Objective: The NKX2-1 gene, also known as TITF-1, TTF-1 or T/ebp, is a member of the homeodomain-containing NK-2 transcription factor gene family and expressed in early development of thyroid, lung and forebrain. Initial screening of patients with isolated congenital hypothyroidism failed to show mutations. The first human heterozygous deletion affecting the NKX2-1 gene to be reported was a neonate with respiratory failure, primary hypothyroidism and neurological signs matching the developmental defects seen in NKX2-1 −/− mice. To date, few NKX2-1 gene mutations were identified in patients matching this highly variable phenotype. Here, we report the systematic molecular screening analysis of the NKX2-1 gene locus of 100 patients with thyroid dysfunction combined with movement disorders and pulmonary affection aiming to delineate the clinical spectrum of NKX2-1 deficiency.
Methods: DNA of all patients was analyzed by PCR followed by direct sequencing. In addition, high-resolution region-specific array-CGH was applied. Furthermore, functional in vitro analysis of missense mutations was performed to identify loss-of-function.
Results: In our series, 25 novel alterations were identified, i.e. 7 heterozygous deletions and 18 intragenic pointmutations. Three missense and two splice site mutations were shown to alter gene function by abolished DNA-binding capacity. All remaining cases were nonsense mutations resulting in prematurely terminated or elongated protein sequences. Genotypic heterogeneity was seen, as neither a common microdeletion nor a mutational hot spot could be revealed. Analyzing the clinical spectrum, NKX2-1 variations were most likely to occur in patients with choreoathetosis and hypothyroidism (38.5%) and less frequent in patients with neurological, thyroid and pulmonal dysfunction (28.3%) or separate choreoathetosis (12.5%).
Conclusion: NKX2-1 deficiency is highly variable in phenotype and genotype as seen in the newly identified 25 individuals. NKX2-1 gene analysis seems to be reasonable if applied in patients with two or three clinical findings, respectively, i.e. hypothyroidism, choreathetosis and pulmonary dysfunction, but also in isolated choreoathetosis.
03 - 07 May 2008
European Society of Endocrinology