Identifying the Deleterious Effect of Rare LHX4 Allelic Variants, a Challenging Issue

Rochette, C.; Jullien, Nicolas; Saveanu, Alexandru; Caldagues, Emmanuelle; Bergadá, Ignacio; Braslavsky, Débora; Pfeifer, Marija; Reynaud, Rachel; Herman, J.P.; Barlier, Anne; Brue, Thierry; Enjalbert, A; Castinetti, Frédéric

doi:10.1371/journal.pone.0126648

Cited by 16 publications

(7 citation statements)

References 16 publications

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“…The two other variants we report emphasize the difficulties in defining the potential affected function induced by new variants, as has been previously shown in the case of another LIM domain transcription factor, LHX4 [26]. The variant NM_178138.5(LHX3):c.929G > C (p.(Arg310Pro)) was considered to be deleterious in silico and considered as "of unknown significance" in dbSNP.…”

Section: Discussionmentioning

confidence: 58%

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

et al. 2018

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LHX3 is an LIM domain transcription factor involved in the early steps of pituitary ontogenesis. We report here functional studies of three allelic variants, including the first heterozygous variant of LHX3 NM_178138.5(LHX3):c.587T>C (p. (Leu196Pro)) that may be responsible for a milder phenotype of hypopituitarism. Our functional studies showed that NM_178138.5(LHX3):c.587T>C (p.(Leu196Pro)) was not able to activate target promoters in vitro, as it did not bind DNA, and likely affected LHX3 function via a mechanism of haplo-insufficiency. Our study demonstrates the possibility that patients with a heterozygous variant of LHX3 may have pituitary deficiencies, with a milder phenotype than patients with homozygous variants. It is thus of vital to propose an optimal follow-up of such patients, who, until now, were considered as not being at risk of presenting pituitary deficiency. The second variant NM_178138.5(LHX3):c.622C>G (p.(Arg208Gly)), present in a homozygous state, displayed decreased transactivating ability without loss of binding capacity in vitro, concordant with in silico analysis; it should thus be considered to affect LHX3 function. In contrast, the NM_178138.5 (LHX3):c.929G>C (p.(Arg310Pro)) variant, in a heterozygous state, also predicted as deleterious in silico, proved functionally active in vitro, and should thus still be classified as a variant of unknown significance. Our study emphasizes the need for functional studies due to the limits of software-based predictions of new variants, and the possible association of a pituitary phenotype to heterozygous LHX3 variants.

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Section: Discussionmentioning

confidence: 58%

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

et al. 2018

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“…LHX4 analysis revealed four previously published gene defects (17, 19, 20): p.Thr99Asnfs53*, 17 one intronic point mutation involving the splice‐acceptor site preceding exon 5 (c.607‐1G>C), 18 p.Arg84Cys 19 and p.Trp204* 20 . Pituitary phenotypes were various forms of CPHD including at least GHD and TSHD, always associated with PSIS.…”

Section: Resultsmentioning

confidence: 98%

Clinical lessons learned in constitutional hypopituitarism from two decades of experience in a large international cohort

Jullien

Saveanu

Vergier

et al. 2020

Clinical Endocrinology

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ContextThe international GENHYPOPIT network collects phenotypical data and screens genetic causes of non‐acquired hypopituitarism.AimsTo describe main phenotype patterns and their evolution through life.DesignPatients were screened according to their phenotype for coding sequence variations in 8 genes: HESX1, LHX3, LHX4, PROP1, POU1F1, TBX19, OTX2 and PROKR2.ResultsAmong 1213 patients (1143 index cases), the age of diagnosis of hypopituitarism was congenital (24%), in childhood (28%), at puberty (32%), in adulthood (7.2%) or not available (8.8%). Noteworthy, pituitary hormonal deficiencies kept on evolving during adulthood in 49 of patients. Growth Hormone deficiency (GHD) affected 85.8% of patients and was often the first diagnosed deficiency. AdrenoCorticoTropic Hormone deficiency rarely preceded GHD, but usually followed it by over 10 years. Pituitary Magnetic Resonance Imaging (MRI) abnormalities were common (79.7%), with 39.4% pituitary stalk interruption syndrome (PSIS). The most frequently associated extrapituitary malformations were ophthalmological abnormalities (16.1%). Prevalence of identified mutations was 7.3% of index cases (84/1143) and 29.5% in familial cases (n = 146). Genetic analysis in 449 patients without extrapituitary phenotype revealed 36 PROP1, 2 POU1F1 and 17 TBX19 mutations.ConclusionThis large international cohort highlights atypical phenotypic presentation of constitutional hypopituitarism, such as post pubertal presentation or adult progression of hormonal deficiencies. These results justify long‐term follow‐up, and the need for systematic evaluation of associated abnormalities. Genetic defects were rarely identified, mainly PROP1 mutations in pure endocrine phenotypes.

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“…The AP gland in patients with LHX4 mutations is hypoplastic, containing all the differentiated cell types but in reduced numbers. Other brain abnormalities can also be present such as an EPP and a hypoplastic sella turcica as well as corpus callosum hypoplasia or Chiari syndrome (97)(98)(99)(100)(101)(102)(103)(104)(105).…”

Section: Hypopituitarism With Cerebellar Abnormalities: Lhx4mentioning

confidence: 99%

Congenital Hypopituitarism During the Neonatal Period: Epidemiology, Pathogenesis, Therapeutic Options, and Outcome

2021

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Introduction: Congenital hypopituitarism (CH) is characterized by a deficiency of one or more pituitary hormones. The pituitary gland is a central regulator of growth, metabolism, and reproduction. The anterior pituitary produces and secretes growth hormone (GH), adrenocorticotropic hormone, thyroid-stimulating hormone, follicle-stimulating hormone, luteinizing hormone, and prolactin. The posterior pituitary hormone secretes antidiuretic hormone and oxytocin.Epidemiology: The incidence is 1 in 4,000–1 in 10,000. The majority of CH cases are sporadic; however, a small number of familial cases have been identified. In the latter, a molecular basis has frequently been identified. Between 80–90% of CH cases remain unsolved in terms of molecular genetics.Pathogenesis: Several transcription factors and signaling molecules are involved in the development of the pituitary gland. Mutations in any of these genes may result in CH including HESX1, PROP1, POU1F1, LHX3, LHX4, SOX2, SOX3, OTX2, PAX6, FGFR1, GLI2, and FGF8. Over the last 5 years, several novel genes have been identified in association with CH, but it is likely that many genes remain to be identified, as the majority of patients with CH do not have an identified mutation.Clinical manifestations: Genotype-phenotype correlations are difficult to establish. There is a high phenotypic variability associated with different genetic mutations. The clinical spectrum includes severe midline developmental disorders, hypopituitarism (in isolation or combined with other congenital abnormalities), and isolated hormone deficiencies.Diagnosis and treatment: Key investigations include MRI and baseline and dynamic pituitary function tests. However, dynamic tests of GH secretion cannot be performed in the neonatal period, and a diagnosis of GH deficiency may be based on auxology, MRI findings, and low growth factor concentrations. Once a hormone deficit is confirmed, hormone replacement should be started. If onset is acute with hypoglycaemia, cortisol deficiency should be excluded, and if identified this should be rapidly treated, as should TSH deficiency. This review aims to give an overview of CH including management of this complex condition.

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Identifying the Deleterious Effect of Rare LHX4 Allelic Variants, a Challenging Issue

Cited by 16 publications

References 16 publications

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

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

Clinical lessons learned in constitutional hypopituitarism from two decades of experience in a large international cohort

Congenital Hypopituitarism During the Neonatal Period: Epidemiology, Pathogenesis, Therapeutic Options, and Outcome

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