Haploinsufficiency of TCF4 Causes Syndromal Mental Retardation with Intermittent Hyperventilation (Pitt-Hopkins Syndrome)
| Autor: | Alexander Dreweke, Alfredo Orrico, Christiane Zweier, Koenraad Devriendt, Raoul C.M. Hennekam, Jorge A. Saraiva, Thomy de Ravel, Sérgio B. Sousa, Armand Bottani, Juliane Hoyer, André Reis, William Reardon, Jill Clayton-Smith, Emilia K. Bijlsma, Peter Nürnberg, Ina Göhring, Monika Cohen, Maarit Peippo, Alexandra Cabral, Anita Rauch |
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| Přispěvatelé: | Clinical sciences, Medical Genetics, ANS - Amsterdam Neuroscience, APH - Amsterdam Public Health, Paediatric Genetics |
| Rok vydání: | 2007 |
| Předmět: |
Adult
Male Adolescent Pitt–Hopkins syndrome Biology medicine.disease_cause Transfection Intellectual Disability/complications Polymorphism Single Nucleotide Cell Line Transcription Factor 4 Intellectual Disability Report Hyperventilation Intellectual disability medicine Genetics Missense mutation Humans Genetics(clinical) Child Hyperventilation/complications Genetics (clinical) In Situ Hybridization Fluorescence TCF Transcription Factors/genetics Genes Dominant Mutation Chromosomes Human Pair 18/genetics Basic Helix-Loop-Helix Leucine Zipper Transcription Factors TCF4 Syndrome Face/abnormalities medicine.disease Developmental disorder DNA-Binding Proteins Phenotype Haplotypes Face Female medicine.symptom Chromosome Deletion Haploinsufficiency Chromosomes Human Pair 18 TCF Transcription Factors Transcription Factor 7-Like 2 Protein Transcription Factors |
| Zdroj: | American journal of human genetics, 80(5), 994-1001. Cell Press |
| ISSN: | 0002-9297 |
| DOI: | 10.1086/515583 |
| Popis: | Pitt-Hopkins syndrome is a rarely reported syndrome of so-far-unknown etiology characterized by mental retardation, wide mouth, and intermittent hyperventilation. By molecular karyotyping with GeneChip Human Mapping 100K SNP arrays, we detected a 1.2-Mb deletion on 18q21.2 in one patient. Sequencing of the TCF4 transcription factor gene, which is contained in the deletion region, in 30 patients with significant phenotypic overlap revealed heterozygous stop, splice, and missense mutations in five further patients with severe mental retardation and remarkable facial resemblance. Thus, we establish the Pitt-Hopkins syndrome as a distinct but probably heterogeneous entity caused by autosomal dominant de novo mutations in TCF4. Because of its phenotypic overlap, Pitt-Hopkins syndrome evolves as an important differential diagnosis to Angelman and Rett syndromes. Both null and missense mutations impaired the interaction of TCF4 with ASCL1 from the PHOX-RET pathway in transactivating an E box-containing reporter construct; therefore, hyperventilation and Hirschsprung disease in patients with Pitt-Hopkins syndrome might be explained by altered development of noradrenergic derivatives. |
| Databáze: | OpenAIRE |
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