Two novel TSHR gene mutations (p.R528C and c.392+4del4) associated with congenital hypothyroidism

Area of Science:

• Genetics
• Endocrinology
• Molecular Biology

Background:

• Non-goitrogenic congenital hypothyroidism (CHNG) is a condition characterized by impaired thyroid hormone production.
• Inactivating mutations in the thyrotropin receptor (TSHR) gene are a known cause of CHNG.

Purpose of the Study:

• To investigate TSHR gene mutations in a cohort of 20 children diagnosed with CHNG.
• To identify novel genetic variants associated with CHNG and elucidate their pathogenic mechanisms.

Main Methods:

• Genomic DNA extraction from peripheral blood leukocytes of CHNG patients.
• Mutation screening of the TSHR gene using direct sequencing.
• Bioinformatics analysis to predict the pathogenicity of identified variants.
• Family segregation analysis to confirm inheritance patterns.

Main Results:

• Two novel inactivating mutations in the TSHR gene were identified in a 2-year-old boy with thyroid hypoplasia: a missense mutation (c.1582C>T, p.R528C) and a splice-site deletion (c.392+4del4).
• Bioinformatics analyses confirmed the disease-causing potential of both identified variants.
• Family studies indicated an autosomal recessive inheritance pattern for these TSHR mutations.

Conclusions:

• The study identified two novel inactivating mutations in the TSHR gene, p.R528C and c.392+4del4, as causative agents of non-goitrogenic congenital hypothyroidism.
• These findings expand the spectrum of TSHR mutations associated with CHNG and highlight the importance of genetic analysis in diagnosing the condition.
• The identified mutations follow an autosomal recessive inheritance, providing insights into the genetic basis of CHNG.