Researcher:
Nabavizadeh, Nasrinsadat

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Nasrinsadat

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Nabavizadeh

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Nabavizadeh, Nasrinsadat

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2022 - 20232

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    A progeroid syndrome caused by a deep intronic variant in TAPT1 is revealed by RNA/SI-NET sequencing
    (John Wiley and Sons Inc, 2023) Bressin, Annkatrin; Shboul, Mohammad; Moreno Traspas, Ricardo; Chia, Poh Hui; Bonnard, Carine; Szenker-Ravi, Emmanuelle; Beillard, Emmanuel; Hojati, Zohreh; Drutman, Scott; Freier, Susanne; El-Khateeb, Mohammad; Fathallah, Rajaa; Casanova, Jean-Laurent; Soror, Wesam; Arafat, Alaa; Mayer, Andreas; Altunoğlu, Umut; Reversade, Bruno; Nabavizadeh, Nasrinsadat; Sarıbaş, Burak; Faculty Member; Faculty Member; Researcher; Researcher; Master Student; School of Medicine; School of Medicine; School of Medicine; N/A; Graduate School of Health Sciences; 126174; 274182; N/A; N/A; N/A
    Exome sequencing has introduced a paradigm shift for the identification of germline variations responsible for Mendelian diseases. However, non-coding regions, which make up 98% of the genome, cannot be captured. The lack of functional annotation for intronic and intergenic variants makes RNA-seq a powerful companion diagnostic. Here, we illustrate this point by identifying six patients with a recessive Osteogenesis Imperfecta (OI) and neonatal progeria syndrome. By integrating homozygosity mapping and RNA-seq, we delineated a deep intronic TAPT1 mutation (c.1237-52 G>A) that segregated with the disease. Using SI-NET-seq, we document that TAPT1's nascent transcription was not affected in patients' fibroblasts, indicating instead that this variant leads to an alteration of pre-mRNA processing. Predicted to serve as an alternative splicing branchpoint, this mutation enhances TAPT1 exon 12 skipping, creating a protein-null allele. Additionally, our study reveals dysregulation of pathways involved in collagen and extracellular matrix biology in disease-relevant cells. Overall, our work highlights the power of transcriptomic approaches in deciphering the repercussions of non-coding variants, as well as in illuminating the molecular mechanisms of human diseases. © 2023 The Authors. Published under the terms of the CC BY 4.0 license.
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    Rabenosyn separation-of-function mutations uncouple endosomal recycling from lysosomal degradation, causing a distinct Mendelian disorder
    (Oxford University Press (OUP), 2022) Paul, Franziska; Ng, Calista; Mohamad Sahari, Umar Bin; Nafissi, Shahriar; Nilipoor, Yalda; Tavasoli, Ali Reza; Bonnard, Carine; Wong, Pui-Mun; Estiar, Mehrdad A.; Majoie, Charles B.; Lee, Hane; Nelson, Stanley F.; Gan-Or, Ziv; Rouleau, Guy A.; Van Veldhoven, Paul P.; Massie, Rami; Hennekam, Raoul C.; Kariminejad, Ariana; Reversade, Bruno; Nabavizadeh, Nasrinsadat; Altunoğlu, Umut; Faculty Member; Researcher; Faculty Member; School of Medicine; N/A; N/A; 126174
    Rabenosyn (RBSN) is a conserved endosomal protein necessary for regulating internalized cargo. Here, we present clinical, genetic, cellular and biochemical evidence that two distinct RBSN missense variants are responsible for a novel Mendelian disorder consisting of progressive muscle weakness, facial dysmorphisms, ophthalmoplegia and intellectual disability. Using exome sequencing, we identified recessively acting germline alleles p.Arg180Gly and p.Gly183Arg, which are both situated in the FYVE domain of RBSN. We find that these variants abrogate binding to its cognate substrate phosphatidylinositol 3-phosphate (PI3P) and thus prevent its translocation to early endosomes. Although the endosomal recycling pathway was unaltered, mutant p.Gly183Arg patient fibroblasts show accumulation of cargo tagged for lysosomal degradation. Our results suggest that these variants are separation-of-function alleles, which cause a delay in endosomal maturation without affecting cargo recycling. We conclude that distinct germline mutations in RBSN cause non-overlapping phenotypes with specific and discrete endolysosomal cellular defects.