A recessive mutation resulting in a disabling amino acid substitution (T194R) in the LHX3 homeodomain causes combined pituitary hormone deficiency

R. Malik; S. Park; Pozza S. Bechtold-Dalla; S. Hiedl; J. Roeb; P. Lohse; M. Duran-Prado; S. Rhodes

P1331

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Endocrine Abstracts (2012) 29 P1331

ICEECE2012 Poster Presentations Pituitary Basic (30 abstracts)

A recessive mutation resulting in a disabling amino acid substitution (T194R) in the LHX3 homeodomain causes combined pituitary hormone deficiency

R. Malik ¹ , S. Park ¹ , S. Bechtold-Dalla Pozza ² , S. Hiedl ² , J. Roeb ² , P. Lohse ² , M. Durán-Prado ³ & S. Rhodes ^1,

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Author affiliations

¹Indiana School of Medicine, Indianapolis, Indiana, USA; ²Ludwig-Maximilians University of Munich, Munich, Germany; ³University of Castilla la Mancha, Ciudad Real, Spain; ⁴Indiana University-Purdue University, Indianapolis, Indiana, USA.

LHX3, a LIM-homeodomain transcription factor, plays a critical role in pituitary and nervous system development. Mutations in the LHX3 gene are associated with combined pituitary hormone deficiency disease (CPHD). Two female siblings with neonatal complications were diagnosed with CPHD resulting from a novel, recessive mutation in LHX3. The index patient presented with classical symptoms of CPHD, featuring deficiencies of GH, LH, FSH, prolactin, TSH and later onset ACTH deficiency. Other complications included a hypoplastic anterior pituitary, respiratory distress, hearing impairment, hypoglycaemia and limited neck rotation. Upon sequencing of the LHX3 gene, it was found that the patients harboured a homozygous C→G transversion mutation in the fourth coding exon of the LHX3 gene, resulting in a change in amino acid 194 from threonine to arginine (T194R) in the DNA-binding homeodomain. Computer modeling predicted that the homeodomain structure resulting from the T194R mutation would be altered. Consistent with this prediction, biochemical analyses demonstrated that the T194 protein did not bind tested LHX3 DNA recognition sites nor did it activate the α glycoprotein subunit and prolactin target genes. This study describes a novel mutation altering a critical residue of the LHX3 protein and thus expands our understanding of the phenotypic features, molecular mechanism, and developmental course associated with mutations in the LHX3 gene.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This work was supported, however funding details unavailable.