Context: Congenital central hypothyroidism (C-CH) is a rare disease. We investigated the molecular basis of unexplained C-CH in 4 Japanese boys.
Patients and methods: C-CH was diagnosed by low free T4 and/or T3 and low basal TSH concentrations. We used whole-exome sequencing of one patient with C-CH to identify potential disease-causing mutations. Thereafter, PCR direct sequencing was performed to Identify genetic defects underlying C-CH in 3 more patients. We then assessed the effects of mutations identified in the Ig superfamily, member 1 (IGSF1), gene on protein expression and membrane trafficking.
Results: All patients had congenital hypothyroidism, and 2 had definitive prolactin deficiency. Two patients were detected by neonatal screening. The other patients were diagnosed by short stature and failure to thrive. We identified a novel nonsense variant in IGSF1 by whole-exome sequencing in patient 1, which was confirmed by PCR direct sequencing (p.R1189X). PCR direct sequencing identified the identical nonsense mutation in patient 2. Patients 3 and 4 harbored distinct missense (p.V1082E) or nonsense (p.Q645X) mutations in IGSF1. The mothers of patients 1, 3, and 4 were heterozygous for these mutations. The R1189X mutant, which lacks the transmembrane domain, failed to traffic to the plasma membrane. V1082E could be observed at the cell surface, but at greatly diminished levels relative to the wild-type form of the protein. The severely truncated Q645X mutant could not be detected by Western blot.
Conclusion: Our findings provide additional genetic evidence that loss-of-function mutations in IGSF1 cause an X-linked form of C-CH and variable prolactin deficiency.