Ashna Nisal

All Publications

• The contribution of de novo coding mutations to meningomyelocele NATURE Ha, Y., Nisal, A., Tang, I., Lee, C., Jhamb, I., Wallace, C., Howarth, R., Schroeder, S., Vong, K., Meave, N., Jiwani, F., Barrows, C., Lee, S., Jiang, N., Patel, A., Bagga, K., Banka, N., Friedman, L., Blanco, F. A., Yu, S., Rhee, S., Jeong, H., Plutzer, I., Major, M. B., Benoit, B., Pous, C., Heffner, C., Kibar, Z., Bot, G., Northrup, H., Au, K., Strain, M., Ashley-Koch, A. E., Finnell, R. H., Le, J. T., Meltzer, H. S., Araujo, C., Machado, H. R., Stevenson, R. E., Yurrita, A., Mumtaz, S., Ahmed, A., Khara, M., Mutchinick, O. M., Medina-Bereciartu, J., Hildebrandt, F., Melikishvili, G., Marwan, A. I., Capra, V., Noureldeen, M. M., Salem, A. M. S., Issa, M. Y., Zaki, M. S., Xu, L., Lee, J., Shin, D., Alkelai, A., Shuldiner, A. R., Kingsmore, S. F., Murray, S. A., Gee, H., Miller, W., Tolias, K. F., Wallingford, J. B., Kim, S., Gleeson, J. G., Spina Bifida Sequencing Consortium, J. T., Koch, A., Lupo, P. J., Magana, T., Kolvenbach, C. M., Shril, S., Takahashi, Y., Salimi-Dafsari, H., Phillips, H., Hanak, B., Kara, B., Gunes, A., Gonda, D. D., Kirmani, S., Tkemaladze, T. 2025

  Abstract

  Meningomyelocele (also known as spina bifida) is considered to be a genetically complex disease resulting from a failure of the neural tube to close. Individuals with meningomyelocele display neuromotor disability and frequent hydrocephalus, requiring ventricular shunting. A few genes have been proposed to contribute to disease susceptibility, but beyond that it remains unexplained1. We postulated that de novo mutations under purifying selection contribute to the risk of developing meningomyelocele2. Here we recruited a cohort of 851 meningomyelocele trios who required shunting at birth and 732 control trios, and found that de novo likely gene disruption or damaging missense mutations occurred in approximately 22.3% of subjects, with 28% of such variants estimated to contribute to disease risk. The 187 genes with damaging de novo mutations collectively define networks including actin cytoskeleton and microtubule-based processes, Netrin-1 signalling and chromatin-modifying enzymes. Gene validation demonstrated partial or complete loss of function, impaired signalling and defective closure of the neural tube in Xenopus embryos. Our results indicate that de novo mutations make key contributions to meningomyelocele risk, and highlight critical pathways required for neural tube closure in human embryogenesis.

  View details for DOI 10.1038/s41586-025-08676-x

  View details for Web of Science ID 001453394800001

  View details for PubMedID 40140573

  View details for PubMedCentralID 7321880

• Lipidomic profiling of mouse brain and human neuron cultures reveals a role for Mboat7 in mTOR-dependent neuronal migration. Science translational medicine Tang, I., Nisal, A., Reed, A., Ware, T. B., Johansen, A., Zaki, M. S., Cravatt, B. F., Gleeson, J. G. 2025; 17 (779): eadp5247

  Abstract

  Mutations in lipid regulator genes are a frequent cause of autism spectrum disorder, including those regulating phosphatidylinositol (PI) and phosphoinositide 3-kinase signaling. MBOAT7 encodes a key acyltransferase in PI synthesis and is mutated in an autism-related condition with neurodevelopmental delay and epilepsy. Using liquid chromatography-tandem mass spectrometry, we analyzed the PI-associated glycerolipidome in mice and humans during neurodevelopment and found dynamic regulation at times corresponding to neural apoptosis in the brains of Mboat7 knockout mice. Mboat7 function was necessary for polyunsaturated lipid synthesis and cortical neural migration, and loss resulted in massive accumulation of the precursor lysophosphatidylinositol and hyperactive mTOR signaling. Inhibiting mTOR signaling rescued migration defects. Our findings demonstrate roles for lipid remodeling during neurodevelopment and implicate lipid regulation in neuronal migration, revealing potential paths to treatment for MBOAT7 deficiency.

  View details for DOI 10.1126/scitranslmed.adp5247

  View details for PubMedID 39742503

• Risk of meningomyelocele mediated by the common 22q11.2 deletion. Science (New York, N.Y.) Vong, K. I., Lee, S., Au, K. S., Crowley, T. B., Capra, V., Martino, J., Haller, M., Araújo, C., Machado, H. R., George, R., Gerding, B., James, K. N., Stanley, V., Jiang, N., Alu, K., Meave, N., Nidhiry, A. S., Jiwani, F., Tang, I., Nisal, A., Jhamb, I., Patel, A., Patel, A., McEvoy-Venneri, J., Barrows, C., Shen, C., Ha, Y. J., Howarth, R., Strain, M., Ashley-Koch, A. E., Azam, M., Mumtaz, S., Bot, G. M., Finnell, R. H., Kibar, Z., Marwan, A. I., Melikishvili, G., Meltzer, H. S., Mutchinick, O. M., Stevenson, D. A., Mroczkowski, H. J., Ostrander, B., Schindewolf, E., Moldenhauer, J., Zackai, E. H., Emanuel, B. S., Garcia-Minaur, S., Nowakowska, B. A., Stevenson, R. E., Zaki, M. S., Northrup, H., McNamara, H. K., Aldinger, K. A., Phelps, I. G., Deng, M., Glass, I. A., Morrow, B., McDonald-McGinn, D. M., Sanna-Cherchi, S., Lamb, D. J., Gleeson, J. G., Koch, A. E., Meltzer, H. S., Le, J., Au, K. S., Northrup, H., Bot, G. M., Capra, V., Finnell, R. H., Kibar, Z., Lupo, P. J., Machado, H. R., Araújo, C., Magana, T., Marwan, A. I., Melikishvili, G., Mutchinick, O. M., Stevenson, R. E., Yurrita, A., Zaki, M. S., Mumtaz, S., Medina-Bereciartu, J. R., Kolvenbach, C. M., Shril, S., Hildebrandt, F., Noureldeen, M. M., Salem, A. M., Takahashi, Y., Salimi-Dafsari, H., Phillips, H. W., Hanak, B., Kara, B., Güneş, A. S., Gonda, D. D., Kirmani, S., Tkemaladze, T., Gleeson, J. G. 2024; 384 (6695): 584-590

  Abstract

  Meningomyelocele is one of the most severe forms of neural tube defects (NTDs) and the most frequent structural birth defect of the central nervous system. We assembled the Spina Bifida Sequencing Consortium to identify causes. Exome and genome sequencing of 715 parent-offspring trios identified six patients with chromosomal 22q11.2 deletions, suggesting a 23-fold increased risk compared with the general population. Furthermore, analysis of a separate 22q11.2 deletion cohort suggested a 12- to 15-fold increased NTD risk of meningomyelocele. The loss of Crkl, one of several neural tube-expressed genes within the minimal deletion interval, was sufficient to replicate NTDs in mice, where both penetrance and expressivity were exacerbated by maternal folate deficiency. Thus, the common 22q11.2 deletion confers substantial meningomyelocele risk, which is partially alleviated by folate supplementation.

  View details for DOI 10.1126/science.adl1624

  View details for PubMedID 38696583