A Recessive Mutation Resulting in a Disabling Amino Acid Substitution (T194R) in the LHX3 Homeodomain Causes Combined Pituitary Hormone Deficiency

Abstract

Background/Aims:Recessive mutations in the LHX3 ho-meodomain transcription factor gene are associated with developmental disorders affecting the pituitary and nervous system. We describe pediatric patients with combined pituitary hormone deficiency (CPHD) who harbor a novel mutation in LHX3. Methods:Two female siblings from related parents were examined. Both patients had neonatal complications. The index patient had CPHD featuring deficiencies of GH, LH, FSH, PRL, and TSH, with later onset of ACTH deficiency. She also had a hypoplastic anterior pituitary, respiratory distress, hearing impairment, and limited neck rotation. The LHX3 gene was sequenced and the biochemical properties of the predicted altered proteins were characterized. Results: A novel homozygous mutation predicted to change amino acid 194 from threonine to arginine (T194R) was detected in both patients. This amino acid is conserved in the DNA-binding homeodomain. Computer modeling predicted that the T194R change would alter the homeodomain structure. The T194R protein did not bind tested LHX3 DNA recognition sites and did not activate the α-glycoprotein and PRL target genes. Conclusion: The T194R mutation affects a critical residue in the LHX3 protein. This study extends our understanding of the phenotypic features, molecular mechanism, and developmental course associated with mutations in the LHX3 gene.

Two novel LHX3 mutations in patients with combined pituitary hormone deficiency including cervical rigidity and sensorineural hearing loss

“…Two of the affected patients also displayed rigidity of the cervical spine and short neck with limited rotation. Clinically, there was no evidence of cardiac defects or skin manifestations as reported earlier in some reports [32, 34]. Birth length in one of our patients was slightly below the mean centile for gestational age, which supports earlier findings that IGFs are necessary for that period but the severe deficiency interacts with intrauterine longitudinal growth [33].…”

Heterozygous LHX3 mutations may lead to a mild phenotype of combined pituitary hormone deficiency

“…In humans, homozygous variants of LHX3 lead to CPHD. To date, 14 autosomal recessive variants of LHX3 have been reported in patients with CPHD [12][13][14][15][16][17][18][19][20][21]. All of these variants were identified in exons, except for one located in an intronic region [18].…”

Analysis of the Asymmetric Gene Expression between the Left and Right Hemispheres of <i>Drosophila</i> Brain

“…Its human homologue is LIM homeobox 3, a member of a large protein family that carries the LIM domain. It is required for pituitary development and motor neuron specification, and its mutations can cause combined pituitary hormone deficiency [16].…”