Symptomatic Heterozygotes and Prenatal Diagnoses in a Nonconsanguineous Family with Syndromic Combined Pituitary Hormone Deficiency Resulting from Two Novel<i>LHX3</i>Mutations

Sobrier, Marie-Laure; Brachet, Cécile; Vié-Luton, Marie-Pierre; Ca, Perez; Copin, Bruno; Legendre, M.; Heinrichs, Claudine; Amselem, Serge

doi:10.1210/jc.2011-2095

Cited by 24 publications

(22 citation statements)

References 25 publications

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“…Interestingly, the father, who was heterozygous, was presenting mild phenotypic signs, with limited neck rotation, suggesting that a dominant negative effect of c.252-3COGLHX3 was also occurring in the heterozygous state. Finally, this study was also the first to our knowledge in which genetic data allowed a prenatal diagnosis on LHX3 that was performed five years later (14).…”

Section: Novel Mode Of Transmissionmentioning

confidence: 81%

MECHANISMS IN ENDOCRINOLOGY: An update in the genetic aetiologies of combined pituitary hormone deficiency

Castinetti¹,

Reynaud²,

Saveanu³

et al. 2016

European Journal of Endocrinology

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Over the last 5 years, new actors involved in the pathogenesis of combined pituitary hormone deficiency in humans have been reported: they included a member of the immunoglobulin superfamily glycoprotein and ciliary G protein-coupled receptors, as well as new transcription factors and signalling molecules. New modes of inheritance for alterations of genes encoding transcription factors have also been described. Finally, actors known to be involved in a very specific phenotype (hypogonadotroph hypogonadism for instance) have been identified in a wider range of phenotypes. These data thus suggest that new mechanisms could explain the low rate of aetiological identification in this heterogeneous group of diseases. Taking into account the fact that several reviews have been published in recent years on classical aetiologies of CPHD such as mutations of POU1F1 or PROP1, we focused the present overview on the data published in the last 5 years, to provide the reader with an updated review on this rapidly evolving field of knowledge.

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Section: Novel Mode Of Transmissionmentioning

confidence: 81%

MECHANISMS IN ENDOCRINOLOGY: An update in the genetic aetiologies of combined pituitary hormone deficiency

Castinetti¹,

Reynaud²,

Saveanu³

et al. 2016

European Journal of Endocrinology

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“…Pou1f1 recognizes a weakly conserved A/T-rich consensus sequence (A/T) (A/T)TATNCAT, binds to well-defined sites within the promoters and/or enhancers of multiple target genes (5,6) and stimulates gene transcription in concert with a number of cofactors. Examples of Pou1f1 interactions include the association with Pitx1 via the Pou1f1-TAD to activate the Prl and Gh promoters (7), and association with the LIM domains of Lhx3 through the Pou1f1-homeodomain to activate the Pou1f1, Tshβ and Prl promoters (8,9) as well as the human PRL promoter (9). Importantly, forced co-expression of Pou1f1 along with a member of ETS oncogene family (ELK1, an ubiquitous transcription factor) is capable of activating the endogenous GH1 in the human HEK293 cell line to levels 23-fold greater than measured in the non-transfected cells (10).…”

Section: Introductionmentioning

confidence: 99%

Functional characterization of a humanPOU1F1mutation associated with isolated growth hormone deficiency: a novel etiology for IGHD

Sobrier

Tsai²,

et al. 2015

Hum. Mol. Genet.

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POU1F1, a pituitary-specific POU-homeo domain transcription factor, plays an essential role in the specification of the somatotroph, lactotroph and thyrotroph lineages and in the activation of GH1, PRL and TSHβ transcription. Individuals with mutations in POU1F1 present with combined deficiency of GH, PRL and TSH. Here, we identified a heterozygous missense mutation with evidence of pathogenicity, at the POU1F1 locus, in a large family in which an isolated growth hormone deficiency segregates as an autosomal dominant trait. The corresponding p.Pro76Leu mutation maps to a conserved site within the POU1F1 transactivation domain. Bandshift assays revealed that the mutation alters wild-type POU1F1 binding to cognate sites within the hGH-LCR and hGH1 promoter, but not to sites within the PRL promoter, and it selectively increases binding affinity to sites within the hGH-LCR. Co-immunoprecipitation studies reveal that this substitution enhances interactions of POU1F1 with three of its cofactors, PITX1, LHX3a and ELK1, and that residue 76 plays a critical role in these interactions. The insertion of the mutation at the mouse Pou1f1 locus results in a dramatic loss of protein expression despite normal mRNA concentrations. Mice heterozygous for the p.Pro76Leu mutation were phenotypically normal while homozygotes demonstrated a dwarf phenotype. Overall, this study unveils the involvement of POU1F1 in dominantly inherited isolated GH deficiency and demonstrates a significant impact of the Pro76Leu mutation on DNA-binding activities, alterations in transactivating functions and interactions with cofactors. Our data further highlight difficulties in modeling human genetic disorders in the mouse despite apparent conservation of gene expression pathways and physiologic functions.

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“…Several variants of these genes have strong contextual support from preexisting genetic data. 27,28 Heterozygous GLI2 mutations have been identified relatively frequently (17%) especially in patients with CPHD and an ectopic posterior pituitary lobe, 38 while LHX3 mutations were found less frequently and all in homozygous state (Supplementary Table S4). 27,28 We also identified a frameshift in the hypopituitary gene TCF7L1 (p.S15Kfs*41), transmitted from an unaffected mother to her son (RaKi_51), suggesting that this variant, possibly in concert with the de novo mutation in NOBOX, contributes to the CPHD phenotype in her son.…”

Section: Discussionmentioning

confidence: 99%

“…27,28 Heterozygous GLI2 mutations have been identified relatively frequently (17%) especially in patients with CPHD and an ectopic posterior pituitary lobe, 38 while LHX3 mutations were found less frequently and all in homozygous state (Supplementary Table S4). 27,28 We also identified a frameshift in the hypopituitary gene TCF7L1 (p.S15Kfs*41), transmitted from an unaffected mother to her son (RaKi_51), suggesting that this variant, possibly in concert with the de novo mutation in NOBOX, contributes to the CPHD phenotype in her son. 29 In our study we focused on variants that are extremely rare or absent in the large contemporary multiethnic sequencing databases (e.g., gnomAD) (e.g., variants in SLC20A1 and SLC15A4), as we initially argued that a fully penetrant disease genotype should be no more common in the population than the disease that it causes.…”

Section: Discussionmentioning

confidence: 99%

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Identification of SLC20A1 and SLC15A4 among other genes as potential risk factors for combined pituitary hormone deficiency

Simm

Griesbeck

Choukair

et al. 2018

Genetics in Medicine

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Purpose: Combined pituitary hormone deficiency (CPHD) is characterized by a malformed or underdeveloped pituitary gland resulting in an impaired pituitary hormone secretion. Several transcription factors have been described in its etiology, but defects in known genes account for only a small proportion of cases.Methods: To identify novel genetic causes for congenital hypopituitarism, we performed exome-sequencing studies on 10 patients with CPHD and their unaffected parents. Two candidate genes were sequenced in further 200 patients. Genotype data of known hypopituitary genes are reviewed.Results: We discovered 51 likely damaging variants in 38 genes; 12 of the 51 variants represent de novo events (24%); 11 of the 38 genes (29%) were present in the E12.5/E14.5 pituitary transcriptome. Targeted sequencing of two candidate genes, SLC20A1 and SLC15A4, of the solute carrier membrane transport protein family in 200 additional patients demonstrated two further variants predicted as damaging. We also found combinations of de novo (SLC20A1/SLC15A4) and transmitted variants (GLI2/LHX3) in the same individuals, leading to the full-blown CPHD phenotype.Conclusion: These data expand the pituitary target genes repertoire for diagnostics and further functional studies. Exome sequencing has identified a combination of rare variants in different genes that might explain incomplete penetrance in CPHD.

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Symptomatic Heterozygotes and Prenatal Diagnoses in a Nonconsanguineous Family with Syndromic Combined Pituitary Hormone Deficiency Resulting from Two NovelLHX3Mutations

Cited by 24 publications

References 25 publications

MECHANISMS IN ENDOCRINOLOGY: An update in the genetic aetiologies of combined pituitary hormone deficiency

MECHANISMS IN ENDOCRINOLOGY: An update in the genetic aetiologies of combined pituitary hormone deficiency

Functional characterization of a humanPOU1F1mutation associated with isolated growth hormone deficiency: a novel etiology for IGHD

Identification of SLC20A1 and SLC15A4 among other genes as potential risk factors for combined pituitary hormone deficiency

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