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Papers of the Week

  • 1) Dis Model Mech. 2012 May 1. [Epub ahead of print]

    Zebrafish homologs of 16p11.2, a genomic region associated with brain disorders, are active during brain development, and include two deletion dosage sensor genes.

    Blaker-Lee A, Gupta S, McCammon JM, Derienzo G, Sive H.

Whitehead Institute for Biomedical Research, Cambridge, MA, USA;

Deletion or duplication of one copy of the human 16p11.2 interval is tightly
associated with impaired brain function, including autism spectrum disorders
(ASD), intellectual disability disorder (IDD), and other phenotypes, indicating
the importance of gene dosage in this copy number variant region (CNV). The core 
of this CNV includes 25 genes, however, the number of genes that contribute to
these phenotypes is not known. Further, genes whose functional levels change with
deletion or duplication (termed 'dosage sensors'), which may associate the CNV
with pathologies, have not been identified. Using the zebrafish as a tool, a set 
of 16p11.2 homologs was identified, primarily on chromosomes 3 and 12. Use of
eleven phenotypic assays, spanning the first five days of development,
demonstrates that this set of genes is highly active, such that 21 out of 22
homologs tested show loss of function phenotypes. Most genes are required for
nervous system development - impacting brain morphology, eye development, axonal 
density or organization, and motor response. In general, human genes can
substitute for the fish homolog, demonstrating orthology, and consistent with
conserved molecular pathways. In a screen for 16p11.2 genes whose function is
sensitive to hemizygosity, the aldolase a (aldoa) and kinesin family member 22
(kif22) genes were identified as giving clear phenotypes when RNA levels are
reduced by ~50%, suggesting that these genes are deletion dosage sensors. This
study leads to two major findings. The first is that the 16p11.2 region comprises
a highly active set of genes, which may present a large genetic target, and may
explain why multiple brain function and other phenotypes are associated with this
interval. The second major finding is that there are (at least) two genes with
deletion dosage sensor properties amongst the 16p11.2 set, which may link this
CNV to brain disorders including ASD and IDD.

PMID: 22566537  [PubMed - as supplied by publisher]
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  • 2) Proc Natl Acad Sci U S A. 2012 May 7. [Epub ahead of print]

    A common X-linked inborn error of carnitine biosynthesis may be a risk factor for nondysmorphic autism.

    Celestino-Soper PB, Violante S, Crawford EL, Luo R, Lionel AC, Delaby E, Cai G,
Sadikovic B, Lee K, Lo C, Gao K, Person RE, Moss TJ, German JR, Huang N, Shinawi 
M, Treadwell-Deering D, Szatmari P, Roberts W, Fernandez B, Schroer RJ, Stevenson
RE, Buxbaum JD, Betancur C, Scherer SW, Sanders SJ, Geschwind DH, Sutcliffe JS,
Hurles ME, Wanders RJ, Shaw CA, Leal SM, Cook EH Jr, Goin-Kochel RP, Vaz FM,
Beaudet AL.

Departments of Molecular and Human Genetics, Psychiatry, and Pediatrics, Baylor
College of Medicine, Houston, TX 77030.

We recently reported a deletion of exon 2 of the trimethyllysine hydroxylase
epsilon (TMLHE) gene in a proband with autism. TMLHE maps to the X chromosome and
encodes the first enzyme in carnitine biosynthesis, 6-N-trimethyllysine
dioxygenase. Deletion of exon 2 of TMLHE causes enzyme deficiency, resulting in
increased substrate concentration (6-N-trimethyllysine) and decreased product
levels (3-hydroxy-6-N-trimethyllysine and γ-butyrobetaine) in plasma and urine.
TMLHE deficiency is common in control males (24 in 8,787 or 1 in 366) and was not
significantly increased in frequency in probands from simplex autism families (9 
in 2,904 or 1 in 323). However, it was 2.82-fold more frequent in probands from
male-male multiplex autism families compared with controls (7 in 909 or 1 in 130;
P = 0.023). Additionally, six of seven autistic male siblings of probands in
male-male multiplex families had the deletion, suggesting that TMLHE deficiency
is a risk factor for autism (metaanalysis Z-score = 2.90 and P = 0.0037),
although with low penetrance (2-4%). These data suggest that dysregulation of
carnitine metabolism may be important in nondysmorphic autism; that abnormalities
of carnitine intake, loss, transport, or synthesis may be important in a larger
fraction of nondysmorphic autism cases; and that the carnitine pathway may
provide a novel target for therapy or prevention of autism.

PMID: 22566635  [PubMed - as supplied by publisher]
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  • 3) Autism Res. 2012 May 4. doi: 10.1002/aur.1229. [Epub ahead of print]

    "Communities" in Community Engagement: Lessons Learned From Autism Research in South Korea and South Africa.

    Grinker RR, Chambers N, Njongwe N, Lagman AE, Guthrie W, Stronach S, Richard BO, 
Kauchali S, Killian B, Chhagan M, Yucel F, Kudumu M, Barker-Cummings C, Grether
J, Wetherby AM.

Department of Anthropology, George Washington University, Washington, D.C.

Little research has been conducted on behavioral characteristics of children with
autism spectrum disorder (ASD) from diverse cultures within the US, or from
countries outside of the US or Europe, with little reliable information yet
reported from developing countries. We describe the process used to engage
diverse communities in ASD research in two community-based research projects-an
epidemiologic investigation of 7- to 12-year olds in South Korea and the Early
Autism Project, an ASD detection program for 18- to 36-month-old Zulu-speaking
children in South Africa. Despite the differences in wealth between these
communities, ASD is underdiagnosed in both settings, and generally not reported
in clinical or educational records. Moreover, in both countries, there is low
availability of services. In both cases, local knowledge helped researchers to
address both ethnographic as well as practical problems. Researchers identified
the ways in which these communities generate and negotiate the cultural meanings 
of developmental disorders. Researchers incorporated that knowledge, as they
engaged communities in a research protocol, adapted and translated screening and 
diagnostic tools, and developed methods for screening, evaluating, and diagnosing
children with ASD. Autism Res 2012, ••: ••-••. © 2012 International Society for
Autism Research, Wiley Periodicals, Inc.

© 2012 International Society for Autism Research, Wiley Periodicals, Inc.

PMID: 22566396  [PubMed - as supplied by publisher]
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  • 4) PLoS One. 2012;7(4):e35003. Epub 2012 Apr 27.

    High-Throughput Sequencing of mGluR Signaling Pathway Genes Reveals Enrichment of Rare Variants in Autism.

    Kelleher Iii RJ, Geigenmüller U, Hovhannisyan H, Trautman E, Pinard R, Rathmell
B, Carpenter R, Margulies D.

Center for Human Genetic Research, Massachusetts General Hospital, Boston,
Massachusetts, United States of America.

Identification of common molecular pathways affected by genetic variation in
autism is important for understanding disease pathogenesis and devising effective
therapies. Here, we test the hypothesis that rare genetic variation in the
metabotropic glutamate-receptor (mGluR) signaling pathway contributes to autism
susceptibility. Single-nucleotide variants in genes encoding components of the
mGluR signaling pathway were identified by high-throughput multiplex sequencing
of pooled samples from 290 non-syndromic autism cases and 300 ethnically matched 
controls on two independent next-generation platforms. This analysis revealed
significant enrichment of rare functional variants in the mGluR pathway in autism
cases. Higher burdens of rare, potentially deleterious variants were identified
in autism cases for three pathway genes previously implicated in syndromic autism
spectrum disorder, TSC1, TSC2, and SHANK3, suggesting that genetic variation in
these genes also contributes to risk for non-syndromic autism. In addition, our
analysis identified HOMER1, which encodes a postsynaptic density-localized
scaffolding protein that interacts with Shank3 to regulate mGluR activity, as a
novel autism-risk gene. Rare, potentially deleterious HOMER1 variants identified 
uniquely in the autism population affected functionally important protein regions
or regulatory sequences and co-segregated closely with autism among children of
affected families. We also identified rare ASD-associated coding variants
predicted to have damaging effects on components of the Ras/MAPK cascade.
Collectively, these findings suggest that altered signaling downstream of mGluRs 
contributes to the pathogenesis of non-syndromic autism.

PMID: 22558107  [PubMed - in process]
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  • 5) Neuroreport. 2012 May 30;23(8):463-8.

    Delayed magnetic mismatch negativity field, but not auditory M100 response, in specific language impairment.

    Roberts TP, Heiken K, Kahn SY, Qasmieh S, Blaskey L, Solot C, Parker WA, Verma R,
Edgar JC.

aDepartment of Radiology, Lurie Family Foundations' MEG Imaging Center
bDepartment of Pediatrics, Center for Autism Research cCenter for Childhood
Communication, Children's Hospital of Philadelphia dDepartment of Radiology,
Section for Biomedical Image Analysis, University of Pennsylvania, Philadelphia, 
Pennsylvania, USA.

Recent studies show that electrophysiological markers of auditory processing such
as the cortical 100 ms response (M100) and the mismatch field, derived from
magnetoencephalography, might be used to identify children with autism spectrum
disorders - M100 peak latency - and to stratify children with autism according to
the degree of language impairment - mismatch field peak latency. The present
study examined the latency of right superior temporal gyrus M100 and mismatch
field in a cohort of children and young adolescents with specific language
impairment (n=17), in comparison with age-matched and nonverbal intelligence
quotient-matched typically developing controls (n=21). Neither group showed
symptoms associated with autism. Although M100 latency (reflecting early auditory
processing) did not distinguish controls from children with specific language
impairment, the later 'change detection' mismatch field response was
significantly delayed (by >50 ms) in the specific language impairment group.
Linear discriminant analysis confirmed the role of mismatch field latency (92%)
but not M100 latency (8%) in distinguishing groups. The present results lend
support to the claim that a delayed M100 is specific to autism spectrum disorders
(with relative independence of degree of language impairment) and that a delayed 
mismatch field reflects an abnormality more generally associated with language
impairment, suggesting that mismatch field delay in the present specific language
impairment group and previously reported in autistic children with language
impairment may be indicative of a common neural system dysfunction.

PMID: 22551948  [PubMed - in process]
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  • 6) PLoS One. 2012;7(4):e36143. Epub 2012 Apr 27.

    MET and AKT Genetic Influence on Facial Emotion Perception.

    Lin MT, Huang KH, Huang CL, Huang YJ, Tsai GE, Lane HY.

Institute of Clinical Medical Science, China Medical University, Taichung,
Taiwan.

BACKGROUND: Facial emotion perception is a major social skill, but its molecular 
signal pathway remains unclear. The MET/AKT cascade affects neurodevelopment in
general populations and face recognition in patients with autism. This study
explores the possible role of MET/AKT cascade in facial emotion perception.
METHODS: One hundred and eighty two unrelated healthy volunteers (82 men and 100 
women) were recruited. Four single nucleotide polymorphisms (SNP) of MET
(rs2237717, rs41735, rs42336, and rs1858830) and AKT rs1130233 were genotyped and
tested for their effects on facial emotion perception. Facial emotion perception 
was assessed by the face task of Mayer-Salovey-Caruso Emotional Intelligence Test
(MSCEIT). Thorough neurocognitive functions were also assessed.
RESULTS: Regarding MET rs2237717, individuals with the CT genotype performed
better in facial emotion perception than those with TT (p = 0.016 by ANOVA, 0.018
by general linear regression model [GLM] to control for age, gender, and
education duration), and showed no difference with those with CC. Carriers with
the most common MET CGA haplotype (frequency = 50.5%) performed better than
non-carriers of CGA in facial emotion perception (p = 0.018, df = 1, F = 5.69,
p = 0.009 by GLM). In MET rs2237717/AKT rs1130233 interaction, the C carrier/G
carrier group showed better facial emotion perception than those with the TT/AA
genotype (p = 0.035 by ANOVA, 0.015 by GLM), even when neurocognitive functions
were controlled (p = 0.046 by GLM).
CONCLUSIONS: To our knowledge, this is the first study to suggest that genetic
factors can affect performance of facial emotion perception. The findings
indicate that MET variances and MET/AKT interaction may affect facial emotion
perception, implicating that the MET/AKT cascade plays a significant role in
facial emotion perception. Further replication studies are needed.

PMID: 22558359  [PubMed - in process]
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  • 7) Dev Neurosci. 2012 May 8. [Epub ahead of print]

    Development and Characterization of NEX-Pten, a Novel Forebrain Excitatory Neuron-Specific Knockout Mouse.

    Kazdoba TM, Sunnen CN, Crowell B, Lee GH, Anderson AE, D'Arcangelo G.

Department of Cell Biology and Neuroscience, The State University of New Jersey, 
Piscataway, N.J., USA.

The phosphatase and tensin homolog located on chromosome 10 (PTEN) suppresses the
activity of the phosphoinositide-3-kinase/Akt/mammalian target of rapamycin
(mTOR) pathway, a signaling cascade critically involved in the regulation of cell
proliferation and growth. Human patients carrying germ line PTEN mutations have
an increased predisposition to tumors, and also display a variety of neurological
symptoms and increased risk of epilepsy and autism, implicating PTEN in neuronal 
development and function. Consistently, loss of Pten in mouse neural cells
results in ataxia, seizures, cognitive abnormalities, increased soma size and
synaptic abnormalities. To better understand how Pten regulates the excitability 
of principal forebrain neurons, a factor that is likely to be altered in
cognitive disorders, epilepsy and autism, we generated a novel conditional
knockout mouse line (NEX-Pten) in which Cre, under the control of the NEX
promoter, drives the deletion of Pten specifically in early postmitotic,
excitatory neurons of the developing forebrain. Homozygous mutant mice exhibited 
a massive enlargement of the forebrain, and died shortly after birth due to
excessive mTOR activation. Analysis of the neonatal cerebral cortex further
identified molecular defects resulting from Pten deletion that likely affect
several aspects of neuronal development and excitability.

Copyright © 2012 S. Karger AG, Basel.

PMID: 22572802  [PubMed - as supplied by publisher]
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  • 8) PLoS One. 2012;7(5):e35414. Epub 2012 May 2.

    Abnormal Intracellular Accumulation and Extracellular Aβ Deposition in Idiopathic and Dup15q11.2-q13 Autism Spectrum Disorders.

    Wegiel J, Frackowiak J, Mazur-Kolecka B, Schanen NC, Cook EH Jr, Sigman M, Brown 
WT, Kuchna I, Wegiel J, Nowicki K, Imaki H, Ma SY, Chauhan A, Chauhan V, Miller
DL, Mehta PD, Flory M, Cohen IL, London E, Reisberg B, de Leon MJ, Wisniewski T.

Department of Developmental Neurobiology, NYS Institute for Basic Research in
Developmental Disabilities, Staten Island, New York, United States of America.

BACKGROUND: It has been shown that amyloid ß (Aβ), a product of proteolytic
cleavage of the amyloid β precursor protein (APP), accumulates in neuronal
cytoplasm in non-affected individuals in a cell type-specific amount.
METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we found that the
percentage of amyloid-positive neurons increases in subjects diagnosed with
idiopathic autism and subjects diagnosed with duplication 15q11.2-q13 (dup15) and
autism spectrum disorder (ASD). In spite of interindividual differences within
each examined group, levels of intraneuronal Aβ load were significantly greater
in the dup(15) autism group than in either the control or the idiopathic autism
group in 11 of 12 examined regions (p<0.0001 for all comparisons; Kruskall-Wallis
test). In eight regions, intraneuronal Aβ load differed significantly between
idiopathic autism and control groups (p<0.0001). The intraneuronal Aβ was mainly 
N-terminally truncated. Increased intraneuronal accumulation of Aβ(17-40/42) in
children and adults suggests a life-long enhancement of APP processing with
α-secretase in autistic subjects. Aβ accumulation in neuronal endosomes,
autophagic vacuoles, Lamp1-positive lysosomes and lipofuscin, as revealed by
confocal microscopy, indicates that products of enhanced α-secretase processing
accumulate in organelles involved in proteolysis and storage of metabolic
remnants. Diffuse plaques containing Aβ(1-40/42) detected in three subjects with 
ASD, 39 to 52 years of age, suggest that there is an age-associated risk of
alterations of APP processing with an intraneuronal accumulation of a short form 
of Aβ and an extracellular deposition of full-length Aβ in nonfibrillar plaques.
CONCLUSIONS/SIGNIFICANCE: The higher prevalence of excessive Aβ accumulation in
neurons in individuals with early onset of intractable seizures, and with a high 
risk of sudden unexpected death in epilepsy in autistic subjects with dup(15)
compared to subjects with idiopathic ASD, supports the concept of mechanistic and
functional links between autism, epilepsy and alterations of APP processing
leading to neuronal and astrocytic Aβ accumulation and diffuse plaque formation.

PMID: 22567102  [PubMed - in process]
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  • 9) J Autism Dev Disord. 2012 May 5. [Epub ahead of print]

    Is Maternal Influenza or Fever During Pregnancy Associated with Autism or Developmental Delays? Results from the CHARGE (CHildhood Autism Risks from Genetics and Environment) Study.

    Zerbo O, Iosif AM, Walker C, Ozonoff S, Hansen RL, Hertz-Picciotto I.

Department of Public Health Sciences, MS1C, University of California, Davis, CA, 
95616, USA, ozerbo@ucdavis.edu.

We analyzed data from case groups of 538 children with autism spectrum disorders 
(ASD) and 163 with developmental delays (DD), and from 421 typically developing
controls to assess associations with maternal influenza or fever during
pregnancy. Exposure information was obtained by telephone interviews, and
outcomes were clinically confirmed. Though neither ASD nor DD was associated with
influenza, both were associated with maternal fever during pregnancy: OR's (odds 
ratios) were 2.12 (95 % CI 1.17, 3.84) and 2.50 (95 % CI 1.20, 5.20)
respectively. However, the fever-associated ASD risk was attenuated among mothers
who reported taking antipyretic medications (OR = 1.30, 95 % CI 0.59, 2.84), but 
remained elevated for those who did not (OR = 2.55, 95 % CI 1.30, 4.99).

PMID: 22562209  [PubMed - as supplied by publisher]
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  • 10) J Neurosci. 2012 May 9;32(19):6525-41.

    Reduced excitatory neurotransmission and mild autism-relevant phenotypes in adolescent shank3 null mutant mice.

    Yang M, Bozdagi O, Scattoni ML, Wöhr M, Roullet FI, Katz AM, Abrams DN, Kalikhman
D, Simon H, Woldeyohannes L, Zhang JY, Harris MJ, Saxena R, Silverman JL, Buxbaum
JD, Crawley JN.

Laboratory of Behavioral Neuroscience, National Institute of Mental Health,
Bethesda, Maryland 20892, and Seaver Autism Center for Research and Treatment,
and Laboratory of Molecular Neuropsychiatry, Department of Psychiatry, Mount
Sinai School of Medicine, New York, New York 10029.

Mutations in the synaptic scaffolding protein gene SHANK3 are strongly implicated
in autism and Phelan-McDermid 22q13 deletion syndrome. The precise location of
the mutation within the Shank3 gene is key to its phenotypic outcomes. Here, we
report the physiological and behavioral consequences of null and heterozygous
mutations in the ankyrin repeat domain in Shank3 mice. Both homozygous and
heterozygous mice showed reduced glutamatergic transmission and long-term
potentiation in the hippocampus with more severe deficits detected in the
homozygous mice. Three independent cohorts were evaluated for magnitude and
replicability of behavioral endophenotypes relevant to autism and Phelan-McDermid
syndrome. Mild social impairments were detected, primarily in juveniles during
reciprocal interactions, while all genotypes displayed normal adult sociability
on the three-chambered task. Impaired novel object recognition and rotarod
performance were consistent across cohorts of null mutants. Repetitive
self-grooming, reduced ultrasonic vocalizations, and deficits in reversal of
water maze learning were detected only in some cohorts, emphasizing the
importance of replication analyses. These results demonstrate the exquisite
specificity of deletions in discrete domains within the Shank3 gene in
determining severity of symptoms.

PMID: 22573675  [PubMed - in process]
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  • 11) Dev Neurosci. 2012 May 8. [Epub ahead of print]

    Modeling of Autism Genetic Variations in Mice: Focusing on Synaptic and Microcircuit Dysfunctions.

    Qiu S, Aldinger KA, Levitt P.

Department of Cell and Neurobiology, Zilkha Neurogenetic Institute, Keck School
of Medicine, University of Southern California, Los Angeles, Calif., USA.

Autism spectrum disorders (ASD) are heterogeneous neurodevelopmental disorders
that are characterized by deficits in social interaction, verbal and nonverbal
communication, and restrictive interests and repetitive behaviors. While human
genetic studies have revealed marked heritability in ASD, it has been challenging
to translate this genetic risk into a biological mechanism that influences brain 
development relevant to the disorder phenotypes. This is partly due to the
complex genetic architecture of ASD, which involves de novo gene mutations,
genomic abnormalities, and common genetic variants. Rather than trying to
reconstitute the clinical disorder, using genetic model animals to examine
specific features of core ASD pathophysiology offers unique opportunities for
refining our understanding of neurodevelopmental mechanisms in ASD. A variety of 
ASD-relevant phenotypes can now be investigated in rodents, including stereotyped
and repetitive behaviors, and deficits in social interaction and communication.
In this review, we focus on several prevailing mouse models and discuss how
studies have advanced our understanding of synaptic mechanisms that may underlie 
ASD pathophysiology. Although synaptic perturbations are not the only alterations
relevant for ASD, we reason that understanding the synaptic underpinnings of ASD 
using mouse models may provide mechanistic insights into its etiology and lead to
novel therapeutic and interventional strategies.

Copyright © 2012 S. Karger AG, Basel.

PMID: 22572629  [PubMed - as supplied by publisher]
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  • 12) Am J Hum Genet. 2012 May 9. [Epub ahead of print]

    Scan-Statistic Approach Identifies Clusters of Rare Disease Variants in LRP2, a Gene Linked and Associated with Autism Spectrum Disorders, in Three Datasets.

    Ionita-Laza I, Makarov V; the ARRA Autism Sequencing Consortium, Buxbaum JD.

Department of Biostatistics, Columbia University, New York, NY 10032, USA.

Cluster-detection approaches, commonly used in epidemiology and astronomy, can be
applied in the context of genetic sequence data for the identification of genetic
regions significantly enriched with rare disease-risk variants (DRVs). Unlike
existing association tests for sequence data, the goal of cluster-detection
methods is to localize significant disease mutation clusters within a gene or
region of interest. Here, we focus on a chromosome 2q replicated linkage region
that is associated with autism spectrum disorder (ASD) and that has been
sequenced in three independent datasets. We found that variants in one gene,
LRP2, residing on 2q are associated with ASD in two datasets (the combined
variable-threshold-test p value is 1.2 × 10(-5)). Using a cluster-detection
method, we show that in the discovery and replication datasets, variants
associated with ASD cluster preponderantly in 25 kb windows (adjusted p values
are p(1) = 0.003 and p(2) = 0.002), and the two windows are highly overlapping.
Furthermore, for the third dataset, a 25 kb region similar to those in the other 
two datasets shows significant evidence of enrichment of rare DRVs. The region
implicated by all three studies is involved in ligand binding, suggesting that
subtle alterations in either LRP2 expression or LRP2 primary sequence modulate
the uptake of LRP2 ligands. BMP4 is a ligand of particular interest given its
role in forebrain development, and modest changes in BMP4 binding, which binds to
LRP2 near the mutation cluster, might subtly affect development and could lead to
autism-associated phenotypes.

Copyright © 2012 The American Society of Human Genetics. Published by Elsevier
Inc. All rights reserved.

PMID: 22578327  [PubMed - as supplied by publisher]
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  • 13) J Clin Endocrinol Metab. 2012 May 10. [Epub ahead of print]

    ZNF764 Haploinsufficiency May Explain Partial Glucocorticoid, Androgen, and Thyroid Hormone Resistance Associated with 16p11.2 Microdeletion.

    Kino T, Pavlatou MG, Moraitis AG, Nemery RL, Raygada M, Stratakis CA.

Unit on Molecular Hormone Action (T.K., M.G.P.), Section on Reproductive
Endocrinology (A.G.M.), Program in Reproductive and Adult Endocrinology, Section 
on Endocrinology and Genetics (A.G.M., M.R., C.A.S.), Program on Developmental
Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child
Health and Human Development, National Institutes of Health, Bethesda, Maryland
20892; and Department of Pediatric Endocrinology (R.L.N.), Joe DiMaggio
Children's Hospital, Hollywood, Florida 33021.

Context:Nuclear hormone receptors exert their transcriptional effects through
shared cofactor molecules; thus, defects in such intermediate proteins may be
associated with multiple hormone resistance. Microdeletion of small chromosomal
segments results in hereditary or sporadic diseases by affecting expression of
residing genes.Objectives:We describe a 7-yr-old boy with partial resistance to
glucocorticoids, thyroid hormones, and possibly androgens. He was diagnosed as
being in the autism spectrum disorder and had developmental delay and several
facial morphological manifestations. We explored genes responsible for multiple
hormone resistance of this case.Results:We found in this patient an approximately
1.1-Mb heterozygous 16p11.2 microdeletion, which included an approximately 500-kb
unique deletion along with the common, previously reported approximately 600-kb
16p11.2 microdeletion. The small interfering RNA-based screening revealed that
knockdown of ZNF764, which is located in the deleted segment unique to our case, 
significantly reduced glucocorticoid-, androgen-, and thyroid hormone-induced
transcriptional activity of their responsive genes in HeLa cells, whereas its
overexpression enhanced their transcriptional activity. The activities of the
estrogen and progesterone receptors, cAMP response element-binding protein, and
p53 were not affected in these cells. ZNF764 (zinc finger protein 764) expression
was reduced in the patient's peripheral blood mononuclear cells, whereas
exogenously supplemented ZNF764 recovered responsiveness to glucocorticoids in
the patient's Epstein-Barr virus-transformed lymphocytes. The effect of ZNF764 on
the glucocorticoid receptor transcriptional activity was mediated through
cooperation with a general nuclear hormone receptor coactivator, transcriptional 
intermediary factor 1.Conclusions:ZNF764 haploinsufficiency caused by
microdeletion may be responsible for the partial multiple hormone resistance
observed in our patient. ZNF764 appears to be involved in glucocorticoid,
androgen, and thyroid hormone action.

PMID: 22577170  [PubMed - as supplied by publisher]
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  • 14) J Autism Dev Disord. 2012 May 11. [Epub ahead of print]

    Social Responsiveness and Competence in Prader-Willi Syndrome: Direct Comparison to Autism Spectrum Disorder.

    Dimitropoulos A, Ho A, Feldman B.

Department of Psychological Sciences, Case Western Reserve University, 11220
Bellflower Road, MTHM 109, Cleveland, OH, 44106-7123, USA, axd116@case.edu.

Prader-Willi syndrome (PWS), a neurodevelopmental disorder primarily
characterized by hyperphagia and food preoccupations, is caused by the absence of
expression of the paternally active genes in the proximal arm of chromosome 15.
Although maladaptive behavior and the cognitive profile in PWS have been well
characterized, social functioning has only more recently been systematically
examined. Findings to date indicate the social impairment exhibited may reflect
specific difficulty interpreting and using social information effectively. In
addition, evidence suggests that there is an increased risk of social deficits in
people with the maternally-derived uniparental disomy (mUPD) subtype of PWS in
comparison to those with 15q11-13 paternal deletion (DEL). Using the Social
Responsiveness Scale (SRS) and the Social Competence Inventory, our goal was to
compare social functioning in PWS to individuals with autism spectrum disorder
(ASD). Participants with mUPD scored similarly to the ASD group across most SRS
domains. All groups had difficulty with social competence, although the DEL group
scored highest on prosocial behavior. Findings suggest further characterization
of social behavior in PWS is necessary to aid in advancing the understanding of
the contributions of genes in the 15q11-13 critical region to ASD susceptibility,
particularly with respect to the overexpression of maternally expressed genes in 
this region, as well as aiding in awareness and development/implementation of
interventions.

PMID: 22576167  [PubMed - as supplied by publisher]
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  • 15) J Child Psychol Psychiatry. 2012 May 10. doi: 10.1111/j.1469-7610.2012.02558.x. [Epub ahead of print]

    Latent class analysis of early developmental trajectory in baby siblings of children with autism.

    Landa RJ, Gross AL, Stuart EA, Bauman M.

Center for Autism and Related Disorders, Kennedy Krieger Institute, Psychiatry
and Behavioral Sciences, The Johns Hopkins University School of Medicine,
Baltimore, MD, USA Mental Health, Johns Hopkins Bloomberg School of Public
Health, Baltimore, MD, USA Biostatistics, Johns Hopkins Bloomberg School of
Public Health, Baltimore, MD, USA Lurie Center/LADDERS, Mass General Hospital for
Children, Neurology, Harvard Medical School, Baltimore, MD, USA.

Background:  Siblings of children with autism (sibs-A) are at increased genetic
risk for autism spectrum disorders (ASD) and milder impairments. To elucidate
diversity and contour of early developmental trajectories exhibited by sibs-A,
regardless of diagnostic classification, latent class modeling was used.
Methods:  Sibs-A (N = 204) were assessed with the Mullen Scales of Early Learning
from age 6 to 36 months. Mullen T scores served as dependent variables. Outcome
classifications at age 36 months included: ASD (N = 52); non-ASD
social/communication delay (broader autism phenotype; BAP; N = 31); and
unaffected (N = 121). Child-specific patterns of performance were studied using
latent class growth analysis. Latent class membership was then related to
diagnostic outcome through estimation of within-class proportions of children
assigned to each diagnostic classification. Results:  A 4-class model was
favored. Class 1 represented accelerated development and consisted of 25.7% of
the sample, primarily unaffected children. Class 2 (40.0% of the sample), was
characterized by normative development with above-average nonverbal cognitive
outcome. Class 3 (22.3% of the sample) was characterized by receptive language,
and gross and fine motor delay. Class 4 (12.0% of the sample), was characterized 
by widespread delayed skill acquisition, reflected by declining trajectories.
Children with an outcome diagnosis of ASD were spread across Classes 2, 3, and 4.
Conclusions:  Results support a category of ASD that involves slowing in early
non-social development. Receptive language and motor development is vulnerable to
early delay in sibs-A with and without ASD outcomes. Non-ASD sibs-A are largely
distributed across classes depicting average or accelerated development.
Developmental trajectories of motor, language, and cognition appear independent
of communication and social delays in non-ASD sibs-A.

© 2012 The Authors. Journal of Child Psychology and Psychiatry © 2012 Association
for Child and Adolescent Mental Health.

PMID: 22574686  [PubMed - as supplied by publisher]
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  • 16) J Dev Behav Pediatr. 2012 May 10. [Epub ahead of print]

    Retention of Autism Spectrum Diagnoses by Community Professionals: Findings From the Autism and Developmental Disabilities Monitoring Network, 2000 and 2006.

    Wiggins LD, Baio J, Schieve L, Lee LC, Nicholas J, Rice CE.

From the *National Center on Birth Defects and Developmental Disabilities,
Centers for Disease Control and Prevention, Atlanta, GA; †Department of
Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD;
‡Department of Medicine, Medical University of South Carolina, Charleston, SC.

OBJECTIVE: Past research is inconsistent in the stability of autism spectrum
disorder (ASD) diagnoses. The authors therefore sought to examine the proportion 
of children identified from a population-based surveillance system that had a
change in classification from ASD to non-ASD and factors associated with such
changes. METHODS: Children with a documented age of first ASD diagnosis noted in 
surveillance records by a community professional (n = 1392) were identified from 
the Autism and Developmental Disabilities Monitoring Network. Children were
considered to have a change in classification if an ASD was excluded after the
age of first recorded ASD diagnosis. Child and surveillance factors were entered 
into a multivariable regression model to determine factors associated with
diagnostic change. RESULTS: Only 4% of our sample had a change in classification 
from ASD to non-ASD noted in evaluation records. Factors associated with change
in classification from ASD to non-ASD were timing of first ASD diagnosis at 30
months or younger, onset other than developmental regression, presence of
specific developmental delays, and participation in a special needs classroom
other than autism at 8 years of age. CONCLUSIONS: Our results found that children
with ASDs are likely to retain an ASD diagnosis, which underscores the need for
continued services. Children diagnosed at 30 months or younger are more likely to
experience a change in classification from ASD to non-ASD than children diagnosed
at 31 months or older, suggesting earlier identification of ASD symptoms may be
associated with response to intervention efforts or increased likelihood for
overdiagnosis.

PMID: 22580734  [PubMed - as supplied by publisher]
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  • 17) Biol Psychiatry. 2012 May 12. [Epub ahead of print]

    Understanding Interpersonal Function in Psychiatric Illness Through Multiplayer Economic Games.

    King-Casas B, Chiu PH.

Virginia Tech Carilion Research Institute, Roanoke, Virginia; Department of
Psychiatry, Virginia Tech Carilion School of Medicine, Roanoke, Virginia;
Department of Psychology, Virginia Tech, Blacksburg, Virginia; Virginia Tech-Wake
Forest School of Biomedical Engineering and Sciences, Blacksburg, Virginia;
Research Service Line, Salem Veterans Affairs Medical Center, Salem, Virginia.

Interpersonal factors play significant roles in the onset, maintenance, and
remission of psychiatric conditions. In the current major diagnostic
classification systems for psychiatric disorders, some conditions are defined by 
the presence of impairments in social interaction or maintaining interpersonal
relationships; these include autism, social phobia, and the personality
disorders. Other psychopathologies confer significant difficulties in the social 
domain, including major depression, posttraumatic stress disorder, and psychotic 
disorders. Still other mental health conditions, including substance abuse and
eating disorders, seem to be exacerbated or triggered in part by the influence of
social peers. For each of these and other psychiatric conditions, the extent and 
quality of social support is a strong determinant of outcome such that high
social support predicts symptom improvement and remission. Despite the central
role of interpersonal factors in psychiatric illness, the neurobiology of social 
impairments remains largely unexplored, in part due to difficulties eliciting and
quantifying interpersonal processes in a parametric manner. Recent advances in
functional neuroimaging, combined with multiplayer exchange games drawn from
behavioral economics, and computational/quantitative approaches more generally,
provide a fitting paradigm within which to study interpersonal function and
dysfunction in psychiatric conditions. In this review, we outline the importance 
of interpersonal factors in psychiatric illness and discuss ways in which
neuroeconomics provides a tractable framework within which to examine the
neurobiology of social dysfunction.

Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All
rights reserved.

PMID: 22579510  [PubMed - as supplied by publisher]
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  • 18) Cell. 2012 May 11;149(4):899-911.

    Species-Dependent Posttranscriptional Regulation of NOS1 by FMRP in the Developing Cerebral Cortex.

    Kwan KY, Lam MM, Johnson MB, Dube U, Shim S, Rašin MR, Sousa AM, Fertuzinhos S,
Chen JG, Arellano JI, Chan DW, Pletikos M, Vasung L, Rowitch DH, Huang EJ,
Schwartz ML, Willemsen R, Oostra BA, Rakic P, Heffer M, Kostović I, Judaš M,
Sestan N.

Department of Neurobiology and Kavli Institute for Neuroscience, Yale University 
School of Medicine, New Haven, CT 06510, USA.

Fragile X syndrome (FXS), the leading monogenic cause of intellectual disability 
and autism, results from loss of function of the RNA-binding protein FMRP. Here, 
we show that FMRP regulates translation of neuronal nitric oxide synthase 1
(NOS1) in the developing human neocortex. Whereas NOS1 mRNA is widely expressed, 
NOS1 protein is transiently coexpressed with FMRP during early synaptogenesis in 
layer- and region-specific pyramidal neurons. These include midfetal layer 5
subcortically projecting neurons arranged into alternating columns in the
prospective Broca's area and orofacial motor cortex. Human NOS1 translation is
activated by FMRP via interactions with coding region binding motifs absent from 
mouse Nos1 mRNA, which is expressed in mouse pyramidal neurons, but not
efficiently translated. Correspondingly, neocortical NOS1 protein levels are
severely reduced in developing human FXS cases, but not FMRP-deficient mice.
Thus, alterations in FMRP posttranscriptional regulation of NOS1 in developing
neocortical circuits may contribute to cognitive dysfunction in FXS.

Copyright © 2012 Elsevier Inc. All rights reserved.

PMID: 22579290  [PubMed - in process]
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  • 19) Annu Rev Biomed Eng. 2012 May 9. [Epub ahead of print]

    Robots for Use in Autism Research.

    Scassellati B, Admoni H, Matarić M.

Department of Computer Science, Yale University, New Haven, CT 06520; email:
scaz@cs.yale.edu.

Autism spectrum disorders are a group of lifelong disabilities that affect
people's ability to communicate and to understand social cues. Research into
applying robots as therapy tools has shown that robots seem to improve engagement
and elicit novel social behaviors from people (particularly children and
teenagers) with autism. Robot therapy for autism has been explored as one of the 
first application domains in the field of socially assistive robotics (SAR),
which aims to develop robots that assist people with special needs through social
interactions. In this review, we discuss the past decade's work in SAR systems
designed for autism therapy by analyzing robot design decisions, human-robot
interactions, and system evaluations. We conclude by discussing challenges and
future trends for this young but rapidly developing research area. Expected final
online publication date for the Annual Review of Biomedical Engineering Volume 14
is July 15, 2012. Please see http://www.annualreviews.org/catalog/pubdates.aspx
for revised estimates.

PMID: 22577778  [PubMed - as supplied by publisher]
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