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Submitted on October 5, 2006
Accepted on February 20, 2007
University Children's Hospital, Leipzig, Germany; Dept. Biology, Indiana University-Purdue University, Indianapolis, USA; University Children's Hospital, Münster, Germany; M.S. Ramaiah Medical College, Bangalore, India; Children's Hospital Regina Margherita, Torino, Italy; University Children's Hospital, Cologne, Germany; Lilly Research Laboratories, Bad Homburg, Germany; Dept. Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, USA
* To whom correspondence should be addressed. E-mail: rpfaeffle{at}medizin.uni-leipzig.de.
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, PRL, TSH, LH, and FSH deficiency, abnormal pituitary morphology, and limited neck rotation.
Objective. To determine the frequency and nature of LHX3 mutations in patients with isolated GH deficiency (IGHD) or combined pituitary hormone deficiency (CPHD) and to 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. 366 patients with IGHD or CPHD.
Results. In 7 patients with CPHD from 4 consanguineous pedigrees, 4 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, PRL, TSH, 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 LHX3 mutations. This study extends the known molecular defects and range of phenotypes found in LHX3-associated diseases.
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