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Identification of a novel mutation in the exon 2 splice donor site of the POU1F1/PIT‐1 gene in Japanese identical twins with mild combined pituitary hormone deficiency
Author(s) -
Inoue Hiroshi,
Mukai Tokuo,
Sakamoto Yukiko,
Kimura Chizuko,
Kangawa Natsumi,
Itakura Mitsuo,
Ogata Tsutomu,
Ito Yoshiya,
Fujieda Kenji
Publication year - 2012
Publication title -
clinical endocrinology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.055
H-Index - 147
eISSN - 1365-2265
pISSN - 0300-0664
DOI - 10.1111/j.1365-2265.2011.04165.x
Subject(s) - exon , endocrinology , mutation , medicine , splice site mutation , gene , pituitary gland , biology , genetics , hormone , alternative splicing
Summary Context To date, approximately 35 different POU1F1 mutations have been described in patients with familial and sporadic combined pituitary hormone deficiency (CPHD) from different ethnic backgrounds. The majority are missense mutations clustered within the conserved POU‐specific and POU‐homeo domains, encoded by exons 4 and 6, respectively. Objectives This study aimed to identify the molecular basis and clinical characteristics of a Japanese CPHD family with a novel POU1F1 mutation. Design The POU1F1 gene was sequenced in identical twin brothers with mild CPHD. The mutation identified was also evaluated in family members as well as 188 Japanese controls and then examined in functional studies. Results A novel heterozygous splice site mutation (Ex2 + 1G>T; c.214 + 1G>T) was detected. This mutation was also present in their undiagnosed mother, but not in any of the controls. In vitro splicing studies suggested this mutation to result in an in‐frame skipping of exon 2, thus producing an internally deleted protein lacking most of the R2 transactivation subdomain (TAD‐R2). Heterologous expression studies of the mutated POU1F1 protein showed only modest reductions in its transactivation activities in HEK293T cells, while acting as a dominant‐negative inhibitor of the endogenous activities of POU1F1 in pituitary GH3 cells. Conclusions This is the first report of a mutation at the exon 2 donor splice site of POU1F1 , affecting TAD‐R2. The addition of this mutation to the growing list of pathological POU1F1 mutations may provide deeper insights into clinical heterogeneity in the expressions of individual mutations and a better understanding of the structure–function relationships of POU1F1.