Marwa Zafarullah

All Publications

• Blood Proteome Profiling Reveals Biomarkers and Pathway Alterations in Fragile X PM at Risk for Developing FXTAS INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Zafarullah, M., Li, J., Salemi, M. R., Phinney, B. S., Durbin-Johnson, B. P., Hagerman, R., Hessl, D., Rivera, S. M., Tassone, F. 2023; 24 (17)

  Abstract

  Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is a neurodegenerative disorder associated with the FMR1 premutation. Currently, it is not possible to determine when and if individual premutation carriers will develop FXTAS. Thus, with the aim to identify biomarkers for early diagnosis, development, and progression of FXTAS, along with associated dysregulated pathways, we performed blood proteomic profiling of premutation carriers (PM) who, as part of an ongoing longitudinal study, emerged into two distinct groups: those who developed symptoms of FXTAS (converters, CON) over time (at subsequent visits) and those who did not (non-converters, NCON). We compared these groups to age-matched healthy controls (HC). We assessed CGG repeat allele size by Southern blot and PCR analysis. The proteomic profile was obtained by liquid chromatography mass spectrometry (LC-MS/MS). We identified several significantly differentiated proteins between HC and the PM groups at Visit 1 (V1), Visit 2 (V2), and between the visits. We further reported the dysregulated protein pathways, including sphingolipid and amino acid metabolism. Our findings are in agreement with previous studies showing that pathways involved in mitochondrial bioenergetics, as observed in other neurodegenerative disorders, are significantly altered and appear to contribute to the development of FXTAS. Lastly, we compared the blood proteome of the PM who developed FXTAS over time with the CSF proteome of the FXTAS patients recently reported and found eight significantly differentially expressed proteins in common. To our knowledge, this is the first report of longitudinal proteomic profiling and the identification of unique biomarkers and dysregulated protein pathways in FXTAS.

  View details for DOI 10.3390/ijms241713477

  View details for Web of Science ID 001060624900001

  View details for PubMedID 37686279

  View details for PubMedCentralID PMC10488017

• Insight and Recommendations for Fragile X-Premutation-Associated Conditions from the Fifth International Conference on <i>FMR1</i> Premutation CELLS Tassone, F., Protic, D., Allen, E., Archibald, A. D., Baud, A., Brown, T. W., Budimirovic, D. B., Cohen, J., Dufour, B., Eiges, R., Elvassore, N., Gabis, L. V., Grudzien, S. J., Hall, D. A., Hessl, D., Hogan, A., Hunter, J., Jin, P., Jiraanont, P., Klusek, J., Kooy, R., Kraan, C. M., Laterza, C., Lee, A., Lipworth, K., Losh, M., Loesch, D., Lozano, R., Mailick, M. R., Manolopoulos, A., Martinez-Cerdeno, V., Mclennan, Y., Miller, R. M., Montanaro, F., Mosconi, M. W., Potter, S., Raspa, M., Rivera, S. M., Shelly, K., Todd, P. K., Tutak, K., Wang, J., Wheeler, A., Winarni, T., Zafarullah, M., Hagerman, R. J., Kalyuzhny, A. E. 2023; 12 (18)

  Abstract

  The premutation of the fragile X messenger ribonucleoprotein 1 (FMR1) gene is characterized by an expansion of the CGG trinucleotide repeats (55 to 200 CGGs) in the 5' untranslated region and increased levels of FMR1 mRNA. Molecular mechanisms leading to fragile X-premutation-associated conditions (FXPAC) include cotranscriptional R-loop formations, FMR1 mRNA toxicity through both RNA gelation into nuclear foci and sequestration of various CGG-repeat-binding proteins, and the repeat-associated non-AUG (RAN)-initiated translation of potentially toxic proteins. Such molecular mechanisms contribute to subsequent consequences, including mitochondrial dysfunction and neuronal death. Clinically, premutation carriers may exhibit a wide range of symptoms and phenotypes. Any of the problems associated with the premutation can appropriately be called FXPAC. Fragile X-associated tremor/ataxia syndrome (FXTAS), fragile X-associated primary ovarian insufficiency (FXPOI), and fragile X-associated neuropsychiatric disorders (FXAND) can fall under FXPAC. Understanding the molecular and clinical aspects of the premutation of the FMR1 gene is crucial for the accurate diagnosis, genetic counseling, and appropriate management of affected individuals and families. This paper summarizes all the known problems associated with the premutation and documents the presentations and discussions that occurred at the International Premutation Conference, which took place in New Zealand in 2023.

  View details for DOI 10.3390/cells12182330

  View details for Web of Science ID 001073435300001

  View details for PubMedID 37759552

  View details for PubMedCentralID PMC10529056

• Intercorrelation of Molecular Biomarkers and Clinical Phenotype Measures in Fragile X Syndrome CELLS Aishworiya, R., Chi, M., Zafarullah, M., Mendoza, G., Ponzini, M., Kim, K., Biag, H., Thurman, A., Abbeduto, L., Hessl, D., Randol, J., Bolduc, F. V., Jacquemont, S., Lippe, S., Hagerman, P., Hagerman, R., Schneider, A., Tassone, F. 2023; 12 (14)

  Abstract

  This study contributes to a greater understanding of the utility of molecular biomarkers to identify clinical phenotypes of fragile X syndrome (FXS). Correlations of baseline clinical trial data (molecular measures-FMR1 mRNA, CYFIP1 mRNA, MMP9 and FMRP protein expression levels, nonverbal IQ, body mass index and weight, language level, NIH Toolbox, adaptive behavior rating, autism, and other mental health correlates) of 59 participants with FXS ages of 6-32 years are reported. FMR1 mRNA expression levels correlated positively with adaptive functioning levels, expressive language, and specific NIH Toolbox measures. The findings of a positive correlation of MMP-9 levels with obesity, CYFIP1 mRNA with mood and autistic symptoms, and FMR1 mRNA expression level with better cognitive, language, and adaptive functions indicate potential biomarkers for specific FXS phenotypes. These may be potential markers for future clinical trials for targeted treatments of FXS.

  View details for DOI 10.3390/cells12141920

  View details for Web of Science ID 001035162100001

  View details for PubMedID 37508583

  View details for PubMedCentralID PMC10377864