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Screening of LHX2 in patients presenting growth retardation with posterior pituitary and ocular abnormalities
Christelle Pérez1, Florence Dastot-Le Moal, Nathalie Collot
1Inserm U.933, Hôpital Armand-Trousseau, Université Pierre et Marie Curie-Paris 6, 75571 Paris Cedex 12, France.
Background:
In humans, pituitary hormone deficiency may be part of a syndrome including extra-pituitary defects like ocular abnormalities. Very few genes have been linked to this particular phenotype. In the mouse, Lhx2, which encodes a member of the LIM (Lin-11, Isl-1, and Mec-3) class of homeodomain proteins, was shown to be expressed during early development in the posterior pituitary, eye, and liver, and its expression persists in adulthood in the central nervous system Lhx2(-/-) mice display absence of posterior pituitary and intermediate lobes, malformation of the anterior lobe, anophthalmia, and they die from anemia.
Methods:
We tested the implication of the LHX2 gene in patients presenting pituitary hormone deficiency associated with ectopic or nonvisible posterior pituitary and developmental ocular defects. A cohort of 59 patients, including two familial cases, was studied. Direct sequencing of the LHX2 coding sequence and intron/exon boundaries was performed. LHX2 transcriptional activity on several pituitary promoters (AGSU, PRL, POU1F1, and TSHB) was tested in vitro.
Results:
Six heterozygous sequence variations were identified, among which two are novel missense changes (p.Ala203Thr and p.Val333Met). In vitro, LHX2 activates transcription of TSHB, PRL, and POU1F1 promoters in the HEK293 cell line. A synergistic action of POU1F1 and LHX2 was also shown on these promoters. The two missense variations were tested and no significant difference was observed, leading to the conclusion that they are not deleterious.
Conclusions:
These results suggest that if LHX2 is involved in pituitary hormone deficiency associated with posterior pituitary and ocular defects, it would be a rare cause of this disease condition.
Insights
The LHX2 gene is rarely implicated in pituitary hormone deficiency with ocular defects. Researchers found no evidence that identified LHX2 variations caused these conditions in patients.
Area of Science:
- Genetics and Molecular Biology
- Endocrinology
- Developmental Biology
Background:
- Pituitary hormone deficiency can co-occur with ocular abnormalities in humans.
- The genetic basis for this combined phenotype is poorly understood, with few genes identified.
- Mouse models lacking Lhx2 exhibit severe developmental defects, including anophthalmia and pituitary malformations.
Purpose of the Study:
- To investigate the role of the LHX2 gene in patients with pituitary hormone deficiency and associated ocular defects.
- To identify potential genetic variations in LHX2 that could contribute to this syndrome.
Main Methods:
- Sequencing of the LHX2 gene in 59 patients with pituitary and ocular defects.
- In vitro analysis of LHX2's transcriptional activity on pituitary-specific gene promoters.
- Evaluation of the pathogenicity of identified LHX2 sequence variations.
Main Results:
- Six heterozygous LHX2 sequence variations were found, including two novel missense changes.
- LHX2 demonstrated transcriptional activation of TSHB, PRL, and POU1F1 promoters in vitro.
- The identified missense variations were determined to be non-deleterious, showing no significant functional difference.
Conclusions:
- LHX2 is unlikely to be a common cause of pituitary hormone deficiency with posterior pituitary and ocular defects.
- The identified variations in LHX2 did not appear to contribute to the observed phenotype in the studied cohort.
