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Molecular analysis of LHX3 and PROP-1 in pituitary hormone deficiency patients with posterior pituitary ectopia
K W Sloop1, E C Walvoord, A D Showalter
1Department of Biology, Indiana University-Purdue University, Indianapolis 46202-5132, USA.
Insights
The cause of posterior pituitary ectopia and pituitary hormone deficiencies in children remains unknown. Genetic analysis ruled out mutations in LHX3 and PROP-1, suggesting other genetic factors are involved.
Area of Science:
- Endocrinology
- Developmental Biology
- Genetics
Background:
- Posterior pituitary ectopia with anterior pituitary hormone deficiencies is a rare condition with an unknown etiology.
- Abnormal pituitary development, including ectopic posterior lobe location and hypoplastic anterior lobes, is observed in affected children.
- Transcription factors like PIT-1 and PROP-1 are crucial for pituitary development, with mutations causing combined pituitary hormone deficiency (CPHD).
Purpose of the Study:
- To investigate the role of human LHX3 isoforms in the pathogenesis of posterior pituitary ectopia associated with anterior pituitary hypopituitarism.
- To determine if mutations in LHX3 or PROP-1 are responsible for this specific pituitary developmental anomaly.
Main Methods:
- Comprehensive molecular analysis of the two human LHX3 isoforms.
- Genetic analysis of the PROP-1 gene.
- Magnetic resonance imaging (MRI) to assess pituitary gland development.
Main Results:
- No loss-of-function mutations were detected in the LHX3 gene.
- Mutations in PROP-1 were not found to be causative for this phenotype.
- The study identified a cohort of children with combined pituitary hormone deficiency (CPHD) or isolated GH deficiency and posterior pituitary ectopia.
Conclusions:
- Aberrant function of LHX3 or PROP-1 does not appear to cause posterior pituitary ectopia with anterior pituitary hypopituitarism.
- The underlying genetic defects likely reside in other gene loci not examined in this study.
- Further research is needed to identify the specific genes involved in this complex pituitary developmental disorder.
Abstract:
The cause of posterior pituitary ectopia associated with anterior pituitary hormone deficiencies is unknown. We describe children with combined pituitary hormone deficiency (CPHD) or isolated GH deficiency. In all cases, magnetic resonance imaging examination revealed abnormal pituitary gland development featuring ectopic posterior lobe location and frequently hypoplastic anterior lobes. Embryonic development of the pituitary requires the coordinated expression of specific transcription factors. Mutations of the PIT-1 and PROP-1 transcription factors are responsible for CPHD in some patients with normally positioned posterior pituitaries. In mice, the Lhx3 LIM homeodomain transcription factor is required for both structural development and cellular differentiation of the pituitary gland. Thus, we hypothesized that mutations in one or both of the two human LHX3 isoforms are responsible for posterior pituitary ectopia associated with anterior pituitary hypopituitarism. Comprehensive molecular analysis of the LHX3 isoforms was performed to test this hypothesis. No loss of function mutations in the LHX3 gene were detected. In addition, analysis of PROP-1 did not reveal mutations that might cause this phenotype. These studies suggest that the abnormal processes leading to the development of CPHD or GH deficiency associated with posterior pituitary ectopia are not a result of aberrant LHX3 or PROP- 1 function, but may be caused by defects at other gene loci.