TY - JOUR
T1 - A novel heterozygous intronic mutation in POU1F1 is associated with combined pituitary hormone deficiency
AU - Takagi, Masaki
AU - Kamasaki, Hotaka
AU - Yagi, Hiroko
AU - Fukuzawa, Ryuji
AU - Narumi, Satoshi
AU - Hasegawa, Tomonobu
N1 - Funding Information:
This work was supported by grants from the Japan Society for the Promotion of Science (16K10007), grants from Takeda Science Foundation, Foundation for Growth Science, the Japanese Society for Pediatric Endocrinology Future Development Grant supported by Novo Nordisk Pharma Ltd, and grants from the Ministry of Health, Labour, and Welfare, Japan (Jitsuyoka Nanbyo-Ippan-014).
Publisher Copyright:
© The Japan Endocrine Society.
PY - 2017
Y1 - 2017
N2 - POU class 1 homeobox 1 (POU1F1) regulates pituitary cell-specific gene expression of somatotropes, lactotropes, and thyrotropes. In humans, two POU1F1 isoforms (long and short isoform), which are generated by the alternative use of the splice acceptor site for exon 2, have been identified. To date, more than 30 POU1F1 mutations in patients with combined pituitary hormone deficiency (CPHD) have been described. All POU1F1 variants reported to date affect both the short and long isoforms of the POU1F1 protein; therefore, it is unclear at present whether a decrease in the function of only one of these two isoforms is sufficient for disease onset in humans. Here, we described a sibling case of CPHD carrying a heterozygous mutation in intron 1 of POU1F1. In vitro experiments showed that this mutation resulted in exon 2-skipping of only in the short isoform of POU1F1, while the long isoform remained intact. This result strongly suggests the possibility, for the first time, that isolated mutations in the short isoform of POU1F1 could be sufficient for induction of POU1F1-related CPHD. This finding improves our understanding of the molecular mechanisms, and developmental course associated with mutations in POU1F1.
AB - POU class 1 homeobox 1 (POU1F1) regulates pituitary cell-specific gene expression of somatotropes, lactotropes, and thyrotropes. In humans, two POU1F1 isoforms (long and short isoform), which are generated by the alternative use of the splice acceptor site for exon 2, have been identified. To date, more than 30 POU1F1 mutations in patients with combined pituitary hormone deficiency (CPHD) have been described. All POU1F1 variants reported to date affect both the short and long isoforms of the POU1F1 protein; therefore, it is unclear at present whether a decrease in the function of only one of these two isoforms is sufficient for disease onset in humans. Here, we described a sibling case of CPHD carrying a heterozygous mutation in intron 1 of POU1F1. In vitro experiments showed that this mutation resulted in exon 2-skipping of only in the short isoform of POU1F1, while the long isoform remained intact. This result strongly suggests the possibility, for the first time, that isolated mutations in the short isoform of POU1F1 could be sufficient for induction of POU1F1-related CPHD. This finding improves our understanding of the molecular mechanisms, and developmental course associated with mutations in POU1F1.
KW - Combined pituitary hormone deficiency
KW - Exon trapping
KW - Pou1f1
KW - Short isoform
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U2 - 10.1507/endocrj.EJ16-0361
DO - 10.1507/endocrj.EJ16-0361
M3 - Comment/debate
C2 - 27885216
AN - SCOPUS:85014057068
SN - 0918-8959
VL - 64
SP - 229
EP - 234
JO - Endocrine journal
JF - Endocrine journal
IS - 2
ER -