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Mutational, functional, and expression studies of the TCF4 gene in Pitt‐Hopkins syndrome
Author(s) -
de Pontual Loïc,
Mathieu Yves,
Golzio Christelle,
Rio Marlène,
Malan Valérie,
Boddaert Nathalie,
Soufflet Christine,
Picard Capucine,
Durandy Anne,
Dobbie Angus,
Heron Delphine,
Isidor Bertrand,
Motte Jacques,
NewburryEcob Ruth,
Pasquier Laurent,
Tardieu Marc,
Viot Géraldine,
Jaubert Francis,
Munnich Arnold,
Colleaux Laurence,
Vekemans Michel,
Etchevers Heather,
Lyonnet Stanislas,
Amiel Jeanne
Publication year - 2009
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.20935
Subject(s) - tcf4 , biology , hum , gene , genetics , mutant , mutation , gene expression , transcription factor , bioinformatics , promoter , art , performance art , art history
Abstract 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. Hum Mutat 0, 1–8, 2009. © 2009 Wiley‐Liss, Inc.