LGI2 Truncation Causes a Remitting Focal Epilepsy in Dogs

Peer reviewe

Mutation in VMAT2 Causing a Pediatric Neurotransmitter Disease

This thesis describes a new disease encompassing infantile-onset movement disorder (including severe parkinsonism and nonambulation), mood disturbance, autonomic instability, and developmental delay that was identified in eight cousins of a consanguineous Bedouin family in Saudi Arabia. The autosomal recessive disease was hypothesized to be a disorder of monoamine neurotransmission, and evidence supporting its causation by a mutation in SLC18A2 (which encodes the vesicular monoamine transporter 2 [VMAT2]) was acquired by single nucleotide polymorphism (SNP) genotyping, homozygosity analysis, and exome sequencing. VMAT2 translocates dopamine and serotonin into synaptic vesicles and is essential for motor control, stable mood, and autonomic function. The loss of VMAT2 function was further confirmed through biochemical assay of serotonin uptake. Consistent with a defect in vesicular monoamine transport, treatment of the patients with levodopa was associated with worsening, whereas treatment with direct dopamine agonists was followed by immediate ambulation, near-complete correction of the movement disorder, and resumption of development. Understanding the underlying mechanism of this disorder extends the spectrum of known pediatric neurotransmitter diseases, serves as the first demonstration of mutation in VMAT2 causing a human phenotype, and thereby provides new insight into the role of VMAT2 in monoamine homeostasis. This thesis additionally demonstrates the utility of implementing genomic diagnosis in the clinic, with respect to providing simple and effective treatments in a timely manner to improve outcomes for patients with rare inborn errors of metabolism.Ph.D

The genome sequence of Bacillus anthracis Ames and comparison to closely related bacteria

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