Researcher: Reversade, Bruno
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Reversade, Bruno
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Publication Metadata only Characterization of a missense variant in COG5 in a Tunisian patient with COG5-CDG syndrome and insights into the effect of non-synonymous variants on COG5 protein(SPRINGERNATURE, 2024) Khabou, Boudour; Sahari, Umar Bin Mohamad; ben Issa, Abir; Bouchaala, Wafa; Szenker-Ravi, Emmanuelle; Ng, Alvin Yu Jin; Bonnard, Carine; Mbarek, Hamdi; Zeyaul, Islam; Fakhfakh, Faiza; Kammoun, Fatma; Triki, Chahnez Charfi; Reversade, Bruno; School of MedicineThe clinical diagnosis of patients with multisystem involvement including a pronounced neurologic damage is challenging. High-throughput sequencing methods remains crucial to provide an accurate diagnosis. In this study, we reported a Tunisian patient manifesting hypotonia and global developmental delay with visual and skin abnormalities. Exome sequencing was conducted followed by segregation analysis and, subsequently additional investigations. In silico analysis of non-synonymous variants (nsSNPs) described in COG5 in conserved positions was made. Results revealed a homozygous missense variant c.298 C > T (p.Leu100Phe) in the COG5 inherited from both parents. This variant altered both protein solubility and stability, in addition to a putative disruption of the COG5-COG7 interaction. This disruption has been confirmed using patient-derived cells in vitro in a COG5 co-immuno-precipitation, where interaction with binding partner COG7 was abrogated. Hence, we established the COG5-CDG diagnosis. Clinically, the patient shared common features with the already described cases with the report of the ichtyosis as a new manifestation. Conversely, the CADD scoring revealed 19 putatively pathogenic nsSNPs (Minor Allele Frequency MAF < 0.001, CADD > 30), 11 of which had a significant impact on the solubility and/or stability of COG5. These properties seem to be disrupted by six of the seven missense COG5-CDG variants. In conclusion, our study expands the genetic and phenotypic spectrum of COG5-CDG disease and highlight the utility of the next generation sequencing as a powerful tool in accurate diagnosis. Our results shed light on a likely molecular mechanism underlying the pathogenic effect of missense COG5 variants, which is the alteration of COG5 stability and solubility.Publication Metadata only DISP1 deficiency: Monoallelic and biallelic variants cause a spectrum of midline craniofacial malformations(Elsevier, 2024) Lavillaureix, Alinoë; Rollier, Paul; Kim, Artem; Panasenkava, Veranika; De Tayrac, Marie; Carré, Wilfrid; Guyodo, Hélène; Faoucher, Marie; Poirel, Elisabeth; Akloul, Linda; Quélin, Chloé; Whalen, Sandra; Bos, Jessica; Broekema, Marjoleine; van Hagen, Johanna M.; Grand, Katheryn; Allen-Sharpley, Michelle; Magness, Emily; McLean, Scott D.; En Qi Chong, Angie; Xue, Shifeng; Jeanne, Médéric; Almontashiri, Naif; Habhab, Wisam; Vanlerberghe, Clemence; Faivre, Laurence; Viora-Dupont, Eléonore; Philippe, Christophe; Safraou, Hana; Laffargue, Fanny; Mittendorf, Luisa; Abou Jamra, Rami; Patil, Siddaramappa Jagdish; Dalal, Ashwin; Sarma, Asodu Sandeep; Keren, Boris; Dubourg, Christèle; Odent, Sylvie; Dupé, Valérie; Kayserili, Hülya; Altunoğlu, Umut; Reversade, Bruno; School of MedicinePurpose: DISP1 encodes a transmembrane protein that regulates the secretion of the morphogen, Sonic hedgehog, a deficiency of which is a major cause of holoprosencephaly (HPE). This disorder covers a spectrum of brain and midline craniofacial malformations. The objective of the present study was to better delineate the clinical phenotypes associated with division transporter dispatched-1 (DISP1) variants. Methods: This study was based on the identification of at least 1 pathogenic variant of the DISP1 gene in individuals for whom detailed clinical data were available. Results: A total of 23 DISP1 variants were identified in heterozygous, compound heterozygous or homozygous states in 25 individuals with midline craniofacial defects. Most cases were minor forms of HPE, with craniofacial features such as orofacial cleft, solitary median maxillary central incisor, and congenital nasal pyriform aperture stenosis. These individuals had either monoallelic loss-of-function variants or biallelic missense variants in DISP1. In individuals with severe HPE, the DISP1 variants were commonly found associated with a variant in another HPE-linked gene (ie, oligogenic inheritance). Conclusion: The genetic findings we have acquired demonstrate a significant involvement of DISP1 variants in the phenotypic spectrum of midline defects. This underlines its importance as a crucial element in the efficient secretion of Sonic hedgehog. We also demonstrated that the very rare solitary median maxillary central incisor and congenital nasal pyriform aperture stenosis combination is part of the DISP1-related phenotype. The present study highlights the clinical risks to be flagged up during genetic counseling after the discovery of a pathogenic DISP1 variant.Publication Metadata only A fatal progeroid syndrome caused by a recessive RAF1 loss-of-function mutation(Springernature, 2023) Wong, Samantha; Tan, Yu Xuan; Tan, Kiat Yi; Loh, Abigail; Ozkan, Engin; Kayserili, Hülya; Reversade, Bruno; Beillard, Nathalie Sonia Escande; School of Medicine; Koç University HospitalPublication Metadata only Loss of FOCAD, operating in the SKI mRNA surveillance pathway, is responsible for a syndromic form of pediatric liver cirrhosis(Springernature, 2023) Traspas, Ricardo Moreno; Teoh, Tze Shin; Wong, Pui Mun; Maier, Michael; Lay, Kenneth; Ali, Nur Ain; Larson, Austin; Al Mutairi, Fuad; Al-Sanna'a, Nouriya; Faqeih, Eissa Ali; Cheema, Huma; Dupont, Juliette; Sandoval, Renata; Ramos, Luiza; Bauer, Peter; Cogne, Benjamin; Bertoli-Avella, Aida; Vincent, Marie; Girisha, Katta; Reversade, Bruno; School of MedicinePublication Metadata only A progeroid syndrome with severe osteogenesis imperfecta segregates with an intronic TAPT1 homozygous variant that creates a knockout allele(Springernature, 2023) Bressin, Annkatrin; Chia, PohHui; Traspas, Ricardo Moreno; Bonnard, Carine; Hojat, Zohreh; Drutman, Scott; Casanova, Jean-Laurent; Shboul, Mohammad; Mayor, Andreas; Nabavizadeh, Nasrinsadat; Beillard, Nathalie Sonia Escande; Reversade, Bruno; School of MedicinePublication Metadata only Direct identification of A-to-I editing sites with nanopore native RNA sequencing(NATURE PORTFOLIO, 2022) Nguyen, Tram Anh; Heng, Jia Wei Joel; Kaewsapsak, Pornchai; Kok, Eng Piew Louis; Stanojevic, Dominik; Liu, Hao; Cardilla, Angelysia; Praditya, Albert; Yi, Zirong; Lin, Mingwan; Aw, Jong Ghut Ashley; Ho, Yin Ying; Peh, Kai Lay Esther; Wang, Yuanming; Zhong, Qixing; Heraud-Farlow, Jacki; Xue, Shifeng; Walkley, Carl; Ho, Ying Swan; Sikic, Mile; Wan, Yue; Tan, Meng How; N/A; Reversade, Bruno; Faculty Member; School of Medicine; 274182Inosine is a prevalent RNA modification in animals and is formed when an adenosine is deaminated by the ADAR family of enzymes. Traditionally, inosines are identified indirectly as variants from Illumina RNA-sequencing data because they are interpreted as guanosines by cellular machineries. However, this indirect method performs poorly in protein-coding regions where exons are typically short, in non-model organisms with sparsely annotated single-nucleotide polymorphisms, or in disease contexts where unknown DNA mutations are pervasive. Here, we show that Oxford Nanopore direct RNA sequencing can be used to identify inosine-containing sites in native transcriptomes with high accuracy. We trained convolutional neural network models to distinguish inosine from adenosine and guanosine, and to estimate the modification rate at each editing site. Furthermore, we demonstrated their utility on the transcriptomes of human, mouse and Xenopus. Our approach expands the toolkit for studying adenosine-to-inosine editing and can be further extended to investigate other RNA modifications.Publication Metadata only Editorial overview: cilia in development and disease(Current Biology Ltd, 2019) Ingham, Philip W.; N/A; Reversade, Bruno; Faculty Member; School of Medicine; 274182N/APublication Metadata only A deleterious recessive mutation in NUAK2 causes absence of brain in humans(Elsevier Science Bv, 2017) Ghosh, Kakaly; Navaratnam, Naveenan; Chan, Puck Wee; Tan, Thong Teck; Ng, Alvin Yu Jin; Tohari, Sumanty; Pomp, Oz; Venkatesh, Byrappa; Altunoglu, Umut; Bonnard, Carine; N/A; Kayserili, Hülya; Reversade, Bruno; Faculty Member; Faculty Member; School of Medicine; School of Medicine; 7945; 274182N/APublication Metadata only Loss-of-function mutations in LGI4, a secreted ligand involved in Schwann cell myelination, are responsible for arthrogryposis multiplex congenita(Cell Press, 2017) Xue, Shifeng; Maluenda, Jérôme; Marguet, Florent; Shboul, Mohammad; Quevarec, Loïc; Bonnard, Carine; Ng, Alvin Yu Jin; Tohari, Sumanty; Tan, Thong Teck; Kong, Mung Kei; Monaghan, Kristin G.; Cho, Megan T.; Siskind, Carly E.; Sampson, Jacinda B.; Rocha, Carolina Tesi; Alkazaleh, Fawaz; Gonzales, Marie; Rigonnot, Luc; Whalen, Sandra; Gut, Marta; Gut, Ivo; Bucourt, Martine; Venkatesh, Byrappa; Laquerrière, Annie; Melki, Judith; Reversade, Bruno; Faculty Member; School of Medicine; 274182Arthrogryposis multiplex congenita (AMC) is a developmental condition characterized by multiple joint contractures resulting from reduced or absent fetal movements. Through genetic mapping of disease loci and whole-exome sequencing in four unrelated multiplex families presenting with severe AMC, we identified biallelic loss-of-function mutations in LGI4 (leucine-rich glioma-inactivated 4). LGI4 is a ligand secreted by Schwann cells that regulates peripheral nerve myelination via its cognate receptor ADAM22 expressed by neurons. Immunolabeling experiments and transmission electron microscopy of the sciatic nerve from one of the affected individuals revealed a lack of myelin. Functional tests using affected individual-derived iPSCs showed that these germline mutations caused aberrant splicing of the endogenous LGI4 transcript and in a cell-based assay impaired the secretion of truncated LGI4 protein. This is consistent with previous studies reporting arthrogryposis in Lgi4-deficient mice due to peripheral hypomyelination. This study adds to the recent reports implicating defective axoglial function as a key cause of AMC.Publication Metadata only Publisher correction: discovery of a genetic module essential for assigning left–right asymmetry in humans and ancestral vertebrates (Nature Genetics, (2022), 54, 1, (62-72), 10.1038/s41588-021-00970-4)(Nature Research, 2022) Szenker-Ravi, Emmanuelle; Ott, Tim; Khatoo, Muznah; de Bellaing, Anne Moreau; Goh, Wei Xuan; Chong, Yan Ling; Beckers, Anja; Kannesan, Darshini; Louvel, Guillaume; Anujan, Priyanka; Ravi, Vydianathan; Bonnard, Carine; Moutton, Sébastien; Schoen, Patric; Fradin, Mélanie; Colin, Estelle; Megarbane, André; Daou, Linda; Chehab, Ghassan; Di Filippo, Sylvie; Rooryck, Caroline; Deleuze, Jean-François; Boland, Anne; Arribard, Nicolas; Eker, Rukiye; Tohari, Sumanty; Ng, Alvin Yu-Jin; Rio, Marlene; Lim, Chun Teck; Eisenhaber, Birgit; Eisenhaber, Frank; Venkatesh, Byrappa; Amiel, Jeanne; Crollius, Hugues Roest; Gordon, Christopher T.; Gossler, Achim; Roy, Sydipto; Attie-Bitach, Tania; Blum, Martin; Bouvagnet, Patrice; N/A; Reversade, Bruno; Faculty Member; School of Medicine; 274182N/A