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.

Inborn errors of DNA repair or replication underlie a variety of clinical phenotypes. We studied 5 patients from 4 kindreds, all of whom displayed intrauterine growth retardation, chronic neutropenia, and NK cell deficiency. Four of the 5 patients also had postnatal growth retardation. The association of neutropenia and NK cell deficiency, which is unusual among primary immunodeficiencies and bone marrow failures, was due to a blockade in the bone marrow and was mildly symptomatic. We discovered compound heterozygous rare mutations in Go-Ichi-Ni-San (GINS) complex subunit 1 (GINS1, also known as PSF1) in the 5 patients. The GINS complex is essential for eukaryotic DNA replication, and homozygous null mutations of GINS component-encoding genes are embryonic lethal in mice. The patients' fibroblasts displayed impaired GINS complex assembly, basal replication stress, impaired checkpoint signaling, defective cell cycle control, and genomic instability, which was rescued by WT GINS1. The residual levels of GINS1 activity reached 3% to 16% in patients' cells, depending on their GINS1 genotype, and correlated with the severity of growth retardation and the in vitro cellular phenotype. The levels of GINS1 activity did not influence the immunological phenotype, which was uniform. Autosomal recessive, partial GINS1 deficiency impairs DNA replication and underlies intra-uterine (and postnatal) growth retardation, chronic neutropenia, and NK cell deficiency.

5α-Reductase type 1 (5αR1) catalyses A-ring reduction of androgens and glucocorticoids in liver, potentially influencing hepatic manifestations of the metabolic syndrome. Male mice, homozygous for a disrupted 5αR1 allele (5αR1 knockout [KO] mice), were studied after metabolic (high-fat diet) and fibrotic (carbon tetrachloride [CCl4]) challenge. The effect of the 5α-reductase inhibitor finasteride on metabolism was investigated in male obese Zucker rats. While eating a high-fat diet, male 5αR1-KO mice demonstrated greater mean weight gain (21.6 ± 1.4 vs 16.2 ± 2.4 g), hyperinsulinemia (insulin area under the curve during glucose tolerance test 609 ± 103 vs. 313 ± 66 ng ⋅ mL−1 ⋅ min), and hepatic steatosis (liver triglycerides 136.1 ± 17.0 vs. 89.3 ± 12.1 μmol ⋅ g−1). mRNA transcript profiles in liver were consistent with decreased fatty acid β-oxidation and increased triglyceride storage. 5αR1-KO male mice were more susceptible to fibrosis after CCl4 administration (37% increase in collagen staining). The nonselective 5α-reductase inhibitor finasteride induced hyperinsulinemia and hepatic steatosis (10.6 ± 1.2 vs. 7.0 ± 1.0 μmol ⋅ g−1) in obese male Zucker rats, both intact and castrated. 5αR1 deficiency induces insulin resistance and hepatic steatosis, consistent with the intrahepatic accumulation of glucocorticoids, and predisposes to hepatic fibrosis. Hepatic steatosis is independent of androgens in rats. Variations in 5αR1 activity in obesity and with nonselective 5α-reductase inhibition in men with prostate disease may have important consequences for the onset and progression of metabolic liver disease.