@article{14543, abstract = {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.}, author = {Kaiyrzhanov, Rauan and Rad, Aboulfazl and Lin, Sheng-Jia and Bertoli-Avella, Aida and Kallemeijn, Wouter W and Godwin, Annie and Zaki, Maha S and Huang, Kevin and Lau, Tracy and Petree, Cassidy and Efthymiou, Stephanie and Ghayoor Karimiani, Ehsan and Hempel, Maja and Normand, Elizabeth A and Rudnik-Schöneborn, Sabine and Schatz, Ulrich A and Baggelaar, Marc P and Ilyas, Muhammad and Sultan, Tipu and Alvi, Javeria Raza and Ganieva, Manizha and Fowler, Ben and Aanicai, Ruxandra and Akay Tayfun, Gulsen and Al Saman, Abdulaziz and Alswaid, Abdulrahman and Amiri, Nafise and Asilova, Nilufar and Shotelersuk, Vorasuk and Yeetong, Patra and Azam, Matloob and Babaei, Meisam and Bahrami Monajemi, Gholamreza and Mohammadi, Pouria and Samie, Saeed and Banu, Selina Husna and Basto, Jorge Pinto and Kortüm, Fanny and Bauer, Mislen and Bauer, Peter and Beetz, Christian and Garshasbi, Masoud and Hameed Issa, Awatif and Eyaid, Wafaa and Ahmed, Hind and Hashemi, Narges and Hassanpour, Kazem and Herman, Isabella and Ibrohimov, Sherozjon and Abdul-Majeed, Ban A and Imdad, Maria and Isrofilov, Maksudjon and Kaiyal, Qassem and Khan, Suliman and Kirmse, Brian and Koster, Janet and Lourenço, Charles Marques and Mitani, Tadahiro and Moldovan, Oana and Murphy, David and Najafi, Maryam and Pehlivan, Davut and Rocha, Maria Eugenia and Salpietro, Vincenzo and Schmidts, Miriam and Shalata, Adel and Mahroum, Mohammad and Talbeya, Jawabreh Kassem and Taylor, Robert W and Vazquez, Dayana and Vetro, Annalisa and Waterham, Hans R and Zaman, Mashaya and Schrader, Tina A and Chung, Wendy K and Guerrini, Renzo and Lupski, James R and Gleeson, Joseph and Suri, Mohnish and Jamshidi, Yalda and Bhatia, Kailash P and Vona, Barbara and Schrader, Michael and Severino, Mariasavina and Guille, Matthew and Tate, Edward W and Varshney, Gaurav K and Houlden, Henry and Maroofian, Reza}, issn = {1460-2156}, journal = {Brain}, keywords = {Neurology (clinical)}, number = {4}, pages = {1436--1456}, publisher = {Oxford University Press}, title = {{Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders}}, doi = {10.1093/brain/awad380}, volume = {147}, year = {2024}, } @article{14368, abstract = {Purpose: Biallelic 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. Methods: Exome 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. Results: We 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. Conclusion: We 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.}, author = {Accogli, Andrea and Lin, Sheng-Jia and Severino, Mariasavina and Kim, Sung-Hoon and Huang, Kevin and Rocca, Clarissa and Landsverk, Megan and Zaki, Maha S. and Al-Maawali, Almundher and Srinivasan, Varunvenkat M. and Al-Thihli, Khalid and Schaefer, G. Bradly and Davis, Monica and Tonduti, Davide and Doneda, Chiara and Marten, Lara M. and Mühlhausen, Chris and Gomez, Maria and Lamantea, Eleonora and Mena, Rafael and Nizon, Mathilde and Procaccio, Vincent and Begtrup, Amber and Telegrafi, Aida and Cui, Hong and Schulz, Heidi L. and Mohr, Julia and Biskup, Saskia and Loos, Mariana Amina and Aráoz, Hilda Verónica and Salpietro, Vincenzo and Keppen, Laura Davis and Chitre, Manali and Petree, Cassidy and Raymond, Lucy and Vogt, Julie and Sawyer, Lindsey B. and Basinger, Alice A. and Pedersen, Signe Vandal and Pearson, Toni S. and Grange, Dorothy K. and Lingappa, Lokesh and McDunnah, Paige and Horvath, Rita and Cognè, Benjamin and Isidor, Bertrand and Hahn, Andreas and Gripp, Karen W. and Jafarnejad, Seyed Mehdi and Østergaard, Elsebet and Prada, Carlos E. and Ghezzi, Daniele and Gowda, Vykuntaraju K. and Taylor, Robert W. and Sonenberg, Nahum and Houlden, Henry and Sissler, Marie and Varshney, Gaurav K. and Maroofian, Reza}, issn = {1098-3600}, journal = {Genetics in Medicine}, keywords = {Genetics (clinical)}, number = {11}, publisher = {Elsevier}, title = {{Clinical, neuroradiological, and molecular characterization of mitochondrial threonyl-tRNA-synthetase (TARS2)-related disorder}}, doi = {10.1016/j.gim.2023.100938}, volume = {25}, year = {2023}, } @article{14639, abstract = {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. Methods: 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. Results: 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. Conclusions: 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”.}, author = {Lin, Sheng-Jia and Vona, Barbara and Lau, Tracy and Huang, Kevin and Zaki, Maha S. and Aldeen, Huda Shujaa and Karimiani, Ehsan Ghayoor and Rocca, Clarissa and Noureldeen, Mahmoud M. and Saad, Ahmed K. and Petree, Cassidy and Bartolomaeus, Tobias and Abou Jamra, Rami and Zifarelli, Giovanni and Gotkhindikar, Aditi and Wentzensen, Ingrid M. and Liao, Mingjuan and Cork, Emalyn Elise and Varshney, Pratishtha and Hashemi, Narges and Mohammadi, Mohammad Hasan and Rad, Aboulfazl and Neira, Juanita and Toosi, Mehran Beiraghi and Knopp, Cordula and Kurth, Ingo and Challman, Thomas D. and Smith, Rebecca and Abdalla, Asmahan and Haaf, Thomas and Suri, Mohnish and Joshi, Manali and Chung, Wendy K. and Moreno-De-Luca, Andres and Houlden, Henry and Maroofian, Reza and Varshney, Gaurav K.}, issn = {1756-994X}, journal = {Genome Medicine}, keywords = {Genetics (clinical), Genetics, Molecular Biology, Molecular Medicine}, publisher = {Springer Nature}, title = {{Evaluating the association of biallelic OGDHL variants with significant phenotypic heterogeneity}}, doi = {10.1186/s13073-023-01258-4}, volume = {15}, year = {2023}, } @article{14355, abstract = {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.}, author = {Cali, Elisa and Lin, Sheng-Jia and Rocca, Clarissa and Sahin, Yavuz and Al Shamsi, Aisha and El Chehadeh, Salima and Chaabouni, Myriam and Mankad, Kshitij and Galanaki, Evangelia and Efthymiou, Stephanie and Sudhakar, Sniya and Athanasiou-Fragkouli, Alkyoni and Celik, Tamer and Narli, Nejat and Bianca, Sebastiano and Murphy, David and Moreira, Francisco Martins De Carvalho and Accogli, Andrea and Petree, Cassidy and Huang, Kevin and Monastiri, Kamel and Edizadeh, Masoud and Nardello, Rosaria and Ognibene, Marzia and De Marco, Patrizia and Ruggieri, Martino and Zara, Federico and Striano, Pasquale and Sahin, Yavuz and Al-Gazali, Lihadh and Warde, Marie Therese Abi and Gerard, Benedicte and Zifarelli, Giovanni and Beetz, Christian and Fortuna, Sara and Soler, Miguel and Valente, Enza Maria and Varshney, Gaurav and Maroofian, Reza and Salpietro, Vincenzo and Houlden, Henry and Grp, SYNaPS Study}, issn = {1098-3600}, journal = {Genetics in Medicine}, keywords = {Human mediator complex, MED11, MEDopathies}, number = {10}, pages = {2194--2203}, publisher = {Elsevier}, title = {{A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease}}, doi = {10.1016/j.gim.2022.07.013}, volume = {24}, year = {2022}, } @article{14356, abstract = {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.}, author = {Lin, Sheng-Jia and Vona, Barbara and Porter, Hillary M. and Izadi, Mahmoud and Huang, Kevin and Lacassie, Yves and Rosenfeld, Jill A. and Khan, Saadullah and Petree, Cassidy and Ali, Tayyiba A. and Muhammad, Nazif and Khan, Sher A. and Muhammad, Noor and Liu, Pengfei and Haymon, Marie-Louise and Rueschendorf, Franz and Kong, Il-Keun and Schnapp, Linda and Shur, Natasha and Chorich, Lynn and Layman, Lawrence and Haaf, Thomas and Pourkarimi, Ehsan and Kim, Hyung-Goo and Varshney, Gaurav K.}, issn = {1059-7794}, journal = {Human Mutation}, keywords = {autosomal recessive, biallelic variants, C, elegans, translation initiation sites, tryptophanyl-tRNA synthetase 1 (WARS1), WHEP domain, zebrafish}, number = {10}, pages = {1472--1489}, publisher = {Wiley}, title = {{Biallelic variants in WARS1 cause a highly variable neurodevelopmental syndrome and implicate a critical exon for normal auditory function}}, doi = {10.1002/humu.24435}, volume = {43}, year = {2022}, } @article{14357, abstract = {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.}, author = {Boegershausen, Nina and Krawczyk, Hannah E. and Jamra, Rami A. and Lin, Sheng-Jia and Yigit, Goekhan and Huening, Irina and Polo, Anna M. and Vona, Barbara and Huang, Kevin and Schmidt, Julia and Altmueller, Janine and Luppe, Johannes and Platzer, Konrad and Doergeloh, Beate B. and Busche, Andreas and Biskup, Saskia and Mendes, I, Marisa and Smith, Desiree E. C. and Salomons, Gajja S. and Zibat, Arne and Bueltmann, Eva and Nuernberg, Peter and Spielmann, Malte and Lemke, Johannes R. and Li, Yun and Zenker, Martin and Varshney, Gaurav K. and Hillen, Hauke S. and Kratz, Christian P. and Wollnik, Bernd}, issn = {1059-7794}, journal = {Human Mutation}, keywords = {aminoacylation, aminoacyl-tRNA synthetase, ARS, CRISPR, Cas9, intellectual disability, microcephaly, SARS1, tRNA, WARS1, zebrafish}, number = {10}, pages = {1454--1471}, publisher = {Wiley}, title = {{WARS1 and SARS1: Two tRNA synthetases implicated in autosomal recessive microcephaly}}, doi = {10.1002/humu.24430}, volume = {43}, year = {2022}, }