Gradual Loss of ACTH Due to a Novel Mutation in LHX4: Comprehensive Mutation Screening in Japanese Patients with Congenital Hypopituitarism

Masaki Takagi,Tomohiro Ishii,Satoshi Narumi,Mikako Inokuchi,Koji Muroya,Yumi Asakura,Tomonobu Hasegawa,Naoko Amano,Yukihiro Hasegawa,Masanori Adachi,Jean-Marc A Lobaccaro

doi:10.1371/journal.pone.0046008

Masaki Takagi, Tomohiro Ishii + Show 9 more

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https://doi.org/10.1371/journal.pone.0046008

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Journal: PloS one	Publication Date: Sep 24, 2012
Citations: 28	License type: CC BY 4.0

Affiliation: Keio University, Kanagawa Children's Medical Center

Abstract

Mutations in transcription factors genes, which are well regulated spatially and temporally in the pituitary gland, result in congenital hypopituitarism (CH) in humans. The prevalence of CH attributable to transcription factor mutations appears to be rare and varies among populations.This study aimed to define the prevalence of CH in terms of nine CH-associated genes among Japanese patients. We enrolled 91 Japanese CH patients for DNA sequencing of POU1F1, PROP1, HESX1, LHX3, LHX4, SOX2, SOX3, OTX2, and GLI2. Additionally, gene copy numbers for POU1F1, PROP1, HESX1, LHX3, and LHX4 were examined by multiplex ligation-dependent probe amplification. The gene regulatory properties of mutant LHX4 proteins were characterized in vitro. We identified two novel heterozygous LHX4 mutations, namely c.249-1G>A, p.V75I, and one common POU1F1 mutation, p.R271W. The patient harboring the c.249-1G>A mutation exhibited isolated growth hormone deficiency at diagnosis and a gradual loss of ACTH, whereas the patient with the p.V75I mutation exhibited multiple pituitary hormone deficiency. In vitro experiments showed that both LHX4 mutations were associated with an impairment of the transactivation capacities of POU1F1 andαGSU, without any dominant-negative effects. The total mutation prevalence in Japanese CH patients was 3.3%. This study is the first to describe, a gradual loss of ACTH in a patient carrying an LHX4 mutation. Careful monitoring of hypothalamic–pituitary -adrenal function is recommended for CH patients with LHX4 mutations.

Highlights

The proliferation and terminal differentiation of the anterior pituitary gland is strongly influenced by the precise spatial and temporal expression of transcription factors [1,2,3]
Previous studies have shown that these transcriptional factor mutations are rare among congenital hypopituitarism (CH) patients and that the mutation prevalence varies among populations, only a few genetic screening studies have been conducted
This study aimed to determine the prevalence of transcription factor mutations in Japanese CH patients with PCR-based sequencing of nine CH-associated genes, namely POU1F1, PROP1, HESX1, LHX3, LHX4, SOX2, SOX3, OTX2, and GLI2

Summary

Introduction

The proliferation and terminal differentiation of the anterior pituitary gland is strongly influenced by the precise spatial and temporal expression of transcription factors [1,2,3]. Mutations in these transcription factors often result in various types of congenital hypopituitarism (CH) [1,2,3]. Previous studies have shown that these transcriptional factor mutations are rare among CH patients and that the mutation prevalence varies among populations, only a few genetic screening studies have been conducted. 90% of the mutations identified in this report were PROP1 common mutations (149delGA and 296delGA). The 296delGA mutation represents a mutational hot spot within the PROP1 gene rather than a common founder mutation [7], studies from other ethnic groups often report a low prevalence of PROP1 mutations [8,9]

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