Three novel missense mutations within the LHX4 gene are associated with variable pituitary hormone deficiencies

Roland W. Pfaeffle, Chad S. Hunter, Jesse J. Savage, Mario Duran-Prado, Rachel D. Mullen, Zachary P. Neeb, Urs Eiholzer, Volker Hesse, Nadine G. Haddad, Heike M. Stobbe, Werner F. Blum, Johannes F W Weigel, Simon Rhodes

Research output: Contribution to journalArticle

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Abstract

Context: The LHX4 LIM-homeodomain transcription factor has essential roles in pituitary gland and nervous system development. Heterozygous mutations in LHX4 are associated with combined pituitary hormone deficiency. Objectives: Our objectives were to determine the nature and frequency of LHX4 mutations in patients with pituitary hormone deficiency and to examine the functional outcomes of observed mutations. Design: The LHX4 gene sequence was determined from patient DNA. The biochemical and gene regulatory properties of aberrant LHX4 proteins were characterized using structural predictions, pituitary gene transcription assays, and DNA binding experiments. Patients: A total of 253 patients from 245 pedigrees with GH deficiency and deficiency of at least one additional pituitary hormone was included in the study. Results: In five patients, three types of heterozygous missense mutations in LHX4 that result in substitution of conserved amino acids were identified. One substitution is between the LIM domains (R84C); the others are in the homeodomain (L190R; A210P). The patients have GH deficiency; some also display reductions in TSH, LH, FSH, or ACTH, and aberrant pituitary morphology. Structural models predict that the aberrant L190R and A210P LHX4 proteins would have impaired DNA binding and gene activation properties. Consistent with these models, EMSAs and transfection experiments using pituitary gene promoters demonstrate that whereas the R84C form has reduced activity, the L190R and A210P proteins are inactive. Conclusions: LHX4 mutations are a relatively rare cause of combined pituitary hormone deficiency. This report extends the range of phenotypes associated with LHX4 gene mutations and describes three novel exonic mutations in the gene.

Original languageEnglish
Pages (from-to)1062-1071
Number of pages10
JournalJournal of Clinical Endocrinology and Metabolism
Volume93
Issue number3
DOIs
StatePublished - Mar 2008

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Pituitary Hormones
Missense Mutation
Genes
Mutation
DNA
Substitution reactions
Proteins
Structural Models
Pituitary Gland
Mutation Rate
Amino Acid Substitution
Pedigree
Regulator Genes
Adrenocorticotropic Hormone
Neurology
Nervous System
Transcriptional Activation
Transcription
Transfection
Transcription Factors

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology, Diabetes and Metabolism

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Three novel missense mutations within the LHX4 gene are associated with variable pituitary hormone deficiencies. / Pfaeffle, Roland W.; Hunter, Chad S.; Savage, Jesse J.; Duran-Prado, Mario; Mullen, Rachel D.; Neeb, Zachary P.; Eiholzer, Urs; Hesse, Volker; Haddad, Nadine G.; Stobbe, Heike M.; Blum, Werner F.; Weigel, Johannes F W; Rhodes, Simon.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 93, No. 3, 03.2008, p. 1062-1071.

Research output: Contribution to journalArticle

Pfaeffle, RW, Hunter, CS, Savage, JJ, Duran-Prado, M, Mullen, RD, Neeb, ZP, Eiholzer, U, Hesse, V, Haddad, NG, Stobbe, HM, Blum, WF, Weigel, JFW & Rhodes, S 2008, 'Three novel missense mutations within the LHX4 gene are associated with variable pituitary hormone deficiencies', Journal of Clinical Endocrinology and Metabolism, vol. 93, no. 3, pp. 1062-1071. https://doi.org/10.1210/jc.2007-1525
Pfaeffle, Roland W. ; Hunter, Chad S. ; Savage, Jesse J. ; Duran-Prado, Mario ; Mullen, Rachel D. ; Neeb, Zachary P. ; Eiholzer, Urs ; Hesse, Volker ; Haddad, Nadine G. ; Stobbe, Heike M. ; Blum, Werner F. ; Weigel, Johannes F W ; Rhodes, Simon. / Three novel missense mutations within the LHX4 gene are associated with variable pituitary hormone deficiencies. In: Journal of Clinical Endocrinology and Metabolism. 2008 ; Vol. 93, No. 3. pp. 1062-1071.
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AU - Hunter, Chad S.

AU - Savage, Jesse J.

AU - Duran-Prado, Mario

AU - Mullen, Rachel D.

AU - Neeb, Zachary P.

AU - Eiholzer, Urs

AU - Hesse, Volker

AU - Haddad, Nadine G.

AU - Stobbe, Heike M.

AU - Blum, Werner F.

AU - Weigel, Johannes F W

AU - Rhodes, Simon

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N2 - Context: The LHX4 LIM-homeodomain transcription factor has essential roles in pituitary gland and nervous system development. Heterozygous mutations in LHX4 are associated with combined pituitary hormone deficiency. Objectives: Our objectives were to determine the nature and frequency of LHX4 mutations in patients with pituitary hormone deficiency and to examine the functional outcomes of observed mutations. Design: The LHX4 gene sequence was determined from patient DNA. The biochemical and gene regulatory properties of aberrant LHX4 proteins were characterized using structural predictions, pituitary gene transcription assays, and DNA binding experiments. Patients: A total of 253 patients from 245 pedigrees with GH deficiency and deficiency of at least one additional pituitary hormone was included in the study. Results: In five patients, three types of heterozygous missense mutations in LHX4 that result in substitution of conserved amino acids were identified. One substitution is between the LIM domains (R84C); the others are in the homeodomain (L190R; A210P). The patients have GH deficiency; some also display reductions in TSH, LH, FSH, or ACTH, and aberrant pituitary morphology. Structural models predict that the aberrant L190R and A210P LHX4 proteins would have impaired DNA binding and gene activation properties. Consistent with these models, EMSAs and transfection experiments using pituitary gene promoters demonstrate that whereas the R84C form has reduced activity, the L190R and A210P proteins are inactive. Conclusions: LHX4 mutations are a relatively rare cause of combined pituitary hormone deficiency. This report extends the range of phenotypes associated with LHX4 gene mutations and describes three novel exonic mutations in the gene.

AB - Context: The LHX4 LIM-homeodomain transcription factor has essential roles in pituitary gland and nervous system development. Heterozygous mutations in LHX4 are associated with combined pituitary hormone deficiency. Objectives: Our objectives were to determine the nature and frequency of LHX4 mutations in patients with pituitary hormone deficiency and to examine the functional outcomes of observed mutations. Design: The LHX4 gene sequence was determined from patient DNA. The biochemical and gene regulatory properties of aberrant LHX4 proteins were characterized using structural predictions, pituitary gene transcription assays, and DNA binding experiments. Patients: A total of 253 patients from 245 pedigrees with GH deficiency and deficiency of at least one additional pituitary hormone was included in the study. Results: In five patients, three types of heterozygous missense mutations in LHX4 that result in substitution of conserved amino acids were identified. One substitution is between the LIM domains (R84C); the others are in the homeodomain (L190R; A210P). The patients have GH deficiency; some also display reductions in TSH, LH, FSH, or ACTH, and aberrant pituitary morphology. Structural models predict that the aberrant L190R and A210P LHX4 proteins would have impaired DNA binding and gene activation properties. Consistent with these models, EMSAs and transfection experiments using pituitary gene promoters demonstrate that whereas the R84C form has reduced activity, the L190R and A210P proteins are inactive. Conclusions: LHX4 mutations are a relatively rare cause of combined pituitary hormone deficiency. This report extends the range of phenotypes associated with LHX4 gene mutations and describes three novel exonic mutations in the gene.

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