Human Molecular Genetics Advance Access originally published online on March 31, 2009
Human Molecular Genetics 2009 18(12):2266-2276; doi:10.1093/hmg/ddp162
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Five new TTF1/NKX2.1 mutations in brain–lung–thyroid syndrome: rescue by PAX8 synergism in one case
1 University Paris-Descartes, INSERM U845 2 AP-HP Hôpital Necker Enfants-Malades, Pediatric Endocrine Unit, Centre des maladies endocriniennes rares de la croissance 3 Faculty of Pharmacy, CNRS UMR 8015 4 Laboratoire de Cristallographie et RMN Biologiques, 75270 Paris, France 5 Pediatric Endocrinology 6 Medical Genetics, University Hospital, 33076 Bordeaux, France 7 Neuropediatrics, AP-HP Hôpital Armand Trousseau, 75571 Paris, France 8 Pediatric Endocrinology, Hôpital Femme Mère Enfant, 69677 Bron, France 9 Pediatrics, University Hospital, 42055 Saint Etienne, France 10 Cytogenetics, 149 rue de Sèvres, 75743 Paris 11 Pediatrics, Centre hospitalier, 59056 Roubaix, France 12 University Paris-Diderot, Faculty of Medicine, Pediatric Endocrinology and Diabetes, AP-HP, Hôpital Robert Debré, 75019, Paris, France
* To whom correspondence should be addressed at: Service d’Endocrinologie Pédiatrique, AP-HP, Hôpital Necker Enfants-Malades, 149 rue de Sèvres, F-75743 Paris, Cedex 15, France. Tel: +33 144494802; Fax: +33 144381648; Email: michel.polak{at}nck.aphp.fr
Received January 30, 2009; Accepted March 26, 2009
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.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
Present address: Pediatric Endocrinology, University Children’s Hospital Basel, Basel, Switzerland.