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Article ; Online: The genetics of autism: key issues, recent findings, and clinical implications.

El-Fishawy, Paul / State, Matthew W

The Psychiatric clinics of North America

2010 Volume 33, Issue 1, Page(s) 83–105

Abstract: Autism spectrum disorders (ASDs) are highly heritable. Gene discovery promises to help illuminate the pathophysiology of these syndromes, yielding opportunities for the development of novel treatments and understanding of their natural history. Although ... ...

Abstract	Autism spectrum disorders (ASDs) are highly heritable. Gene discovery promises to help illuminate the pathophysiology of these syndromes, yielding opportunities for the development of novel treatments and understanding of their natural history. Although the underlying genetic architecture of ASDs is not yet known, the literature demonstrates that it is not a monogenic disorder with mendelian inheritance, rather a group of complex genetic syndromes with risk deriving from genetic variations in multiple genes. This article reviews the origins of the common versus rare variant debate, highlights recent findings in the field, and addresses the clinical implications of common and rare variant discoveries.
MeSH term(s)	Abnormalities, Multiple ; Alleles ; Autistic Disorder/epidemiology ; Autistic Disorder/genetics ; Gene Expression/genetics ; Genetic Association Studies ; Genetic Variation/genetics ; Humans ; Karyotyping ; Point Mutation/genetics ; Social Behavior
Language	English
Publishing date	2010-02-14
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	431518-2
ISSN	1558-3147 ; 0193-953X
ISSN (online)	1558-3147
ISSN	0193-953X
DOI	10.1016/j.psc.2009.12.002
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Article ; Online: Homozygous loss of DIAPH1 is a novel cause of microcephaly in humans.

European journal of human genetics : EJHG

2014 Volume 23, Issue 2, Page(s) 165–172

Abstract: The combination of family-based linkage analysis with high-throughput sequencing is a powerful approach to identifying rare genetic variants that contribute to genetically heterogeneous syndromes. Using parametric multipoint linkage analysis and whole ... ...

Abstract	The combination of family-based linkage analysis with high-throughput sequencing is a powerful approach to identifying rare genetic variants that contribute to genetically heterogeneous syndromes. Using parametric multipoint linkage analysis and whole exome sequencing, we have identified a gene responsible for microcephaly (MCP), severe visual impairment, intellectual disability, and short stature through the mapping of a homozygous nonsense alteration in a multiply-affected consanguineous family. This gene, DIAPH1, encodes the mammalian Diaphanous-related formin (mDia1), a member of the diaphanous-related formin family of Rho effector proteins. Upon the activation of GTP-bound Rho, mDia1 generates linear actin filaments in the maintenance of polarity during adhesion, migration, and division in immune cells and neuroepithelial cells, and in driving tangential migration of cortical interneurons in the rodent. Here, we show that patients with a homozygous nonsense DIAPH1 alteration (p.Gln778*) have MCP as well as reduced height and weight. diap1 (mDia1 knockout (KO))-deficient mice have grossly normal body and brain size. However, our histological analysis of diap1 KO mouse coronal brain sections at early and postnatal stages shows unilateral ventricular enlargement, indicating that this mutant mouse shows both important similarities as well as differences with human pathology. We also found that mDia1 protein is expressed in human neuronal precursor cells during mitotic cell division and has a major impact in the regulation of spindle formation and cell division.
MeSH term(s)	Adaptor Proteins, Signal Transducing/genetics ; Adolescent ; Adult ; Animals ; Brain/growth & development ; Brain/metabolism ; Brain/pathology ; Carrier Proteins/genetics ; Carrier Proteins/metabolism ; Cell Line ; Child ; Child, Preschool ; Codon, Nonsense ; Female ; Formins ; Homozygote ; Humans ; Infant ; Male ; Mice ; Microcephaly/diagnosis ; Microcephaly/genetics ; Pedigree
Chemical Substances	Adaptor Proteins, Signal Transducing ; Carrier Proteins ; Codon, Nonsense ; DIAPH1 protein, human ; Diap1 protein, mouse ; Formins
Language	English
Publishing date	2014-04-30
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1141470-4
ISSN	1476-5438 ; 1018-4813
ISSN (online)	1476-5438
ISSN	1018-4813
DOI	10.1038/ejhg.2014.82
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Article ; Online: Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy.

Science (New York, N.Y.)

2012 Volume 338, Issue 6105, Page(s) 394–397

Abstract: Autism spectrum disorders are a genetically heterogeneous constellation of syndromes characterized by impairments in reciprocal social interaction. Available somatic treatments have limited efficacy. We have identified inactivating mutations in the gene ... ...

Abstract	Autism spectrum disorders are a genetically heterogeneous constellation of syndromes characterized by impairments in reciprocal social interaction. Available somatic treatments have limited efficacy. We have identified inactivating mutations in the gene BCKDK (Branched Chain Ketoacid Dehydrogenase Kinase) in consanguineous families with autism, epilepsy, and intellectual disability. The encoded protein is responsible for phosphorylation-mediated inactivation of the E1α subunit of branched-chain ketoacid dehydrogenase (BCKDH). Patients with homozygous BCKDK mutations display reductions in BCKDK messenger RNA and protein, E1α phosphorylation, and plasma branched-chain amino acids. Bckdk knockout mice show abnormal brain amino acid profiles and neurobehavioral deficits that respond to dietary supplementation. Thus, autism presenting with intellectual disability and epilepsy caused by BCKDK mutations represents a potentially treatable syndrome.
MeSH term(s)	3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)/administration & dosage ; 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)/deficiency ; 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)/genetics ; Adolescent ; Amino Acids, Branched-Chain/administration & dosage ; Amino Acids, Branched-Chain/blood ; Amino Acids, Branched-Chain/deficiency ; Animals ; Arginine/genetics ; Autistic Disorder/diet therapy ; Autistic Disorder/enzymology ; Autistic Disorder/genetics ; Base Sequence ; Brain/metabolism ; Child ; Child, Preschool ; Diet ; Epilepsy/diet therapy ; Epilepsy/enzymology ; Epilepsy/genetics ; Female ; Homozygote ; Humans ; Intellectual Disability/diet therapy ; Intellectual Disability/enzymology ; Intellectual Disability/genetics ; Male ; Mice ; Mice, Knockout ; Molecular Sequence Data ; Mutation ; Pedigree ; Phosphorylation ; Protein Folding ; Protein Structure, Tertiary ; RNA, Messenger/metabolism ; Young Adult
Chemical Substances	Amino Acids, Branched-Chain ; RNA, Messenger ; Arginine (94ZLA3W45F) ; 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide) (EC 1.2.4.4)
Language	English
Publishing date	2012-09-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	128410-1
ISSN	1095-9203 ; 0036-8075
ISSN (online)	1095-9203
ISSN	0036-8075
DOI	10.1126/science.1224631
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Article ; Online: De novo mutations revealed by whole-exome sequencing are strongly associated with autism.

Sanders, Stephan J / Murtha, Michael T / Gupta, Abha R / Murdoch, John D / Raubeson, Melanie J / Willsey, A Jeremy / Ercan-Sencicek, A Gulhan / DiLullo, Nicholas M / Parikshak, Neelroop N / Stein, Jason L / Walker, Michael F / Ober, Gordon T / Teran, Nicole A / Song, Youeun / El-Fishawy, Paul / Murtha, Ryan C / Choi, Murim / Overton, John D / Bjornson, Robert D /

Carriero, Nicholas J / Meyer, Kyle A / Bilguvar, Kaya / Mane, Shrikant M / Sestan, Nenad / Lifton, Richard P / Günel, Murat / Roeder, Kathryn / Geschwind, Daniel H / Devlin, Bernie / State, Matthew W

Nature

2012 Volume 485, Issue 7397, Page(s) 237–241

Abstract: Multiple studies have confirmed the contribution of rare de novo copy number variations to the risk for autism spectrum disorders. But whereas de novo single nucleotide variants have been identified in affected individuals, their contribution to risk has ...

Abstract	Multiple studies have confirmed the contribution of rare de novo copy number variations to the risk for autism spectrum disorders. But whereas de novo single nucleotide variants have been identified in affected individuals, their contribution to risk has yet to be clarified. Specifically, the frequency and distribution of these mutations have not been well characterized in matched unaffected controls, and such data are vital to the interpretation of de novo coding mutations observed in probands. Here we show, using whole-exome sequencing of 928 individuals, including 200 phenotypically discordant sibling pairs, that highly disruptive (nonsense and splice-site) de novo mutations in brain-expressed genes are associated with autism spectrum disorders and carry large effects. On the basis of mutation rates in unaffected individuals, we demonstrate that multiple independent de novo single nucleotide variants in the same gene among unrelated probands reliably identifies risk alleles, providing a clear path forward for gene discovery. Among a total of 279 identified de novo coding mutations, there is a single instance in probands, and none in siblings, in which two independent nonsense variants disrupt the same gene, SCN2A (sodium channel, voltage-gated, type II, α subunit), a result that is highly unlikely by chance.
MeSH term(s)	Alleles ; Autistic Disorder/genetics ; Codon, Nonsense/genetics ; Exome/genetics ; Exons/genetics ; Genetic Heterogeneity ; Genetic Predisposition to Disease/genetics ; Humans ; Mutation/genetics ; NAV1.2 Voltage-Gated Sodium Channel ; Nerve Tissue Proteins/genetics ; RNA Splice Sites/genetics ; Siblings ; Sodium Channels/genetics
Chemical Substances	Codon, Nonsense ; NAV1.2 Voltage-Gated Sodium Channel ; Nerve Tissue Proteins ; RNA Splice Sites ; SCN2A protein, human ; Sodium Channels
Language	English
Publishing date	2012-04-04
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	120714-3
ISSN	1476-4687 ; 0028-0836
ISSN (online)	1476-4687
ISSN	0028-0836
DOI	10.1038/nature10945
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Article: The growth of cutaneous T-cell lymphoma is stimulated by immature dendritic cells.

Berger, Carole L / Hanlon, Douglas / Kanada, Daniel / Dhodapkar, Madhav / Lombillo, Vivian / Wang, Nianci / Christensen, Inger / Howe, Gregory / Crouch, Jill / El-Fishawy, Paul / Edelson, Richard

Blood

2002 Volume 99, Issue 8, Page(s) 2929–2939

Abstract: In the initial stage of cutaneous T-cell lymphoma (CTCL), proliferating CTCL cells are concentrated in the epidermis in close association with an immature dendritic cell (DC), the Langerhans cell. Because long-term in vitro culture of CTCL cells has ... ...

Abstract	In the initial stage of cutaneous T-cell lymphoma (CTCL), proliferating CTCL cells are concentrated in the epidermis in close association with an immature dendritic cell (DC), the Langerhans cell. Because long-term in vitro culture of CTCL cells has proven difficult, the in vivo association with the major antigen-presenting cell (APC) of the epidermis has been postulated to play a role in directly stimulating the clonal T-cell proliferation. We report that CTCL cells can be reproducibly grown in culture for 3 months when cocultured with immature DCs. CTCL cells retain the phenotype and genotype of the initial malignant clone, whereas the APCs are a mixture of immature and mature DCs. CTCL cell and DC survival was dependent on direct membrane contact. Growth was inhibited by antibodies that bound to the T-cell receptor (TCR) or interfered with the interaction of CD40 with its ligand on the CTCL cell. Addition of antibody to CD3 or the clonotypic TCR caused rapid CTCL cell apoptosis followed by engulfment by avidly phagocytic immature DCs and subsequent DC maturation. The opportunity to study CTCL cells and immature DCs for prolonged periods will facilitate studies of tumor cell biology and will allow investigation of the intriguing hypothesis that CTCL cell growth is driven through TCR recognition of class II-presented self-peptides. In addition, the culture of CTCL cells will permit evaluation of therapies in vitro before clinical intervention, thereby improving safety and efficacy.
MeSH term(s)	Antigen Presentation/immunology ; Antigens, Neoplasm/immunology ; Apoptosis ; CD3 Complex/physiology ; Cell Communication/physiology ; Cell Differentiation/drug effects ; Cell Division/physiology ; Coculture Techniques ; Cytokines/metabolism ; Cytokines/pharmacology ; Dendritic Cells/cytology ; Dendritic Cells/immunology ; Dendritic Cells/physiology ; HLA Antigens/immunology ; HLA Antigens/metabolism ; Humans ; Lymphoma, T-Cell, Cutaneous/immunology ; Lymphoma, T-Cell, Cutaneous/pathology ; Phagocytosis
Chemical Substances	Antigens, Neoplasm ; CD3 Complex ; Cytokines ; HLA Antigens
Language	English
Publishing date	2002-04-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
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Article: Mutations in BCKD-kinase Lead to a Potentially Treatable Form of Autism with Epilepsy

Science. 2012 Oct. 19, v. 338, no. 6105

2012

Abstract: A Fine Balance Intellectual and neurological disabilities can arise from diverse developmental aberrations. Novarino et al. (p. 394, published online 6 September; see the Perspective by Beaudet) have now determined the genetic basis for one such disorder ...

Abstract	A Fine Balance Intellectual and neurological disabilities can arise from diverse developmental aberrations. Novarino et al. (p. 394, published online 6 September; see the Perspective by Beaudet) have now determined the genetic basis for one such disorder for a small group of patients. Exome sequencing led to identification of mutations in a kinase BCKDK (Branched Chain Ketoacid Dehydrogenase Kinase) that regulates metabolism of branched-chain amino acids such as valine, leucine, and isoleucine. Mice with homozygous mutations in the BCKDK gene showed developmental and neurological abnormalities resembling those in certain mouse autism models. Analysis of transport mechanisms responsible for carrying amino acids across the blood-brain barrier revealed competition between the branched-chain amino acids and large neutral amino acids. Nutritional supplementation with extra branched-chain amino acids in the diet of mice carrying homozygous mutations in the BCKDK gene normalized their phenotype.
Keywords	3-methyl-2-oxobutanoate dehydrogenase (lipoamide) ; autism ; blood-brain barrier ; dietary supplements ; epilepsy ; genes ; homozygosity ; isoleucine ; leucine ; metabolism ; mice ; models ; mutation ; patients ; phenotype ; sequence analysis ; valine
Language	English
Dates of publication	2012-1019
Size	p. 394-397.
Publishing place	American Association for the Advancement of Science
Document type	Article
ZDB-ID	128410-1
ISSN	1095-9203 ; 0036-8075
ISSN (online)	1095-9203
ISSN	0036-8075
DOI	10.1126/science.1224631
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: The genetics of autism: key issues, recent findings, and clinical implications.

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Article ; Online: Homozygous loss of DIAPH1 is a novel cause of microcephaly in humans.

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Article ; Online: Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy.

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Article ; Online: De novo mutations revealed by whole-exome sequencing are strongly associated with autism.

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Article: The growth of cutaneous T-cell lymphoma is stimulated by immature dendritic cells.

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Article: Mutations in BCKD-kinase Lead to a Potentially Treatable Form of Autism with Epilepsy

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