Mutations in LHX3 result in a new syndrome revealed by combined pituitary hormone deficiency

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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Figure 1: Predicted amino acid sequence, genomic organization and chromosomal mapping of human LHX3.
Figure 2: MRI of the neck and the pituitary region of one patient with CPHD and the Y116C homozygous LHX3 mutation.
Figure 3: The missense mutation identified in several members of family A.
Figure 4: The intragenic deletion identified in several members of family B.

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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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Correspondence to Serge Amselem.

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