Screening of LHX2 in patients presenting growth retardation with posterior pituitary and ocular abnormalities

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.