Five new TTF1/NKX2.1 mutations in brain-lung-thyroid syndrome: Rescue by PAX8 synergism in one case
Human Molecular Genetics. 2009-03-31; 18(12): 2266-2276
DOI: 10.1093/hmg/ddp162
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1. Hum Mol Genet. 2009 Jun 15;18(12):2266-76. doi: 10.1093/hmg/ddp162. Epub 2009 Mar
31.
Five new TTF1/NKX2.1 mutations in brain-lung-thyroid syndrome: rescue by PAX8
synergism in one case.
Carré A(1), Szinnai G, Castanet M, Sura-Trueba S, Tron E, Broutin-L’Hermite I,
Barat P, Goizet C, Lacombe D, Moutard ML, Raybaud C, Raynaud-Ravni C, Romana S,
Ythier H, Léger J, Polak M.
Author information:
(1)University Paris-Descartes, INSERM U845, 75270 Paris, France.
Thyroid transcription factor 1 (NKX2-1/TITF1) mutations cause brain-lung-thyroid
syndrome, characterized by congenital hypothyroidism (CH), infant respiratory
distress syndrome (IRDS) and benign hereditary chorea (BHC). The objectives of
the present study were (i) detection of NKX2-1 mutations in patients with CH
associated with pneumopathy and/or BHC, (ii) functional analysis of new mutations
in vitro and (iii) description of the phenotypic spectrum of brain-lung-thyroid
syndrome. We identified three new heterozygous missense mutations (L176V, P202L,
Q210P), a splice site mutation (376-2A–>G), and one deletion of NKX2-1 at 14q13.
Functional analysis of the three missense mutations revealed loss of
transactivation capacity on the human thyroglobulin enhancer/promoter.
Interestingly, we showed that deficient transcriptional activity of NKX2-1-P202L
was completely rescued by cotransfected PAX8-WT, whereas the synergistic effect
was abolished by L176V and Q210P. The clinical spectrum of 6 own and 40 published
patients with NKX2-1 mutations ranged from the complete triad of
brain-lung-thyroid syndrome (50%), brain and thyroid disease (30%), to isolated
BHC (13%). Thyroid morphology was normal (55%) and compensated hypothyroidism
occurred in 61%. Lung disease occurred in 54% of patients (IRDS at term 76%;
recurrent pulmonary infections 24%). On follow-up, 20% developed severe chronic
interstitial lung disease, and 16% died. In conclusion, we describe five new
NKX2.1 mutations with, for the first time, complete rescue by PAX8 of the
deficient transactivating capacity in one case. Additionally, our review shows
that the majority of affected patients display neurological and/or thyroidal
problems and that, although less frequent, lung disease is responsible for a
considerable mortality.
DOI: 10.1093/hmg/ddp162
PMID: 19336474 [Indexed for MEDLINE]