ArticlePloS one2015
Identifying the Deleterious Effect of Rare LHX4 Allelic Variants, a Challenging Issue.
Article in PloS one, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 20 citations in OpenAlex.
- A case of congenital hypopituitarism harboring a nonsense variant in theClinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology · 2025Article
- A Novel Missense Variant inChildren (Basel, Switzerland) · 2025Article
- A Pedigree WithClinical case reports · 2025Article
- Impact of AHR Ligand TCDD on Human Embryonic Stem Cells and Early Differentiation.International journal of molecular sciences · 2020Article
- Congenital Hypopituitarism During the Neonatal Period: Epidemiology, Pathogenesis, Therapeutic Options, and Outcome.Frontiers in pediatrics · 2020Review
- Genetic analysis of adult Slovenian patients with combined pituitary hormone deficiency.Endocrine · 2019Article
- Heterozygous LHX3 mutations may lead to a mild phenotype of combined pituitary hormone deficiency.European journal of human genetics : EJHG · 2019Article
- Central hypothyroidism - a neglected thyroid disorder.Nature reviews. Endocrinology · 2017Review
- Genetics of Combined Pituitary Hormone Deficiency: Roadmap into the Genome Era.Endocrine reviews · 2016Review
- GPR101 Mutations are not a Frequent Cause of Congenital Isolated Growth Hormone Deficiency.Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme · 2016Article
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Authors and funding
13 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
LHX4 is a LIM homeodomain transcription factor involved in the early steps of pituitary ontogenesis. To date, 8 heterozygous LHX4 mutations have been reported as responsible of combined pituitary hormone deficiency (CPHD) in Humans. We identified 4 new LHX4 heterozygous allelic variants in patients with congenital hypopituitarism: W204X, delK242, N271S and Q346R. Our objective was to determine the role of LHX4 variants in patients' phenotypes. Heterologous HEK293T cells were transfected with plasmids encoding for wild-type or mutant LHX4. Protein expression was analysed by Western Blot, and DNA binding by electro-mobility shift assay experiments. Target promoters of LHX4 were cotransfected with wild type or mutant LHX4 to test the transactivating abilities of each variant. Our results show that the W204X mutation was associated with early GH and TSH deficiencies and later onset ACTH deficiency. It led to a truncated protein unable to bind to alpha-Gsu promoter binding consensus sequence. W204X was not able to activate target promoters in vitro. Cotransfection experiments did not favour a dominant negative effect. In contrast, all other mutants were able to bind the promoters and led to an activation similar as that observed with wild type LHX4, suggesting that they were likely polymorphisms. To conclude, our study underlines the need for functional in vitro studies to ascertain the role of rare allelic variants of LHX4 in disease phenotypes. It supports the causative role of the W204X mutation in CPHD and adds up childhood onset ACTH deficiency to the clinical spectrum of the various phenotypes related to LHX4 mutations.
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