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1.  Effects of Ethanol on Axon Outgrowth and Branching in Developing Rat Cortical Neurons 
Neuroscience  2008;157(3):556-565.
Humans exposed prenatally to ethanol can exhibit brain abnormalities and cognitive impairment similar to those seen in patients expressing mutant forms of the cell adhesion molecule L1CAM. The resemblance suggests that L1CAM may be a target for ethanol, and consistent with this idea, ethanol can inhibit L1CAM adhesion in cell lines and L1CAM-mediated outgrowth and signaling in cerebellar granule neurons. However, it is not known whether ethanol inhibits L1CAM function in other neuron types known to require L1CAM for appropriate development. Here we asked whether ethanol alters L1CAM function in neurons of the cerebral cortex. We find that ethanol does not alter axonal polarization, L1CAM-dependent axon outgrowth or branching, or L1CAM recycling in axonal growth cones. Thus, ethanol inhibition of L1CAM is highly dependent on neuronal context.
PMCID: PMC2626542  PMID: 18926887
L1CAM; alcohol; cell adhesion molecules; N-cadherin
2.  A large-scale screen for coding variants in SERT/SLC6A4 in autism spectrum disorders 
In the current study we explored the hypothesis that rare variants in SLC6A4 contribute to autism susceptibility and to rigid-compulsive behaviors in autism. We made use of a large number of unrelated cases with autism spectrum disorders (∼350) and controls (∼420) and screened for rare exonic variants in SLC6A4 by a high-throughput method followed by sequencing. We observed no difference in the frequency of such variants in the two groups. Furthermore, we did not observe an association of rare coding variants in SLC6A4 with rigid-compulsive traits scores in the cases. These results do not support a significant role for rare coding variants in SLC6A4 in autism spectrum disorders, nor do they support a significant role for SLC6A4 in rigid-compulsive traits in these disorders.
PMCID: PMC2678895  PMID: 19360675
3.  Multiplex ligation-dependent probe amplification for genetic screening in autism spectrum disorders: Efficient identification of known microduplications and identification of a novel microduplication in ASMT 
BMC Medical Genomics  2008;1:50.
It has previously been shown that specific microdeletions and microduplications, many of which also associated with cognitive impairment (CI), can present with autism spectrum disorders (ASDs). Multiplex ligation-dependent probe amplification (MLPA) represents an efficient method to screen for such recurrent microdeletions and microduplications.
In the current study, a total of 279 unrelated subjects ascertained for ASDs were screened for genomic disorders associated with CI using MLPA. Fluorescence in situ hybridization (FISH), quantitative polymerase chain reaction (Q-PCR) and/or direct DNA sequencing were used to validate potential microdeletions and microduplications. Methylation-sensitive MLPA was used to characterize individuals with duplications in the Prader-Willi/Angelman (PWA) region.
MLPA showed two subjects with typical ASD-associated interstitial duplications of the 15q11-q13 PWA region of maternal origin. Two additional subjects showed smaller, de novo duplications of the PWA region that had not been previously characterized. Genes in these two novel duplications include GABRB3 and ATP10A in one case, and MKRN3, MAGEL2 and NDN in the other. In addition, two subjects showed duplications of the 22q11/DiGeorge syndrome region. One individual was found to carry a 12 kb deletion in one copy of the ASPA gene on 17p13, which when mutated in both alleles leads to Canavan disease. Two subjects showed partial duplication of the TM4SF2 gene on Xp11.4, previously implicated in X-linked non-specific mental retardation, but in our subsequent analyses such variants were also found in controls. A partial duplication in the ASMT gene, located in the pseudoautosomal region 1 (PAR1) of the sex chromosomes and previously suggested to be involved in ASD susceptibility, was observed in 6–7% of the cases but in only 2% of controls (P = 0.003).
MLPA proves to be an efficient method to screen for chromosomal abnormalities. We identified duplications in 15q11-q13 and in 22q11, including new de novo small duplications, as likely contributing to ASD in the current sample by increasing liability and/or exacerbating symptoms. Our data indicate that duplications in TM4SF2 are not associated with the phenotype given their presence in controls. The results in PAR1/PAR2 are the first large-scale studies of gene dosage in these regions, and the findings at the ASMT locus indicate that further studies of the duplication of the ASMT gene are needed in order to gain insight into its potential involvement in ASD. Our studies also identify some limitations of MLPA, where single base changes in probe binding sequences alter results. In summary, our studies indicate that MLPA, with a focus on accepted medical genetic conditions, may be an inexpensive method for detection of microdeletions and microduplications in ASD patients for purposes of genetic counselling if MLPA-identified deletions are validated by additional methods.
PMCID: PMC2588447  PMID: 18925931

Results 1-3 (3)