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.

Keywords:
LIM, Development, Pediatric patients, Growth, Transcription
1.
Davis SW, Castinetti F, Carvalho LR, Ellsworth BS, Potok MA, Lyons RH, Brinkmeier ML, Mendonça BB, Brue T, Camper SA: Molecular mechanisms of pituitary organogenesis: in search of novel regulatory genes. Mol Cell Endocrinol 2010;323:4-19.
2.
Kelberman D, Dattani MT: Role of transcription factors in midline central nervous system and pituitary defects. Endocr Dev 2009;14:67-82.
3.
Pfäffle R, Klammt J: Pituitary transcription factors in the aetiology of combined pituitary hormone deficiency. Best Pract Res Clin Endocrinol Metab 2011;25:43-60.
4.
Prince KL, Walvoord EC, Rhodes SJ: The role of homeodomain transcription factors in heritable pituitary disease. Nat Rev Endocrinol 2011;7:727-737.
5.
Bach I, Rhodes SJ, Pearse RV 2nd, Heinzel T, Gloss B, Scully KM, Sawchenko PE, Rosenfeld MG: P-lim, a lim homeodomain factor, is expressed during pituitary organ and cell commitment and synergizes with pit-1. Proc Natl Acad Sci USA 1995;92:2720-2724.
6.
Granger A, Bleux C, Kottler ML, Rhodes SJ, Counis R, Laverriere JN: The lim-homeodomain proteins isl-1 and lhx3 act with steroidogenic factor 1 to enhance gonadotrope-specific activity of the gonadotropin-releasing hormone receptor gene promoter. Mol Endocrinol 2006;20:2093-2108.
7.
Sloop KW, Meier BC, Bridwell JL, Parker GE, Schiller AM, Rhodes SJ: Differential activation of pituitary hormone genes by human lhx3 isoforms with distinct DNA binding properties. Mol Endocrinol 1999;13:2212-2225.
8.
Seidah NG, Barale JC, Marcinkiewicz M, Mattei MG, Day R, Chretien M: The mouse homeoprotein mlim-3 is expressed early in cells derived from the neuroepithelium and persists in adult pituitary. DNA Cell Biol 1994;13:1163-1180.
9.
Sheng HZ, Moriyama K, Yamashita T, Li H, Potter SS, Mahon KA, Westphal H: Multistep control of pituitary organogenesis. Science 1997;278:1809-1812.
10.
Sobrier ML, Attie-Bitach T, Netchine I, Encha-Razavi F, Vekemans M, Amselem S: Pathophysiology of syndromic combined pituitary hormone deficiency due to a lhx3 defect in light of lhx3 and lhx4 expression during early human development. Gene Expr Patterns 2004;5:279-284.
11.
Sheng HZ, Zhadanov AB, Mosinger B Jr, Fujii T, Bertuzzi S, Grinberg A, Lee EJ, Huang SP, Mahon KA, Westphal H: Specification of pituitary cell lineages by the lim homeobox gene lhx3. Science 1996;272:1004-1007.
12.
Colvin SC, Malik RE, Showalter AD, Sloop KW, Rhodes SJ: Model of pediatric pituitary hormone deficiency separates the endocrine and neural functions of the lhx3 transcription factor in vivo. Proc Natl Acad Sci USA 2011;108:173-178.
13.
Bhangoo AP, Hunter CS, Savage JJ, Anhalt H, Pavlakis S, Walvoord EC, Ten S, Rhodes SJ: Clinical case seminar: a novel lhx3 mutation presenting as combined pituitary hormonal deficiency. J Clin Endocrinol Metab 2006;91:747-753.
14.
Bonfig W, Krude H, Schmidt H: A novel mutation of lhx3 is associated with combined pituitary hormone deficiency including ACTH deficiency, sensorineural hearing loss, and short neck - a case report and review of the literature. Eur J Pediatr 2011;170:1017-1021.
15.
Kristrom B, Zdunek AM, Rydh A, Jonsson H, Sehlin P, Escher SA: A novel mutation in the lim homeobox 3 gene is responsible for combined pituitary hormone deficiency, hearing impairment, and vertebral malformations. J Clin Endocrinol Metab 2009;94:1154-1161.
16.
Netchine I, Sobrier ML, Krude H, Schnabel D, Maghnie M, Marcos E, Duriez B, Cacheux V, Moers A, Goossens M, Gruters A, Amselem S: Mutations in lhx3 result in a new syndrome revealed by combined pituitary hormone deficiency. Nat Genet 2000;25:182-186.
17.
Pfäffle RW, Savage JJ, Hunter CS, Palme C, Ahlmann M, Kumar P, Bellone J, Schoenau E, Korsch E, Bramswig JH, Stobbe HM, Blum WF, Rhodes SJ: Four novel mutations of the lhx3 gene cause combined pituitary hormone deficiencies with or without limited neck rotation. J Clin Endocrinol Metab 2007;92:1909-1919.
18.
Rajab A, Kelberman D, de Castro SC, Biebermann H, Shaikh H, Pearce K, Hall CM, Shaikh G, Gerrelli D, Grueters A, Krude H, Dattani MT: Novel mutations in lhx3 are associated with hypopituitarism and sensorineural hearing loss. Hum Mol Genet 2008;17:2150-2159.
19.
Sloop KW, Dwyer CJ, Rhodes SJ: An isoform-specific inhibitory domain regulates the lhx3 lim homeodomain factor holoprotein and the production of a functional alternate translation form. J Biol Chem 2001;276:36311-36319.
20.
Sloop KW, Parker GE, Hanna KR, Wright HA, Rhodes SJ: Lhx3 transcription factor mutations associated with combined pituitary hormone deficiency impair the activation of pituitary target genes. Gene 2001;265:61-69.
21.
Pfäffle RW, Hunter CS, Savage JJ, Duran-Prado M, Mullen RD, Neeb ZP, Eiholzer U, Hesse V, Haddad NG, Stobbe HM, Blum WF, Weigel JF, Rhodes SJ: Three novel missense mutations within the lhx4 gene are associated with variable pituitary hormone deficiencies. J Clin Endocrinol Metab 2008;93:1062-1071.
22.
Kissinger CR, Liu BS, Martin-Blanco E, Kornberg TB, Pabo CO: Crystal structure of an engrailed homeodomain-DNA complex at 2.8 Å resolution: a framework for understanding homeodomain-DNA interactions. Cell 1990;63:579-590.
23.
Bridwell JA, Price JR, Parker GE, McCutchan Schiller A, Sloop KW, Rhodes SJ: Role of the lim domains in DNA recognition by the lhx3 neuroendocrine transcription factor. Gene 2001;277:239-250.
24.
Savage JJ, Hunter CS, Clark-Sturm SL, Jacob TM, Pfäffle RW, Rhodes SJ: Mutations in the lhx3 gene cause dysregulation of pituitary and neural target genes that reflect patient phenotypes. Gene 2007;400:44-51.
25.
Li H, Witte DP, Branford WW, Aronow BJ, Weinstein M, Kaur S, Wert S, Singh G, Schreiner CM, Whitsett JA, et al: Gsh-4 encodes a lim-type homeodomain, is expressed in the developing central nervous system and is required for early postnatal survival. EMBO J 1994;13:2876-2885.
26.
Nasonkin IO, Ward RD, Raetzman LT, Seasholtz AF, Saunders TL, Gillespie PJ, Camper SA: Pituitary hypoplasia and respiratory distress syndrome in prop1 knockout mice. Hum Mol Genet 2004;13:2727-2735.
27.
De Zegher F, Pernasetti F, Vanhole C, De-vlieger H, Van den Berghe G, Martial JA: The prenatal role of thyroid hormone evidenced by fetomaternal pit-1 deficiency. J Clin Endocrinol Metab 1995;80:3127-3130.
28.
Böttner A, Keller E, Kratzsch J, Stobbe H, Weigel JF, Keller A, Hirsch W, Kiess W, Blum WF, Pfäffle RW: Prop1 mutations cause progressive deterioration of anterior pituitary function including adrenal insufficiency: a longitudinal analysis. J Clin Endocrinol Metab 2004;89:5256-5265.
29.
Banerjee-Basu S, Baxevanis AD: Molecular evolution of the homeodomain family of transcription factors. Nucleic Acids Res 2001;29:3258-3269.
30.
Grow MW, Krieg PA: Tinman function is essential for vertebrate heart development: elimination of cardiac differentiation by dominant inhibitory mutants of the tinman-related genes, xnkx2-3 and xnkx2-5. Dev Biol 1998;204:187-196.
31.
Mead PE, Brivanlou IH, Kelley CM, Zon LI: Bmp-4-responsive regulation of dorsal-ventral patterning by the homeobox protein mix.1. Nature 1996;382:357-360.
32.
Sloop KW, Dwyer CJ, Rhodes SJ: An isoform-specific inhibitory domain regulates the lhx3 lim homeodomain factor holoprotein and the production of a functional alternate translation form. J Biol Chem 2001;276:36311-36319.
33.
Prader A, Largo RH, Molinari L, Issler C: Physical growth of Swiss children from birth to 20 years of age. First Zurich longitudinal study of growth and development. Helv Paediatr Acta Suppl 1989;52:1-125.
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2012
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