Mutational, functional, and expression studies of the TCF4 gene in Pitt-Hopkins syndrome.
Pitt-Hopkins syndrome is a severe congenital encephalopathy recently ascribed to de novo heterozygous TCF4 gene mutations. We report a series of 13 novel PHS cases with a TCF4 mutation and show that EEG, brain magnetic resonance imagain (MRI), and immunological investigations provide valuable additional clues to the diagnosis. We confirm a mutational hot spot in the basic domain of the E-protein. Functional studies illustrate that heterodimerisation of mutant TCF4 proteins with a tissue-specific transcription factor is less effective than that homodimerisation in a luciferase reporter assay. We also show that the TCF4 expression pattern in human embryonic development is widespread but not ubiquitous. In summary, we further delineate an underdiagnosed mental retardation syndrome, highlighting TCF4 function during development and facilitating diagnosis within the first year of life.
de Pontual
Loïc
L
Unité INSERM U-781, Université Paris Descartes, Faculté de Médecine, INSERM.
Mathieu
Yves
Y
Golzio
Christelle
C
Rio
Marlène
M
Malan
Valérie
V
Boddaert
Nathalie
N
Soufflet
Christine
C
Picard
Capucine
C
Durandy
Anne
A
Dobbie
Angus
A
Heron
Delphine
D
Isidor
Bertrand
B
Motte
Jacques
J
Newburry-Ecob
Ruth
R
Pasquier
Laurent
L
Tardieu
Marc
M
Viot
Géraldine
G
Jaubert
Francis
F
Munnich
Arnold
A
Colleaux
Laurence
L
Vekemans
Michel
M
Etchevers
Heather
H
Lyonnet
Stanislas
S
Amiel
Jeanne
J
D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D000293:Adolescent; D000328:Adult; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002648:Child; D002675:Child, Preschool; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D019281:Dimerization; D004569:Electroencephalography; D005260:Female; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D006367:HeLa Cells; D006801:Humans; D006985:Hyperventilation / Q000473:pathology; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007223:Infant; D008607:Intellectual Disability / Q000473:pathology; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013577:Syndrome; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D055815:Young Adult
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D008156:Luciferases