Gerard B, Zifarelli G, Beetz C, Fortuna S, Soler M, Valente EM, Varshney G, Maroofian R, Salpietro V, Houlden H, Grp SynS. 2022. A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease. Genetics in Medicine. 24(10), 2194–2203. mla: Cali, Elisa, et al. “A Homozygous MED11 C-Terminal Variant Causes a Lethal Neurodegenerative Disease.” Genetics in Medicine, vol. 24, no. 10, Elsevier, 2022, pp. 2194–203, doi:10.1016/j.gim.2022.07.013. short: E. Cali, S.-J. Lin, C. Rocca, Y. Sahin, A. Al Shamsi, S. El Chehadeh, M. Chaabouni, K. Mankad, E. Galanaki, S. Efthymiou, S. Sudhakar, A. Athanasiou-Fragkouli, T. Celik, N. Narli, S. Bianca, D. Murphy, F.M.D.C. Moreira, A. Accogli, C. Petree, K. Huang, K. Monastiri, M. Edizadeh, R. Nardello, M. Ognibene, P. De Marco, M. Ruggieri, F. Zara, P. Striano, Y. Sahin, L. Al-Gazali, M.T.A. Warde, B. Gerard, G. Zifarelli, C. Beetz, S. Fortuna, M. Soler, E.M. Valente, G. Varshney, R. Maroofian, V. Salpietro, H. Houlden, Syn.S. Grp, Genetics in Medicine 24 (2022) 2194–2203. date_created: 2023-09-20T20:57:18Z date_published: 2022-10-01T00:00:00Z date_updated: 2023-09-25T08:57:07Z day: '01' ddc: - '570' department: - _id: GradSch doi: 10.1016/j.gim.2022.07.013 extern: '1' file: - access_level: open_access checksum: 8117175a89129eb5022d81ffe7625f9f content_type: application/pdf creator: dernst date_created: 2023-09-25T08:56:06Z date_updated: 2023-09-25T08:56:06Z file_id: '14371' file_name: 2022_GeneticsMedicine_Calin.pdf file_size: 1434037 relation: main_file success: 1 file_date_updated: 2023-09-25T08:56:06Z has_accepted_license: '1' intvolume: ' 24' issue: '10' keyword: - Human mediator complex - MED11 - MEDopathies language: - iso: eng month: '10' oa: 1 oa_version: Published Version page: 2194-2203 publication: Genetics in Medicine publication_identifier: issn: - 1098-3600 publication_status: published publisher: Elsevier quality_controlled: '1' scopus_import: '1' status: public title: A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease tmp: image: /images/cc_by.png legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0) short: CC BY (4.0) type: journal_article user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87 volume: 24 year: '2022' ... --- _id: '14356' abstract: - lang: eng text: Aminoacyl-tRNA synthetases (ARSs) are essential enzymes for faithful assignment of amino acids to their cognate tRNA. Variants in ARS genes are frequently associated with clinically heterogeneous phenotypes in humans and follow both autosomal dominant or recessive inheritance patterns in many instances. Variants in tryptophanyl-tRNA synthetase 1 (WARS1) cause autosomal dominantly inherited distal hereditary motor neuropathy and Charcot-Marie-Tooth disease. Presently, only one family with biallelic WARS1 variants has been described. We present three affected individuals from two families with biallelic variants (p.Met1? and p.(Asp419Asn)) in WARS1, showing varying severities of developmental delay and intellectual disability. Hearing impairment and microcephaly, as well as abnormalities of the brain, skeletal system, movement/gait, and behavior were variable features. Phenotyping of knocked down wars-1 in a Caenorhabditis elegans model showed depletion is associated with defects in germ cell development. A wars1 knockout vertebrate model recapitulates the human clinical phenotypes, confirms variant pathogenicity, and uncovers evidence implicating the p.Met1? variant as potentially impacting an exon critical for normal hearing. Together, our findings provide consolidating evidence for biallelic disruption of WARS1 as causal for an autosomal recessive neurodevelopmental syndrome and present a vertebrate model that recapitulates key phenotypes observed in patients. article_processing_charge: No article_type: original author: - first_name: Sheng-Jia full_name: Lin, Sheng-Jia last_name: Lin - first_name: Barbara full_name: Vona, Barbara last_name: Vona - first_name: Hillary M. full_name: Porter, Hillary M. last_name: Porter - first_name: Mahmoud full_name: Izadi, Mahmoud last_name: Izadi - first_name: Kevin full_name: Huang, Kevin id: 3b3d2888-1ff6-11ee-9fa6-8f209ca91fe3 last_name: Huang orcid: 0000-0002-2512-7812 - first_name: Yves full_name: Lacassie, Yves last_name: Lacassie - first_name: Jill A. full_name: Rosenfeld, Jill A. last_name: Rosenfeld - first_name: Saadullah full_name: Khan, Saadullah last_name: Khan - first_name: Cassidy full_name: Petree, Cassidy last_name: Petree - first_name: Tayyiba A. full_name: Ali, Tayyiba A. last_name: Ali - first_name: Nazif full_name: Muhammad, Nazif last_name: Muhammad - first_name: Sher A. full_name: Khan, Sher A. last_name: Khan - first_name: Noor full_name: Muhammad, Noor last_name: Muhammad - first_name: Pengfei full_name: Liu, Pengfei last_name: Liu - first_name: Marie-Louise full_name: Haymon, Marie-Louise last_name: Haymon - first_name: Franz full_name: Rueschendorf, Franz last_name: Rueschendorf - first_name: Il-Keun full_name: Kong, Il-Keun last_name: Kong - first_name: Linda full_name: Schnapp, Linda last_name: Schnapp - first_name: Natasha full_name: Shur, Natasha last_name: Shur - first_name: Lynn full_name: Chorich, Lynn last_name: Chorich - first_name: Lawrence full_name: Layman, Lawrence last_name: Layman - first_name: Thomas full_name: Haaf, Thomas last_name: Haaf - first_name: Ehsan full_name: Pourkarimi, Ehsan last_name: Pourkarimi - first_name: Hyung-Goo full_name: Kim, Hyung-Goo last_name: Kim - first_name: Gaurav K. full_name: Varshney, Gaurav K. last_name: Varshney citation: ama: Lin S-J, Vona B, Porter HM, et al. Biallelic variants in WARS1 cause a highly variable neurodevelopmental syndrome and implicate a critical exon for normal auditory function. Human Mutation. 2022;43(10):1472-1489. doi:10.1002/humu.24435 apa: Lin, S.-J., Vona, B., Porter, H. M., Izadi, M., Huang, K., Lacassie, Y., … Varshney, G. K. (2022). Biallelic variants in WARS1 cause a highly variable neurodevelopmental syndrome and implicate a critical exon for normal auditory function. Human Mutation. Wiley. https://doi.org/10.1002/humu.24435 chicago: Lin, Sheng-Jia, Barbara Vona, Hillary M. Porter, Mahmoud Izadi, Kevin Huang, Yves Lacassie, Jill A. Rosenfeld, et al. “Biallelic Variants in WARS1 Cause a Highly Variable Neurodevelopmental Syndrome and Implicate a Critical Exon for Normal Auditory Function.” Human Mutation. Wiley, 2022. https://doi.org/10.1002/humu.24435. ieee: S.-J. Lin et al., “Biallelic variants in WARS1 cause a highly variable neurodevelopmental syndrome and implicate a critical exon for normal auditory function,” Human Mutation, vol. 43, no. 10. Wiley, pp. 1472–1489, 2022. ista: Lin S-J, Vona B, Porter HM, Izadi M, Huang K, Lacassie Y, Rosenfeld JA, Khan S, Petree C, Ali TA, Muhammad N, Khan SA, Muhammad N, Liu P, Haymon M-L, Rueschendorf F, Kong I-K, Schnapp L, Shur N, Chorich L, Layman L, Haaf T, Pourkarimi E, Kim H-G, Varshney GK. 2022. Biallelic variants in WARS1 cause a highly variable neurodevelopmental syndrome and implicate a critical exon for normal auditory function. Human Mutation. 43(10), 1472–1489. mla: Lin, Sheng-Jia, et al. “Biallelic Variants in WARS1 Cause a Highly Variable Neurodevelopmental Syndrome and Implicate a Critical Exon for Normal Auditory Function.” Human Mutation, vol. 43, no. 10, Wiley, 2022, pp. 1472–89, doi:10.1002/humu.24435. short: S.-J. Lin, B. Vona, H.M. Porter, M. Izadi, K. Huang, Y. Lacassie, J.A. Rosenfeld, S. Khan, C. Petree, T.A. Ali, N. Muhammad, S.A. Khan, N. Muhammad, P. Liu, M.-L. Haymon, F. Rueschendorf, I.-K. Kong, L. Schnapp, N. Shur, L. Chorich, L. Layman, T. Haaf, E. Pourkarimi, H.-G. Kim, G.K. Varshney, Human Mutation 43 (2022) 1472–1489. date_created: 2023-09-20T20:58:24Z date_published: 2022-10-01T00:00:00Z date_updated: 2023-09-25T08:54:14Z day: '01' ddc: - '570' doi: 10.1002/humu.24435 extern: '1' file: - access_level: open_access checksum: 74b01d4e4084b2f64c30ed32b18ee928 content_type: application/pdf creator: dernst date_created: 2023-09-25T08:52:54Z date_updated: 2023-09-25T08:52:54Z file_id: '14370' file_name: 2022_HumanMutation_Lin.pdf file_size: 12131312 relation: main_file success: 1 file_date_updated: 2023-09-25T08:52:54Z has_accepted_license: '1' intvolume: ' 43' issue: '10' keyword: - autosomal recessive - biallelic variants - C - elegans - translation initiation sites - tryptophanyl-tRNA synthetase 1 (WARS1) - WHEP domain - zebrafish language: - iso: eng month: '10' oa: 1 oa_version: Published Version page: 1472-1489 publication: Human Mutation publication_identifier: issn: - 1059-7794 publication_status: published publisher: Wiley quality_controlled: '1' scopus_import: '1' status: public title: Biallelic variants in WARS1 cause a highly variable neurodevelopmental syndrome and implicate a critical exon for normal auditory function tmp: image: /images/cc_by.png legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0) short: CC BY (4.0) type: journal_article user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87 volume: 43 year: '2022' ... --- _id: '14357' abstract: - lang: eng text: 'Aminoacylation of transfer RNA (tRNA) is a key step in protein biosynthesis, carried out by highly specific aminoacyl-tRNA synthetases (ARSs). ARSs have been implicated in autosomal dominant and autosomal recessive human disorders. Autosomal dominant variants in tryptophanyl-tRNA synthetase 1 (WARS1) are known to cause distal hereditary motor neuropathy and Charcot-Marie-Tooth disease, but a recessively inherited phenotype is yet to be clearly defined. Seryl-tRNA synthetase 1 (SARS1) has rarely been implicated in an autosomal recessive developmental disorder. Here, we report five individuals with biallelic missense variants in WARS1 or SARS1, who presented with an overlapping phenotype of microcephaly, developmental delay, intellectual disability, and brain anomalies. Structural mapping showed that the SARS1 variant is located directly within the enzyme’s active site, most likely diminishing activity, while the WARS1 variant is located in the N-terminal domain. We further characterize the identified WARS1 variant by showing that it negatively impacts protein abundance and is unable to rescue the phenotype of a CRISPR/Cas9 wars1 knockout zebrafish model. In summary, we describe two overlapping autosomal recessive syndromes caused by variants in WARS1 and SARS1, present functional insights into the pathogenesis of the WARS1-related syndrome and define an emerging disease spectrum: ARS-related developmental disorders with or without microcephaly.' article_processing_charge: No article_type: original author: - first_name: Nina full_name: Boegershausen, Nina last_name: Boegershausen - first_name: Hannah E. full_name: Krawczyk, Hannah E. last_name: Krawczyk - first_name: Rami A. full_name: Jamra, Rami A. last_name: Jamra - first_name: Sheng-Jia full_name: Lin, Sheng-Jia last_name: Lin - first_name: Goekhan full_name: Yigit, Goekhan last_name: Yigit - first_name: Irina full_name: Huening, Irina last_name: Huening - first_name: Anna M. full_name: Polo, Anna M. last_name: Polo - first_name: Barbara full_name: Vona, Barbara last_name: Vona - first_name: Kevin full_name: Huang, Kevin id: 3b3d2888-1ff6-11ee-9fa6-8f209ca91fe3 last_name: Huang orcid: 0000-0002-2512-7812 - first_name: Julia full_name: Schmidt, Julia last_name: Schmidt - first_name: Janine full_name: Altmueller, Janine last_name: Altmueller - first_name: Johannes full_name: Luppe, Johannes last_name: Luppe - first_name: Konrad full_name: Platzer, Konrad last_name: Platzer - first_name: Beate B. full_name: Doergeloh, Beate B. last_name: Doergeloh - first_name: Andreas full_name: Busche, Andreas last_name: Busche - first_name: Saskia full_name: Biskup, Saskia last_name: Biskup - first_name: Marisa full_name: Mendes, I, Marisa last_name: Mendes, I - first_name: Desiree E. C. full_name: Smith, Desiree E. C. last_name: Smith - first_name: Gajja S. full_name: Salomons, Gajja S. last_name: Salomons - first_name: Arne full_name: Zibat, Arne last_name: Zibat - first_name: Eva full_name: Bueltmann, Eva last_name: Bueltmann - first_name: Peter full_name: Nuernberg, Peter last_name: Nuernberg - first_name: Malte full_name: Spielmann, Malte last_name: Spielmann - first_name: Johannes R. full_name: Lemke, Johannes R. last_name: Lemke - first_name: Yun full_name: Li, Yun last_name: Li - first_name: Martin full_name: Zenker, Martin last_name: Zenker - first_name: Gaurav K. full_name: Varshney, Gaurav K. last_name: Varshney - first_name: Hauke S. full_name: Hillen, Hauke S. last_name: Hillen - first_name: Christian P. full_name: Kratz, Christian P. last_name: Kratz - first_name: Bernd full_name: Wollnik, Bernd last_name: Wollnik citation: ama: 'Boegershausen N, Krawczyk HE, Jamra RA, et al. WARS1 and SARS1: Two tRNA synthetases implicated in autosomal recessive microcephaly. Human Mutation. 2022;43(10):1454-1471. doi:10.1002/humu.24430' apa: 'Boegershausen, N., Krawczyk, H. E., Jamra, R. A., Lin, S.-J., Yigit, G., Huening, I., … Wollnik, B. (2022). WARS1 and SARS1: Two tRNA synthetases implicated in autosomal recessive microcephaly. Human Mutation. Wiley. https://doi.org/10.1002/humu.24430' chicago: 'Boegershausen, Nina, Hannah E. Krawczyk, Rami A. Jamra, Sheng-Jia Lin, Goekhan Yigit, Irina Huening, Anna M. Polo, et al. “WARS1 and SARS1: Two TRNA Synthetases Implicated in Autosomal Recessive Microcephaly.” Human Mutation. Wiley, 2022. https://doi.org/10.1002/humu.24430.' ieee: 'N. Boegershausen et al., “WARS1 and SARS1: Two tRNA synthetases implicated in autosomal recessive microcephaly,” Human Mutation, vol. 43, no. 10. Wiley, pp. 1454–1471, 2022.' ista: 'Boegershausen N, Krawczyk HE, Jamra RA, Lin S-J, Yigit G, Huening I, Polo AM, Vona B, Huang K, Schmidt J, Altmueller J, Luppe J, Platzer K, Doergeloh BB, Busche A, Biskup S, Mendes, I M, Smith DEC, Salomons GS, Zibat A, Bueltmann E, Nuernberg P, Spielmann M, Lemke JR, Li Y, Zenker M, Varshney GK, Hillen HS, Kratz CP, Wollnik B. 2022. WARS1 and SARS1: Two tRNA synthetases implicated in autosomal recessive microcephaly. Human Mutation. 43(10), 1454–1471.' mla: 'Boegershausen, Nina, et al. “WARS1 and SARS1: Two TRNA Synthetases Implicated in Autosomal Recessive Microcephaly.” Human Mutation, vol. 43, no. 10, Wiley, 2022, pp. 1454–71, doi:10.1002/humu.24430.' short: N. Boegershausen, H.E. Krawczyk, R.A. Jamra, S.-J. Lin, G. Yigit, I. Huening, A.M. Polo, B. Vona, K. Huang, J. Schmidt, J. Altmueller, J. Luppe, K. Platzer, B.B. Doergeloh, A. Busche, S. Biskup, M. Mendes, I, D.E.C. Smith, G.S. Salomons, A. Zibat, E. Bueltmann, P. Nuernberg, M. Spielmann, J.R. Lemke, Y. Li, M. Zenker, G.K. Varshney, H.S. Hillen, C.P. Kratz, B. Wollnik, Human Mutation 43 (2022) 1454–1471. date_created: 2023-09-20T20:59:33Z date_published: 2022-10-01T00:00:00Z date_updated: 2023-09-25T08:43:06Z day: '01' ddc: - '570' doi: 10.1002/humu.24430 extern: '1' external_id: pmid: - '35790048' file: - access_level: open_access checksum: c31fc91e0445c35b9da83eb911a9b552 content_type: application/pdf creator: dernst date_created: 2023-09-25T08:41:23Z date_updated: 2023-09-25T08:41:23Z file_id: '14367' file_name: 2022_HumanMutation_Boegershausen.pdf file_size: 4863605 relation: main_file success: 1 file_date_updated: 2023-09-25T08:41:23Z has_accepted_license: '1' intvolume: ' 43' issue: '10' keyword: - aminoacylation - aminoacyl-tRNA synthetase - ARS - CRISPR - Cas9 - intellectual disability - microcephaly - SARS1 - tRNA - WARS1 - zebrafish language: - iso: eng license: https://creativecommons.org/licenses/by-nc-nd/4.0/ month: '10' oa: 1 oa_version: Published Version page: 1454-1471 pmid: 1 publication: Human Mutation publication_identifier: issn: - 1059-7794 publication_status: published publisher: Wiley quality_controlled: '1' scopus_import: '1' status: public title: 'WARS1 and SARS1: Two tRNA synthetases implicated in autosomal recessive microcephaly' tmp: image: /images/cc_by_nc_nd.png legal_code_url: https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode name: Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) short: CC BY-NC-ND (4.0) type: journal_article user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87 volume: 43 year: '2022' ...