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

Susanne Bechtold Dalla Pozza, Stefan Hiedl, Julia Roeb, Peter Lohse, Raleigh E. Malik, Soyoung Park, Mario Durán-Prado, Simon Rhodes

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Background/Aims: Recessive mutations in the LHX3 homeodomain 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 LHX. 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*-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.

Original languageEnglish
Pages (from-to)41-51
Number of pages11
JournalHormone Research in Paediatrics
Volume77
Issue number1
DOIs
StatePublished - Feb 2012

Fingerprint

Amino Acid Substitution
Mutation
Genes
Pituitary Diseases
Amino Acids
Proteins
DNA
Threonine
Hearing Loss
Adrenocorticotropic Hormone
Nervous System
Arginine
Siblings
Glycoproteins
Transcription Factors
Neck
Parents
Combined Pituitary Hormone Deficiency
Pediatrics

Keywords

  • Development
  • Growth
  • LIM
  • Pediatric patients
  • Transcription

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism
  • Pediatrics, Perinatology, and Child Health

Cite this

A recessive mutation resulting in a disabling amino acid substitution (T194R) in the LHX3 homeodomain causes combined pituitary hormone deficiency. / Pozza, Susanne Bechtold Dalla; Hiedl, Stefan; Roeb, Julia; Lohse, Peter; Malik, Raleigh E.; Park, Soyoung; Durán-Prado, Mario; Rhodes, Simon.

In: Hormone Research in Paediatrics, Vol. 77, No. 1, 02.2012, p. 41-51.

Research output: Contribution to journalArticle

Pozza, Susanne Bechtold Dalla ; Hiedl, Stefan ; Roeb, Julia ; Lohse, Peter ; Malik, Raleigh E. ; Park, Soyoung ; Durán-Prado, Mario ; Rhodes, Simon. / A recessive mutation resulting in a disabling amino acid substitution (T194R) in the LHX3 homeodomain causes combined pituitary hormone deficiency. In: Hormone Research in Paediatrics. 2012 ; Vol. 77, No. 1. pp. 41-51.
@article{a37deaa355ff4685880cb3e9fee7f7e1,
title = "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 homeodomain 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 LHX. 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*-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 = "Development, Growth, LIM, Pediatric patients, Transcription",
author = "Pozza, {Susanne Bechtold Dalla} and Stefan Hiedl and Julia Roeb and Peter Lohse and Malik, {Raleigh E.} and Soyoung Park and Mario Dur{\'a}n-Prado and Simon Rhodes",
year = "2012",
month = "2",
doi = "10.1159/000335929",
language = "English",
volume = "77",
pages = "41--51",
journal = "Hormone Research in Paediatrics",
issn = "1663-2818",
publisher = "S. Karger AG",
number = "1",

}

TY - JOUR

T1 - A recessive mutation resulting in a disabling amino acid substitution (T194R) in the LHX3 homeodomain causes combined pituitary hormone deficiency

AU - Pozza, Susanne Bechtold Dalla

AU - Hiedl, Stefan

AU - Roeb, Julia

AU - Lohse, Peter

AU - Malik, Raleigh E.

AU - Park, Soyoung

AU - Durán-Prado, Mario

AU - Rhodes, Simon

PY - 2012/2

Y1 - 2012/2

N2 - Background/Aims: Recessive mutations in the LHX3 homeodomain 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 LHX. 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*-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.

AB - Background/Aims: Recessive mutations in the LHX3 homeodomain 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 LHX. 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*-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.

KW - Development

KW - Growth

KW - LIM

KW - Pediatric patients

KW - Transcription

UR - http://www.scopus.com/inward/record.url?scp=84862783757&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84862783757&partnerID=8YFLogxK

U2 - 10.1159/000335929

DO - 10.1159/000335929

M3 - Article

C2 - 22286346

AN - SCOPUS:84862783757

VL - 77

SP - 41

EP - 51

JO - Hormone Research in Paediatrics

JF - Hormone Research in Paediatrics

SN - 1663-2818

IS - 1

ER -