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PMID: 18621663 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Identifying autism loci and genes by tracing recent shared ancestry.

Science (New York, N.Y.) ·Vol. 321 ·No. 5886 ·2008-07-11 ·Pages 218-23

Morrow EM, Yoo SY, Flavell SW, Kim TK, Lin Y, Hill RS, Mukaddes NM, Balkhy S, Gascon G, Hashmi A, Al-Saad S, Ware J, Joseph RM, Greenblatt R, Gleason D, Ertelt JA, Apse KA, Bodell A, Partlow JN, Barry B, Yao H, Markianos K, Ferland RJ, Greenberg ME, Walsh CA

Abstract

To find inherited causes of autism-spectrum disorders, we studied families in which parents share ancestors, enhancing the role of inherited factors. We mapped several loci, some containing large, inherited, homozygous deletions that are likely mutations. The largest deletions implicated genes, including PCDH10 (protocadherin 10) and DIA1 (deleted in autism1, or c3orf58), whose level of expression changes in response to neuronal activity, a marker of genes involved in synaptic changes that underlie learning. A subset of genes, including NHE9 (Na+/H+ exchanger 9), showed additional potential mutations in patients with unrelated parents. Our findings highlight the utility of "homozygosity mapping" in heterogeneous disorders like autism but also suggest that defective regulation of gene expression after neural activity may be a mechanism common to seemingly diverse autism mutations.

MeSH Terms
Adaptor Proteins, Signal Transducing/genetics Animals Autistic Disorder/genetics,physiopathology Brain/metabolism Cadherins/genetics Chromosome Mapping Consanguinity Female Formins Gene Deletion Gene Dosage Gene Expression Regulation Genes, Recessive Genetic Predisposition to Disease Homozygote Humans Lod Score Male Mutation Neurons/physiology Oligonucleotide Array Sequence Analysis Pedigree Polymorphism, Single Nucleotide Protocadherins Rats Sodium-Hydrogen Exchangers/genetics Transcription Factors/genetics,metabolism
Chemicals
Adaptor Proteins, Signal Transducing Cadherins DIAPH1 protein, human Formins PCDH10 protein, human Protocadherins SLC9A9 protein, human Sodium-Hydrogen Exchangers Transcription Factors
Authors & Affiliations
25 authors, click to expand affiliations / ORCID
Morrow Eric M
Division of Genetics, Children's Hospital Boston and Harvard Medical School, Boston, MA 02115, USA.
Yoo Seung-Yun
Flavell Steven W
Kim Tae-Kyung
Lin Yingxi
Hill Robert Sean
Mukaddes Nahit M
Balkhy Soher
Gascon Generoso
Hashmi Asif
Al-Saad Samira
Ware Janice
Joseph Robert M
Greenblatt Rachel
Gleason Danielle
Ertelt Julia A
Apse Kira A
Bodell Adria
Partlow Jennifer N
Barry Brenda
Yao Hui
Markianos Kyriacos
Ferland Russell J
Greenberg Michael E
Walsh Christopher A
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Article Info
Journal
Science (New York, N.Y.)
Abbr.
Science
ISSN
1095-9203
DOI
10.1126/science.1157657
Published
2008-07-11
Pages
218-23
Language
English
Region
United States
NLM ID
0404511
PMCID
PMC2586171
Subset
IM
Grants
NIMH NIH HHS · MH64547 · United States
NIMH NIH HHS · R01 MH083565 · United States
NIMH NIH HHS · K01 MH071801-04 · United States
NINDS NIH HHS · R01 NS048276-04 · United States
NINDS NIH HHS · R01 NS048276-01 · United States
NICHD NIH HHS · 5P30HD018655-26 · United States
Howard Hughes Medical Institute · United States
NINDS NIH HHS · R01 NS048276-03 · United States
NIMH NIH HHS · 1K01MH71801 · United States
NIMH NIH HHS · 1R01 MH083565 · United States
NIMH NIH HHS · K23 MH080954-01 · United States
NIMH NIH HHS · 1K23MH080954-01 · United States
NINDS NIH HHS · R01 NS048276 · United States
NIMH NIH HHS · K01 MH071801 · United States
NIMH NIH HHS · K23 MH080954 · United States
NINDS NIH HHS · R01 NS048276-02 · United States
NIMH NIH HHS · K01 MH071801-05 · United States
NINDS NIH HHS · 5R01NS048276-05 · United States
NHGRI NIH HHS · N01-HG-65403 · United States
NINDS NIH HHS · R01 NS048276-05 · United States
Corrections
ErratumIn
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CommentIn
PMID: 18621658
CommentIn
PMID: 19131610
External Links
PubMed source DOI: 10.1126/science.1157657 PMC Full Text View journal details
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