Four novel mutations of the LHX3 gene cause combined pituitary hormone deficiencies with or without limited neck rotation

Roland W. Pfaeffle, Jesse J. Savage, Chad S. Hunter, Christina Palme, Martina Ahlmann, Prasanna Kumar, Jaele Bellone, Eckhard Schoenau, Eckhard Korsch, Jürgen H. Brämswig, Heike M. Stobbe, Werner F. Blum, Simon J. Rhodes

Research output: Contribution to journalArticle

74 Scopus citations


Context: The Lhx3 LIM-homeodomain transcription factor gene is required for development of the pituitary and motoneurons in mice. Human LHX3 gene mutations have been reported in five subjects with a phenotype consisting of GH, prolactin, TSH, LH, and FSH deficiency; abnormal pituitary morphology; and limited neck rotation. Objective: The objective of the study was to determine the frequency and nature of LHX3 mutations in patients with isolated GH deficiency or combined pituitary hormone deficiency (CPHD) and characterize the molecular consequences of mutations. Design: The LHX3 sequence was determined. The biochemical properties of aberrant LHX3 proteins resulting from observed mutations were characterized using reporter gene and DNA binding experiments. Patients: The study included 366 patients with isolated GH deficiency or CPHD. Results: In seven patients with CPHD from four consanguineous pedigrees, four novel, recessive mutations were identified: a deletion of the entire gene (del/del), mutations causing truncated proteins (E173ter, W224ter), and a mutation causing a substitution in the homeodomain (A210V). The mutations were associated with diminished DNA binding and pituitary gene activation, consistent with observed hormone deficiencies. Whereas subjects with del/del, E173ter, and A210V mutations had limited neck rotation, patients with the W224ter mutation did not. Conclusions: LHX3 mutations are a rare cause of CPHD involving deficiencies for GH, prolactin, TSH, and LH/FSH in all patients. Whereas most patients have a severe hormone deficiency manifesting after birth, milder forms can be observed, and limited neck rotation is not a universal feature of patients with LHX3mutations. This study extends the known molecular defects and range of phenotypes found in LHX3-associated diseases.

Original languageEnglish (US)
Pages (from-to)1909-1919
Number of pages11
JournalJournal of Clinical Endocrinology and Metabolism
Issue number5
StatePublished - May 2007


ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

Cite this

Pfaeffle, R. W., Savage, J. J., Hunter, C. S., Palme, C., Ahlmann, M., Kumar, P., Bellone, J., Schoenau, E., Korsch, E., Brämswig, J. H., Stobbe, H. M., Blum, W. F., & Rhodes, S. J. (2007). Four novel mutations of the LHX3 gene cause combined pituitary hormone deficiencies with or without limited neck rotation. Journal of Clinical Endocrinology and Metabolism, 92(5), 1909-1919.