Five new TTF1/NKX2.1 mutations in brain-lung-thyroid syndrome: rescue by PAX8 synergism in one case

Abstract

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.

NKX2-1mutations leading to surfactant protein promoter dysregulation cause interstitial lung disease in “Brain-Lung-Thyroid Syndrome”

“…The mutations were introduced by site-directed mutagenesis as described earlier [Carre et al, 2009], using the sense primer 5'-CCGCGCAGGAAGCGCTGGGTGCTCTTCTCGC-3' and the antisense primer 5'-GCGAGAAGAGCACCCAGCGCTTCCTGCGCGG-3' for the NKX2-1-p.R165W mutation, and the sense primer 5'GCGTGGCGGTGCCGGTCCTGGTGAAAGACGGCAAACCGTG-3' and the antisense primer 5'-CACGGTTTGCCGTCTTTCACCAGGACCGGCACCGCCACGC-3' for the NKX2-1-p.L263fs mutation.…”

“…earlier [Carre et al, 2009]. Nucleotide numbering reflects cDNA numbering, with +1 corresponding to the A of the ATG translation initiation codon in the reference sequence NM_003317.3.…”

NKX2-1 mutation in a family diagnosed with ataxic dyskinetic cerebral palsy

“…This is predicted to cause haploinsufficiency, either as a result of a non-functional, truncated NKX2-1 protein or 50% reduction of the protein levels due to NMD degradation of the premature termination codon containing NKX2-1 mRNA allele. [6,7] While BHC, with its characteristic choreiform movements, would not commonly be confused with ataxic CP, similar cases have been reported [11,12]. Doyle et al 12 reported siblings with an NKX2-1 mutation who had congenital hypothyroidism, global developmental delay and later ataxia, choreoathetosis and dysarthria.…”

“…[6,7] While BHC, with its characteristic choreiform movements, would not commonly be confused with ataxic CP, similar cases have been reported [11,12]. Doyle et al 12 reported siblings with an NKX2-1 mutation who had congenital hypothyroidism, global developmental delay and later ataxia, choreoathetosis and dysarthria. Their mother had been diagnosed with CP during childhood; she was described as having ataxia as an adult.…”

“…Their mother had been diagnosed with CP during childhood; she was described as having ataxia as an adult. Carre et al [12] described a child with an NKX2-1 mutation who had congenital hypothyroidism and respiratory distress syndrome and in whom ataxic movements and psychomotor delay presented in the first year.…”