Current Research

- Creatine (Cr) transporter deficiency syndrome affects 1 million people, resulting in X-linked intellectual disability (XLID) and autism spectrum disorder (ASD). Lacking comprehensive genetic testing, this number is likely grossly underestimated, especially in females, who have milder symptoms due to their second X-chromosome and random inactivation. SLC6A8 codes for the Cr transporter (CrT), without which Cr cannot pass the blood-brain barrier (BBB), nor enter neuronal cells, thus hindering ATP production and metabolic activity in the brain. Patients with SLC6A8 mutations do not respond to treatment with oral Cr supplements and thus currently there are no available treatment modalities. Using the zebrafish as a model we are testing N-modified Cr analogs for their ability to cross the blood-brain barrier and enter neuronal cells, thereby rescuing the phenotype.

- Mutations in MECP2, an X-linked gene, are responsible for 96% of Rett Syndrome cases, which in turn account for 1% of all autism cases. Patients are mostly female due to lethal effects in male fetuses. They exhibit a number of clinical signs; a lack of verbal skills; failure to walk, small hands and microcephaly, stereotyped hand movements and 80% have seizures in addition to other behavioral and physiological impairments. Until recently monogenic diseases were thought to result in a single phenotypic outcome, no matter the position of the pathogenic mutation in the gene. 233 missense SNPs have been identified in the MECP2 gene. However, of the few individual SNPs studied, varying severities of Rett syndrome result, and in a few cases non-Rett syndrome phenotypes have developed. This suggests that the position of the SNP in the DNA acts as the driving force behind the phenotypic outcome. Recapitulating each missense SNP in zebrafish will reveal the molecular basis for the variants within Rett syndrome and between Rett, Angelman, mental retardation and encephalopathy phenotypes from SNPs in the MECP2 gene.

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