Bio

Professional Education


  • Bachelor of Science, University College Cork (2010)
  • Doctor of Philosophy, University College London (2015)
  • Master of Science, Imperial College of Science, Technology & Medicine (2011)

Stanford Advisors


Publications

All Publications


  • Towards the Prevention of Aminoglycoside-Related Hearing Loss Frontiers in Cellular Neuroscience O'Sullivan, M. E., Perez, A., Lin, R., Ricci, A. J., Cheng, A. G. 2017; 11: 325

    Abstract

    Aminoglycosides are potent antibiotics deployed worldwide despite their known side-effect of sensorineural hearing loss. The main etiology of this sensory deficit is death of inner ear sensory hair cells selectively triggered by aminoglycosides. For decades, research has sought to unravel the molecular events mediating sensory cell demise, emphasizing the roles of reactive oxygen species and their potentials as therapeutic targets. Studies in recent years have revealed candidate transport pathways including the mechanotransducer channel for drug entry into sensory cells. Once inside sensory cells, intracellular targets of aminoglycosides, such as the mitochondrial ribosomes, are beginning to be elucidated. Based on these results, less ototoxic aminoglycoside analogs are being generated and may serve as alternate antimicrobial agents. In this article, we review the latest findings on mechanisms of aminoglycoside entry into hair cells, their intracellular actions and potential therapeutic targets for preventing aminoglycoside ototoxicity.

    View details for DOI 10.3389/fncel.2017.00325

    View details for PubMedCentralID PMC5651232

  • The kinetochore protein, CENPF, is mutated in human ciliopathy and microcephaly phenotypes JOURNAL OF MEDICAL GENETICS Waters, A. M., Asfahani, R., Carroll, P., Bicknell, L., Lescai, F., Bright, A., Chanudet, E., Brooks, A., Christou-Savina, S., Osman, G., Walsh, P., Bacchelli, C., Chapgier, A., Vernay, B., Bader, D. M., Deshpande, C., O' Sullivan, M., Ocaka, L., Stanescu, H., Stewart, H. S., Hildebrandt, F., Otto, E., Johnson, C. A., Szymanska, K., Katsanis, N., Davis, E., Kleta, R., Hubank, M., Doxsey, S., Jackson, A., Stupka, E., Winey, M., Beales, P. L. 2015; 52 (3): 147-156

    Abstract

    Mutations in microtubule-regulating genes are associated with disorders of neuronal migration and microcephaly. Regulation of centriole length has been shown to underlie the pathogenesis of certain ciliopathy phenotypes. Using a next-generation sequencing approach, we identified mutations in a novel centriolar disease gene in a kindred with an embryonic lethal ciliopathy phenotype and in a patient with primary microcephaly.Whole exome sequencing data from a non-consanguineous Caucasian kindred exhibiting mid-gestation lethality and ciliopathic malformations revealed two novel non-synonymous variants in CENPF, a microtubule-regulating gene. All four affected fetuses showed segregation for two mutated alleles [IVS5-2A>C, predicted to abolish the consensus splice-acceptor site from exon 6; c.1744G>T, p.E582X]. In a second unrelated patient exhibiting microcephaly, we identified two CENPF mutations [c.1744G>T, p.E582X; c.8692 C>T, p.R2898X] by whole exome sequencing. We found that CENP-F colocalised with Ninein at the subdistal appendages of the mother centriole in mouse inner medullary collecting duct cells. Intraflagellar transport protein-88 (IFT-88) colocalised with CENP-F along the ciliary axonemes of renal epithelial cells in age-matched control human fetuses but did not in truncated cilia of mutant CENPF kidneys. Pairwise co-immunoprecipitation assays of mitotic and serum-starved HEKT293 cells confirmed that IFT88 precipitates with endogenous CENP-F.Our data identify CENPF as a new centriolar disease gene implicated in severe human ciliopathy and microcephaly related phenotypes. CENP-F has a novel putative function in ciliogenesis and cortical neurogenesis.

    View details for DOI 10.1136/jmedgenet-2014-102691

    View details for Web of Science ID 000349874700002

    View details for PubMedID 25564561

  • Mitochondrial m.1584A 12S m(2)(6)A rRNA methylation in families with m.1555A > G associated hearing loss HUMAN MOLECULAR GENETICS O'Sullivan, M., Rutland, P., Lucas, D., Ashton, E., Hendricks, S., Rahman, S., Bitner-Glindzicz, M. 2015; 24 (4): 1036-1044

    Abstract

    The mitochondrial DNA mutation m.1555A>G predisposes to hearing loss following aminoglycoside antibiotic exposure in an idiosyncratic dose-independent manner. However, it may also cause maternally inherited hearing loss in the absence of aminoglycoside exposure or any other clinical features (non-syndromic hearing loss). Although m.1555A>G was identified as a cause of deafness more than twenty years ago, the pathogenic mechanism of this mutation of ribosomal RNA remains controversial. Different mechanistic concepts have been proposed. Most recently, evidence from cell lines and animal models suggested that patients with m.1555A>G may have more 12S rRNA N6, N6-dimethyladenosine (m(6) 2A) methylation than controls, so-called 'hypermethylation'. This has been implicated as a pathogenic mechanism of mitochondrial dysfunction but has yet to be validated in patients. 12S m(6) 2A rRNA methylation, by the mitochondrial transcription factor 1 (TFB1M) enzyme, occurs at two successive nucleotides (m.1584A and m.1583A) in close proximity to m.1555A>G. We examined m(6) 2A methylation in 14 patients with m.1555A>G, and controls, and found all detectable 12S rRNA transcripts to be methylated in both groups. Moreover, different RNA samples derived from the same patient (lymphocyte, fibroblast and lymphoblast) revealed that only transformed cells contained some unmethylated 12S rRNA transcripts, with all detectable 12S rRNA transcripts derived from primary samples m(6) 2A-methylated. Our data indicate that TFB1M 12S m(6) 2A rRNA hypermethylation is unlikely to be a pathogenic mechanism and may be an artefact of previous experimental models studied. We propose that RNA methylation studies in experimental models should be validated in primary clinical samples to ensure that they are applicable to the human situation.

    View details for DOI 10.1093/hmg/ddu518

    View details for Web of Science ID 000350138300012

    View details for PubMedID 25305075

  • Mutations in SNX14 Cause a Distinctive Autosomal-Recessive Cerebellar Ataxia and Intellectual Disability Syndrome AMERICAN JOURNAL OF HUMAN GENETICS Thomas, A. C., Williams, H., Seto-Salvia, N., Bacchelli, C., Jenkins, D., O'Sullivan, M., Mengrelis, K., Ishida, M., Ocaka, L., Chanudet, E., James, C., Lescai, F., Anderson, G., Morrogh, D., Ryten, M., Duncan, A. J., Pai, Y. J., Saraiva, J. M., Ramos, F., Farren, B., Saunders, D., Vernay, B., Gissen, P., Straatmaan-Iwanowska, A., Baas, F., Wood, N. W., Hersheson, J., Houlden, H., Hurst, J., Scott, R., Bitner-Glindzicz, M., Moore, G. E., Sousa, S. B., Stanier, P. 2014; 95 (5): 611-621

    Abstract

    Intellectual disability and cerebellar atrophy occur together in a large number of genetic conditions and are frequently associated with microcephaly and/or epilepsy. Here we report the identification of causal mutations in Sorting Nexin 14 (SNX14) found in seven affected individuals from three unrelated consanguineous families who presented with recessively inherited moderate-severe intellectual disability, cerebellar ataxia, early-onset cerebellar atrophy, sensorineural hearing loss, and the distinctive association of progressively coarsening facial features, relative macrocephaly, and the absence of seizures. We used homozygosity mapping and whole-exome sequencing to identify a homozygous nonsense mutation and an in-frame multiexon deletion in two families. A homozygous splice site mutation was identified by Sanger sequencing of SNX14 in a third family, selected purely by phenotypic similarity. This discovery confirms that these characteristic features represent a distinct and recognizable syndrome. SNX14 encodes a cellular protein containing Phox (PX) and regulator of G protein signaling (RGS) domains. Weighted gene coexpression network analysis predicts that SNX14 is highly coexpressed with genes involved in cellular protein metabolism and vesicle-mediated transport. All three mutations either directly affected the PX domain or diminished SNX14 levels, implicating a loss of normal cellular function. This manifested as increased cytoplasmic vacuolation as observed in cultured fibroblasts. Our findings indicate an essential role for SNX14 in neural development and function, particularly in development and maturation of the cerebellum.

    View details for DOI 10.1016/j.ajhg.2014.10.007

    View details for Web of Science ID 000344845000012

    View details for PubMedID 25439728