Thyroid dysgenesis (TD) accounts for most cases of congenital hypothyroidism. Although mutations in thyroid hormone receptor β (THRB) have been identified in TD, the mutational spectrum of THRB and phenotype-genotype correlations have not been fully elucidated. In this study, we aimed to find mutations of THRB, examine the functions of these mutations, and attempt to elucidate the relationship between THRB and TD. Thus, we screened the exons of THRB in 280 patients with TD and 200 normal subjects in samples collected from China. We performed cell morphology assays, MTT assays, flow cytometric analyses, and a quantitative reverse-transcription polymerase chain reaction in human thyroid follicular epithelial cells (Nthy-ori cell line) to examine the impact of THRB mutations. In two unrelated patients, two novel missense mutations, c.76G>A (p.D26N) and c.107G>A (p.C36Y), were identified in THRB. Functional studies suggested that the C36Y mutant caused changes in morphology, inhibiting cell proliferation and promoting apoptosis in a human thyroid cell line. In addition, we found that messenger RNA expressions of thyroglobulin (TG) and the Na /I symporter (NIS) were decreased in a time-dependent manner in mutant THRB compared with the wild type. To our knowledge, this is the first study to document the prevalence of THRB mutations and the genotype-phenotype spectrum of TD in a Chinese population. We characterized the function of a C36Y mutation, which reduced cell proliferation and increased cell death in thyroid epithelial cells. This study provides further evidence for genetic THRB defects and disease mechanisms in TD.

Background Although Mitochondrial DNA depletion syndrome (MDS) can be classified into three forms: myopathic, encephalomyopathic and hepatocerebral form, it is difficult to identify its form due to its clinical heterogeneity. Therefore, it is very important to conduct molecular genetic analysis on suspected patients. This study presented a male 38 weeks and 5 days infant with liver cytolysis and leukodystrophy. Case presentation A male infant proband was admitted to the department of NICU for feeding intolerance, irregular rhythm of respiration, hypoglycemia, lactic acidosis, liver cytolysis and neurological abnormalities. He was onset of mild jaundice with leukodystrophy and high lactate and phenylderivatives for urine organic acids on the 7th day. Whole exome sequencing (WES) and Sanger sequencing were performed to screen and confirm the suspicious pathogenic mutations. The results revealed this proband carried two compound heterozygous mutations in TWNK : c.1186 C > T / p.Pro396Ser and c.1844 G > C / p.Gly615Ala inherited by an autosomal recessive form from his parents, of which protein conservative analysis and structural modeling supported the pathogenicity of the two mutations. Unfortunately, the conditions described above were not improved until he was discharged from the hospital on the 23rd day and died at 4 months of age. Conclusions In this study, we investigated a Chinese family with the hepatocerebral form of MDS and conducted WES and Sanger sequencing to explore the causative mutations for this proband born from non-consanguineous and healthy parents. We identified two novel TWNK c.1186 C > T/ c.1844 G > C compound heterozygous mutations which were probably the disease-causing mutations of hepatocerebral form of MDS and described the clinical manifestations of the proband, which expanded the phenotypic spectrum of MDS caused by variants in TWNK . This study also emphasized WES technology can provide the genetic diagnosis of Mendelian genetic disease.

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