Abstract
Combined pituitary hormone deficiency (CPHD) has been linked with rare abnormalities in genes encoding transcription factors necessary for pituitary development1. We have isolated LHX3, a gene involved in a new syndrome, using a candidate-gene approach developed on the basis of documented pituitary abnormalities of a recessive lethal mutation in mice generated by targeted disruption of Lhx3 (ref. 2). LHX3, encoding a member of the LIM class of homeodomain proteins3, consists of at least six exons located at 9q34. We identified a homozygous LHX3 defect in patients of two unrelated consanguineous families displaying a complete deficit in all but one (adrenocorticotropin) anterior pituitary hormone and a rigid cervical spine leading to limited head rotation. Two of these patients also displayed a severe pituitary hypoplasia, whereas one patient presented secondarily with an enlarged anterior pituitary. These LHX3 mutations consist of a missense mutation (Y116C) in the LIM2 domain at a phylogenetically conserved residue and an intragenic deletion predicting a severely truncated protein lacking the entire homeodomain. These data are consistent with function of LHX3 in the proper development of all anterior pituitary cell types, except corticotropes, and extrapituitary structures.
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References
Burrows, H., Douglas, K., Seasholtz, A. & Camper, S. Genealogy of anterior pituitary gland: tracing a family tree. Trends Endocrinol. Metab. 10, 343–352 (1999).
Sheng, H.Z. et al. Specification of pituitary cell lineages by the LIM homeobox gene Lhx3. Science 272, 1004–1007 (1996).
Dawid, I.B., Breen, J.J. & Toyama, R. LIM domains: multiple roles as adapters and functional modifiers in protein interactions. Trends Genet. 14, 156–162 (1998).
Couly, G. & Le Douarin, N.M. The fate map of the cephalic neural primordium at the presomitic to the 3-somite stage in the avian embryo. Development 103, 101–113 (1988).
Eagleson, G.W. & Harris, W.A. Mapping of the presumptive brain regions in the neural plate of Xenopus laevis. J. Neurobiol. 21, 427–440 (1990).
Ikeda, H., Suzuki, J., Sasano, N. & Niizuma, H. The development and morphogenesis of the human pituitary gland. Anat. Embryol. 178, 327–336 (1988).
Japon, M.A., Rubinstein, M. & Low, M.J. In situ hybridization analysis of anterior pituitary hormone gene expression during fetal mouse development. J. Histochem. Cytochem. 42, 1117–1125 (1994).
Zhadanov, A.B., Copeland, N.G., Gilbert, D.J., Jenkins, N.A. & Westphal, H. Genomic structure and chromosomal localization of the mouse LIM/homeobox gene Lhx3. Genomics 27, 27–32 (1995).
Sanchez-Garcia, I. & Rabbitts, T.H. The LIM domain: a new structural motif found in zinc-finger-like proteins. Trends Genet. 10, 315–320 (1994).
Wu, W. et al. Mutations in PROP1 cause familial combined pituitary hormone deficiency. Nature Genet. 18, 147–149 (1998).
Duquesnoy, P. et al. Human Prop-1: cloning, mapping, genomic structure. Mutations in familial combined pituitary hormone deficiency. FEBS Lett. 437, 216–220 (1998).
Bach, I. et al. P-Lim, a LIM homeodomain factor, is expressed during pituitary organ and cell commitment and synergizes with Pit-1. Proc. Natl Acad. Sci. USA 92, 2720–2724 (1995).
Mendonca, B.B. et al. Longitudinal hormonal and pituitary imaging changes in two females with combined pituitary hormone deficiency due to deletion of A301,G302 in the PROP1 gene. J. Clin. Endocrinol. Metab. 84, 942–945 (1999).
Sharma, K. et al. LIM homeodomain factors Lhx3 and Lhx4 assign subtype identities for motor neurons. Cell 95, 817–828 (1998).
Parks, J.S., Brown, M.R., Hurley, D.L., Phelps, C.J. & Wajnrajch, M.P. Heritable disorders of pituitary development. J. Clin. Endocrinol. Metab. 84, 4362–4370 (1999).
Tsuchida, T. et al. Topographic organization of embryonic motor neurons defined by expression of LIM homeobox genes. Cell 79, 957–970 (1994).
Taira, M., Hayes, W.P., Otani, H. & Dawid, I.B. Expression of LIM class homeobox gene Xlim-3 in Xenopus development is limited to neural and neuroendocrine tissues. Dev. Biol. 159, 245–256 (1993).
Appel, B. et al. Motoneuron fate specification revealed by patterned LIM homeobox gene expression in embryonic zebrafish. Development 121, 4117–4125 (1995).
Thompson, J.D., Higgins, D.G. & Gibson, T.J. CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res. 22, 4673–4680 (1994).
Pinkel, D., Straume, T. & Gray, J.W. Cytogenetic analysis using quantitative, high-sensitivity, fluorescence hybridization. Proc. Natl Acad. Sci. USA 83, 2934–2938 (1986).
Acknowledgements
We thank the families for participation; J. Blustajn, F. Dastot, P. Duquesnoy, S. Michel, J. Pantel, F. Renault and C. Zindel for discussions and technical help; and M. Le Guennec for editorial assistance. I.N. has been the recipient of a fellowship from Novo Nordisk. This work was supported by grants from the Association Française contre les Myopathies.
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Netchine, I., Sobrier, ML., Krude, H. et al. Mutations in LHX3 result in a new syndrome revealed by combined pituitary hormone deficiency. Nat Genet 25, 182–186 (2000). https://doi.org/10.1038/76041
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DOI: https://doi.org/10.1038/76041
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