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Three Novel IGSF1 Mutations in Four Japanese Patients With X-Linked Congenital Central Hypothyroidism

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Please use this identifier to cite or link to this item:http://hdl.handle.net/2115/57864

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)

Submitter: 田島 敏広

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