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Hokkaido University Collection of Scholarly and Academic Papers >
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Three Novel IGSF1 Mutations in Four Japanese Patients With X-Linked Congenital Central Hypothyroidism
| Title: | Three Novel IGSF1 Mutations in Four Japanese Patients With X-Linked Congenital Central Hypothyroidism |
| Authors: | Nakamura, Akie Browse this author | | Bak, Beata Browse this author | | Silander, Tanya L. R. Browse this author | | Lam, Jessica Browse this author | | Hotsubo, Tomoyuki Browse this author | | Yorifuji, Toru Browse this author | | Ishizu, Katsura Browse this author | | Bernard, Daniel J. Browse this author | | Tajima, Toshihiro Browse this author →KAKEN DB |
| Issue Date: | Oct-2013 |
| Publisher: | Endocrine Society |
| Journal Title: | Journal of clinical endocrinology & metabolism |
| Volume: | 98 |
| Issue: | 10 |
| Start Page: | E1682 |
| End Page: | E1691 |
| Publisher DOI: | 10.1210/jc.2013-1224 |
| PMID: | 23966245 |
| Abstract: | 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 T-4 and/or T-3 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. |
| Type: | article |
| URI: | http://hdl.handle.net/2115/57864 |
| Appears in Collections: | 医学院・医学研究院 (Graduate School of Medicine / Faculty of Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)
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Submitter: 田島 敏広
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