Document Detail

Recurrent distal 7q11.23 deletion including HIP1 and YWHAG identified in patients with intellectual disabilities, epilepsy, and neurobehavioral problems.
MedLine Citation:
PMID:  21109226     Owner:  NLM     Status:  MEDLINE    
We report 26 individuals from ten unrelated families who exhibit variable expression and/or incomplete penetrance of epilepsy, learning difficulties, intellectual disabilities, and/or neurobehavioral abnormalities as a result of a heterozygous microdeletion distally adjacent to the Williams-Beuren syndrome region on chromosome 7q11.23. In six families with a common recurrent ∼1.2 Mb deletion that includes the Huntingtin-interacting protein 1 (HIP1) and tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein gamma (YWHAG) genes and that is flanked by large complex low-copy repeats, we identified sites for nonallelic homologous recombination in two patients. There were no cases of this ∼1.2 Mb distal 7q11.23 deletion copy number variant identified in over 20,000 control samples surveyed. Three individuals with smaller, nonrecurrent deletions (∼180-500 kb) that include HIP1 but not YWHAG suggest that deletion of HIP1 is sufficient to cause neurological disease. Mice with targeted mutation in the Hip1 gene (Hip1⁻(/)⁻) develop a neurological phenotype characterized by failure to thrive, tremor, and gait ataxia. Overall, our data characterize a neurodevelopmental and epilepsy syndrome that is likely caused by recurrent and nonrecurrent deletions, including HIP1. These data do not exclude the possibility that YWHAG loss of function is also sufficient to cause neurological phenotypes. Based on the current knowledge of Hip1 protein function and its proposed role in AMPA and NMDA ionotropic glutamate receptor trafficking, we believe that HIP1 haploinsufficiency in humans will be amenable to rational drug design for improved seizure control and cognitive and behavioral function.
Melissa B Ramocki; Magdalena Bartnik; Przemyslaw Szafranski; Katarzyna E Kołodziejska; Zhilian Xia; Jaclyn Bravo; G Steve Miller; Diana L Rodriguez; Charles A Williams; Patricia I Bader; Elżbieta Szczepanik; Tomasz Mazurczak; Dorota Antczak-Marach; James G Coldwell; Cigdem I Akman; Karen McAlmon; Melinda P Cohen; James McGrath; Elizabeth Roeder; Jennifer Mueller; Sung-Hae L Kang; Carlos A Bacino; Ankita Patel; Ewa Bocian; Chad A Shaw; Sau Wai Cheung; Tadeusz Mazurczak; Paweł Stankiewicz
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-11-25
Journal Detail:
Title:  American journal of human genetics     Volume:  87     ISSN:  1537-6605     ISO Abbreviation:  Am. J. Hum. Genet.     Publication Date:  2010 Dec 
Date Detail:
Created Date:  2010-12-07     Completed Date:  2011-01-18     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  0370475     Medline TA:  Am J Hum Genet     Country:  United States    
Other Details:
Languages:  eng     Pagination:  857-65     Citation Subset:  IM    
Copyright Information:
Copyright © 2010 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Data Bank Information
Bank Name/Acc. No.:
GENBANK/HQ148673; GEO/GSE23834
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MeSH Terms
Child, Preschool
Chromosome Deletion*
Chromosomes, Human, Pair 7*
DNA Copy Number Variations
DNA-Binding Proteins / genetics*
Epilepsy / genetics*
Intellectual Disability / genetics*
Mental Disorders / genetics*
Middle Aged
Molecular Sequence Data
Grant Support
Reg. No./Substance:
0/DNA-Binding Proteins; 0/HIP1 protein, human

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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