title: Mutations in TCF4, encoding a class I basic helix-loop-helix transcription factor, are responsible for Pitt-Hopkins syndrome, a severe epileptic encephalopathy associated with autonomic dysfunction.
abstract: Pitt-Hopkins syndrome (PHS) is a rare syndromic encephalopathy characterized by daily bouts of hyperventilation and a facial gestalt. We report a 1.8-Mb de novo microdeletion on chromosome 18q21.1, identified by array-comparative genomic hybridization in one patient with PHS. We subsequently identified two de novo heterozygous missense mutations of a conserved amino acid in the basic region of the TCF4 gene in three additional subjects with PHS. These findings demonstrate that TCF4 anomalies are responsible for PHS and provide the first evidence of a human disorder related to class I basic helix-loop-helix transcription-factor defects (also known as "E proteins"). Moreover, our data may shed new light on the normal processes underlying autonomic nervous system development and maintenance of an appropriate ventilatory neuronal circuitry.
authors: From the Departments of Genetics, Pediatric Radiology and INSERM U-797, Universite Paris-Descartes, Faculte de Medecine, Hopitaux de Paris, Hopital Necker-Enfants Malades, Paris, France. amiel@necker.fr
authors: Jeanne
authors: J
authors: Amiel
authors: Marlene
authors: M
authors: Rio
authors: Loic
authors: L
authors: de Pontual
authors: Richard
authors: R
authors: Redon
authors: Valerie
authors: V
authors: Malan
authors: Nathalie
authors: N
authors: Boddaert
authors: Perrine
authors: P
authors: Plouin
authors: Nigel P
authors: NP
authors: Carter
authors: Stanislas
authors: S
authors: Lyonnet
authors: Arnold
authors: A
authors: Munnich
authors: Laurence
authors: L
authors: Colleaux
mesh_terms: D000595:Amino Acid Sequence; D001342:Autonomic Nervous System Diseases / Q000150:complications* / Q000235:genetics* / Q000473:pathology; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D002874:Chromosome Mapping; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics; D004268:DNA-Binding Proteins; D004827:Epilepsy / Q000150:complications* / Q000235:genetics* / Q000473:pathology; D005260:Female; D018257:Helix-Loop-Helix Motifs / Q000235:genetics; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D017386:Sequence Homology, Amino Acid; D013577:Syndrome; D051820:TCF Transcription Factors / Q000235:genetics*; D000073940:Transcription Factor 4; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D051820:TCF Transcription Factors; C532096:TCF4 protein, human; C544894:TCF7L2 protein, human; D000073940:Transcription Factor 4; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors