title: A novel loss-of-function mutation in TTF-2 is associated with congenital hypothyroidism, thyroid agenesis and cleft palate.
abstract: Thyroid dysgenesis is the most common cause of congenital hypothyroidism (CH) and its genetic basis is largely unknown. Here, we describe the second homozygous missense mutation in TTF-2 (or FOXE1), a transcription factor that has been implicated in thyroid development. Two male siblings, born to consanguineous parents, presented with CH, athyreosis and cleft palate and were found to be homozygous for a mutation corresponding to a serine to asparagine substitution at codon 57 (S57N) in the forkhead DNA binding domain of TTF-2. Their heterozygous parents were unaffected and this mutation was not found in 31 unrelated cases of athyreosis or normal controls. Consistent with its location, the S57N TTF-2 mutant protein showed impaired DNA binding and partial loss of transcriptional function. Such incomplete loss of TTF-2 function may account for the absence of choanal atresia and bifid epiglottis in our patients, anomalies which were present together with CH and cleft palate in two other individuals with the only other, more deleterious, TTF-2 mutation (A65V) described previously. Our observations support the role of TTF-2 in both thyroid and palate development but suggest phenotypic heterogeneity of this syndromic form of CH.
authors.affiliation: Paediatric Endocrinology Unit and INSERM U457, Paris, France.
authors.forename: Mireille
authors.initials: M
authors.lastname: Castanet
authors.forename: Soo-Mi
authors.initials: SM
authors.lastname: Park
authors.forename: Aaron
authors.initials: A
authors.lastname: Smith
authors.forename: Michel
authors.initials: M
authors.lastname: Bost
authors.forename: Juliane
authors.initials: J
authors.lastname: Léger
authors.forename: Stanislas
authors.initials: S
authors.lastname: Lyonnet
authors.forename: Anna
authors.initials: A
authors.lastname: Pelet
authors.forename: Paul
authors.initials: P
authors.lastname: Czernichow
authors.forename: Krishna
authors.initials: K
authors.lastname: Chatterjee
authors.forename: Michel
authors.initials: M
authors.lastname: Polak
mesh_terms: D000293:Adolescent; D000328:Adult; D002972:Cleft Palate / Q000235:genetics*; D003409:Congenital Hypothyroidism; D003241:Consanguinity; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D051858:Forkhead Transcription Factors; D006801:Humans; D007037:Hypothyroidism / Q000235:genetics*; D007223:Infant; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D018807:Polymorphism, Single-Stranded Conformational; D011485:Protein Binding; D012097:Repressor Proteins / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D013961:Thyroid Gland / Q000002:abnormalities*
chemical_list: D004268:DNA-Binding Proteins; C106894:FOXE1 protein, human; D051858:Forkhead Transcription Factors; D012097:Repressor Proteins; D004247:DNA