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Four Novel Mutations of the LHX3 Gene Cause Combined Pituitary Hormone Deficiencies with or without Limited Neck Rotation

University Children’s Hospital (R.W.P., C.P., H.M.S., W.F.B.), 04317 Leipzig, Germany; Department of Biology (J.J.S., C.S.H.), Indiana University-Purdue University, Indianapolis, Indiana 46202-5120; University Children’s Hospital (M.A., J.H.B.), D-48149 Münster, Germany; M. S. Ramaiah Medical College (P.K.), 560054 Bangalore, India; Children’s Hospital Regina Margherita (J.B.), 10126 Torino, Italy; University Children’s Hospital (E.S., E.K.), 50931 Cologne, Germany; Lilly Research Laboratories (W.F.B.), 22419 Bad Homburg, Germany; and Department of Cellular and Integrative Physiology (S.J.R.), Indiana University School of Medicine, Indianapolis, Indiana 46202

Address all correspondence and requests for reprints to: Simon J. Rhodes, Ph.D., Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Medical Science Room 362A, 635 North Barnhill Drive, Indianapolis, Indiana 46202-5120. E-mail: srhodes{at}iupui.edu; or Roland Pfaeffle, M.D., University Children’s Hospital, Oststrasse 21-25, 04317 Leipzig, Germany. 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, 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 LHX3 mutations. This study extends the known molecular defects and range of phenotypes found in LHX3-associated diseases.

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