L. Alison McInnes, MD
- ADJUNCT ASSOCIATE PROFESSOR | Psychiatry
Neurobehavioral Genetics Laboratory
We are studying molecular genetic mechanisms underlying neuropsychiatric disorders including autism, schizophrenia and Alzheimer's disease.
Identifying the genetic basis of complex neuropsychiatric phenotypes requires a multifaceted approach, including the use of increasingly sophisticated gene expression technologies. We are applying these methodologies to study schizophrenia, autism and Alzheimer's disease. For instance, recent expression studies suggest that abnormalities of RNA splicing and processing may contribute to the pathology of schizophrenia and Alzheimer's disease. As spatially and temporally regulated alternative splicing is considered the most important mechanism for increasing the functional diversity of proteins, it is not surprising that subtle perturbations of this process might play a prominent role in diseases of the central nervous system. Therefore, we are using a custom alternative splicing microarray to detect abnormal spliceforms in schizophrenic brain. Abnormal splicing and processing of widely expressed molecules such as the glutamate type 1 transporter may also be involved in neurodegenerative disease and this is another area of investigation in the laboratory. In addition, we are also exploring potential functional relationships between RNA splicing and processing proteins with the goal of identifying candidate schizophrenia susceptibility genes.
We have a population genetic study of autism ongoing in the Central Valley of Costa Rica. The population of the CVCR began with only a few founding families and grew exponentially in isolation until the 1970's. This type of genetically isolated founder population may be useful for mapping complex genetic traits. Although autism is a highly heritable disorder, it now appears that microduplications and deletions may explain a significant fraction of cases. It is also possible that cytogenetic abnormalities interact with autism susceptibility alleles in other genes. Array-based Comparative Genomic Hybridization, or CGH, is a novel technology for high-throughput detection of both known and novel microdups/dels including sub-telomeric abnormalities. We are screening our autism cases using this technology in order to identify known and novel cytogenetic abnormalities associated with autism and to identify possible genotype-phenotype correlations which may help us find underlying autism susceptibility genes.
Current projects in the lab include:
Edelmann L, McInnes LA, Pardo S, Bhatt J, Cohen N, Lauriat T, Ouchanov L, Gonzalez PJ, Manghi ER, Bondy P, Esquivel M, Monge S, Delgado MF, Splendore A, Francke U, Burton BK, Prosnitz A. An atypical deletion of the Williams-Beuren syndrome interval implicates genes associated with defective visuospatial processing and autism. J Med Genet 2007 February; 44(2): 136-143.
Lauriat TL, McInnes LA, Schmeidler J. Early rapid rise in EAAT2 expression follows the period of maximal seizure susceptibility in human brain. Neurosci Lett 2006 Nov 24; Epub ahead of print.
Lauriat TL, McInnes LA, Richler E. A quantitative regional expression profile of EAAT2 known and novel splice variants reopens the question of aberrant EAAT2 splicing in disease. Neurochem Int 2007 January ; 50(1): 271-280.
Lauriat TL, Dracheva S, Kremerskothen J, Duning K, McInnes LA, Buxbaum JD, Hyde TM, Kleinman JE, Haroutunian V. Characterization of KIAA0513, a novel signaling molecule that interacts with modulators of neuroplasticity, apoptosis, and the cytoskeleton. Brain Res 2006 Nov 22; 1121(1): 1-11.
Edelmann L, McInnes LA, Pardo S, Bhatt J, Cohen N, Lauriat T, Ouchanov L, Jimenez Gonzalez P, Manghi ER, Bondy P, Esquivel M, Monge S, Fallas M, Splendore A, Francke U, Burton BK, Prosnitz A. An atypical deletion of the Williams-Beuren Syndrome interval implicates genes associated with defective visuospatial processing and autism. J Med Genet 2006 Sept 13; Epub ahead of print.
Lauriat TL, McInnes LA. RNA metabolism and dysmyelination in schizophrenia. Neuroscience and Biobehav Rev 2006; 30(4): 551-561.
Mcinnes LA, Gonzalez PJ, Manghi ER, Esquivel M, Monge S, Delgado MF, Fournier E, Bondy P, Castelle K. A genetic study of autism in Costa Rica: multiple variables affecting IQ scores observed in a preliminary sample of autistic cases. BMC Psychiatry 2005 Mar 21; 5(1): 15.
Richler E, Reichert JG, Buxbaum JD, Mcinnes LA. Autism and ultraconserved non-coding sequence on chromosome 7q. Psychiatr Genet 2006 Feb; 16(1): 19-23.
Lauriat TL, Dracheva S, Chin B, Schmeidler J, Mcinnes LA, Haroutunian V. Quantitative analysis of glutamate transporter mRNA expression in prefrontal and primary visual cortex in normal and schizophrenic brain. Neuroscience 2006; 137(3): 843-851.
Mcinnes L, L Lauriat T. RNA metabolism and dysmyelination in schizophrenia. Neurosci Biobehav Rev 2006 Jan 27; [Epub ahead of print].