The Autism Spectrum Disorders - Albert Einstein College of Medicine

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The Autism Spectrum Disorders:
from gene to function
My laboratory is interested in the Autism Spectrum
Disorders (ASDs) and related disorders of human
cognition. Defined entirely in terms of behavior, the
ASDs represent a unique class of clinical conditions
involving deficits in language use, impaired social
behavior, and a circumscribed range of interests.
Work in my lab employs a blend of molecular
genetics and developmental neurobiology to identify
genes that may influence risk and in turn understand
how they operate functionally. Ongoing studies in
cells and mouse seek to better understand the
function of Contactin-Associated Protein-like 2
(CNTNAP2), a gene known to modulate ASD risk
and also contribute to each of specific language
impairment and intellectual disability. Efforts towards
understanding CNTNAP2 signaling, and how
individual molecular variants work alongside one
another to modulate risk, are likely to prove
important in the development of therapeutics.
(A)
Assistant Professor, Depts. of Genetics & Neuroscience
Price Center for Genetic & Translational Medicine
Albert Einstein College of Medicine, 1301 Morris Park Av
413.347.9060; [email protected]
(B)
eDels - 304 genes (e.g. ASPM, DPP10, CNTNAP2, PCDH9 and NRXN1
eDups - 189 genes (e.g. TSC2, RAI1)
gDups - 484 genes at fewer loci (e.g. 15q13, 22q11)
(C)
(D)
Brett S. Abrahams, PhD
(E)
Measurement of gene expression can
provide important insight into gene
function. (C) Towards interrogation of
language-related regions in the developing
human brain we characterized transcript
levels by microarray (PNAS, 2007,
104:17849). These genome-wide studies
also highlighted CNTNAP2 identifying a
marked enrichment of mRNA in prefrontal
cortex. Separate work (D) demonstrated
functional interaction with language-related
FOXP2 (NEJM, 2009, 359(22):2337) and
(E) enrichment in songbird nuclei necessary
for vocal communication (JCN, 2010,
518:1995). These data are consistent with
the hypothesis that variation in CNTNAP2
may increase risk for autism through
disrupting circuitry necessary for language.
Current functional work led by postdoctoral fellow Dr. Galyna Sidyelyeva is aimed a deeper understanding of CNTNAP2 gene function. Ongoing
studies, using cell culture and transgenic mice, seek to explore segments of the “ASDome” (molecules that modulate autism risk and operate in
concert in health or disease). DHCR7, the final enzyme in cholesterol synthesis, and mutated in a form of syndromic autism (SLOS) is of particular
interest. We are evaluating a two hit model whereby interventions that disrupt DHCR7 function impact CNTNAP2 and vice versa.
We seek a technician with experience in cell culture and/or microscopy to become involved in these studies.
Previous work has employed a variety of
strategies to identify genetic variants likely
to modulate autism risk (A) For example,
genome-wide analyses of structural
variation identified a large number of
candidate genes (PLoS Genetics, 2009, 5(6):
e1000536). (B) Regional studies evaluating
the role of both common (AJHG, 2008,
82: 165; not shown) and rare variation
(AJHG, 2008, 82: 150) have drawn a focus
to CNTNAP2, a member of the neurexin
superfamily. Ongoing work rooted in next
generation sequencing aims to make use of
newly identified genetic risk factors to
improve the ability of local physicians to
provide information to families. The lab is
currently recruiting a graduate student
with strong computer skills to carry out
work in human genetics.
Additional References
Abrahams, B.S., (201_). Syndromic vs. Idiopathic
ASCs. Autism Spectrum Conditions: International Experts answer
your Questions on Autism, Asperger syndrome and PDD-NOS. Eds.
Hallmayer and Boelte. Hogrefe Press. In press.
Abrahams, B.S., (201_). Many roads to the Autism Spectrum
Disorders. Neuropsychology of Autism. Ed. D. Fein. Oxford Univ
Press. In press.
Abrahams, B.S., & Geschwind D.H.. (2010). Genetics of
Autism. Human Genetics: Problems & Approaches.Eds. Speicher,
Antonarakiso, and Motulsky. 4th Ed. Springer-Verlag. [ISBN:
9783540376538]
Abrahams, B.S. and Geschwind, D.H. (2008). Advances in
autism genetics: on the threshold of a new
neurobiology. Nature Reviews Genetics. 9:341-355.
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