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Three Novel Missense Mutations within the LHX4 Gene Are Associated with Variable Pituitary Hormone Deficiencies

University Children’s Hospital (R.W.P., H.M.S., W.F.B., J.F.W.W.), 04317 Leipzig, Germany; Department of Biology (C.S.H., J.J.S., Z.P.N.), Indiana University-Purdue University, Indianapolis, Indiana 46202-5196; Department of Cell Biology, Physiology, and Immunology (M.D.-P.), University of Cordoba, 14014 Cordoba, Spain; Departments of Cellular and Integrative Physiology (R.D.M., S.J.R.) and Pediatrics (N.G.H.), Indiana University School of Medicine, Indianapolis, Indiana 46202-5120; Center for Pediatric Endocrinology Zürich (PEZZ) (U.E.), CH-8006 Zürich, Switzerland; Department of Pediatrics (V.H.), Children’s Hospital Berlin-Lichtenberg, 10365 Berlin, Germany; and Lilly Research Laboratories (W.F.B.), 61350 Bad Homburg, Germany

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 Building Room 362A, 635 N. Barnhill Drive, Indianapolis, Indiana 46202-5120. E-mail: srhodes{at}iupui.edu.

Context: The LHX4 LIM-homeodomain transcription factor has essential roles in pituitary gland and nervous system development. Heterozygous mutations in LHX4 are associated with combined pituitary hormone deficiency.

Objectives: Our objectives were to determine the nature and frequency of LHX4 mutations in patients with pituitary hormone deficiency and to examine the functional outcomes of observed mutations.

Design: The LHX4 gene sequence was determined from patient DNA. The biochemical and gene regulatory properties of aberrant LHX4 proteins were characterized using structural predictions, pituitary gene transcription assays, and DNA binding experiments.

Patients: A total of 253 patients from 245 pedigrees with GH deficiency and deficiency of at least one additional pituitary hormone was included in the study.

Results: In five patients, three types of heterozygous missense mutations in LHX4 that result in substitution of conserved amino acids were identified. One substitution is between the LIM domains (R84C); the others are in the homeodomain (L190R; A210P). The patients have GH deficiency; some also display reductions in TSH, LH, FSH, or ACTH, and aberrant pituitary morphology. Structural models predict that the aberrant L190R and A210P LHX4 proteins would have impaired DNA binding and gene activation properties. Consistent with these models, EMSAs and transfection experiments using pituitary gene promoters demonstrate that whereas the R84C form has reduced activity, the L190R and A210P proteins are inactive.

Conclusions: LHX4 mutations are a relatively rare cause of combined pituitary hormone deficiency. This report extends the range of phenotypes associated with LHX4 gene mutations and describes three novel exonic mutations in the gene.

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				F. Castinetti, A. Saveanu, R. Reynaud, M. H. Quentien, A. Buffin, R. Brauner, N. Kaffel, F. Albarel, A. M. Guedj, M. El Kholy, et al. A Novel Dysfunctional LHX4 Mutation with High Phenotypical Variability in Patients with Hypopituitarism J. Clin. Endocrinol. Metab., July 1, 2008; 93(7): 2790 - 2799. [Abstract] [Full Text] [PDF]