Diabetes, polycystic thyroid and urogenital malformations associated with a transcription factor 1 (TCF1) splice site mutation

Background: Maturity onset diabetes of the young (MODY) may result from mutations of POU homeodomain-containing transcription factors, including TCF1 and TCF2, that regulate tissue-specific gene expression in the pancreas and other epithelial organs.

Methods: We here identify and characterize a kindred with MODY and a novel clinical phenotype with extrapancreatic malformations.

Results: The index patient (female, age 13yrs) presented with fasting blood glucose of 9.3 mmol/l, HbA1c of 8.5%, and fasting C peptide of 3.2 ng/ml. In the father and paternal grandmother, diabetes not requiring insulin had been diagnosed at young age. Two sisters had fasting glucose of 7.3 and 6.8 mmol/l, and 2h glucose during OGTT was 10.1 and 13.1 mmol/l, respectively. Islet cell antibodies were negative. In the index patient, ultrasound revealed unilateral agenesis of the kidney and uterus unicornis. Polycystic thyroid lesions were found in the index patient and one sister. In the coding sequence and promoter region of HNF1beta (TCF2), no disease-associated sequence variation was found. However, sequence analysis of TCF1 revealed a novel heterozygous genomic 4nt deletion at the splice donor site of intron 2 in all patients. This mutation leads to a predicted alternative mRNA splicing, resulting in a premature termination codon and HNFalpha protein truncation.

Conclusion: A hereditary diabetes syndrome associated with urogenital and thyroid malformations is due to a splice site mutation of TCF1, compatible with a role of this transcription factor in thyroid and urogenital development.