Syndromic Short Stature in Patients with a Germline Mutation in the LIM Homeobox LHX4

Machinis, Kalotina; Pantel, Jacques; Netchine, Irène; Léger, Juliane; Camand, Olivier; Sobrier, Marie-Laure; Moal, Florence Dastot-Le; Duquesnoy, Philippe; Abitbol, Marc; Czernichow, P; Amselem, Serge

doi:10.1086/323764

Cited by 253 publications

(159 citation statements)

References 24 publications

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“…Magnetic resonance imaging analyses of affected family members revealed a hypoplastic pituitary, small sella turcica, chiari malformation, and an ectopic posterior pituitary (Machinis et al, 2001). The observed LHX4 mutation is a G to C transversion at a splice acceptor site predicted to result in the production of either a protein with deletion of four conserved amino acids within the HD or a truncated protein.…”

Section: Lhx4mentioning

confidence: 97%

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Roles of the LHX3 and LHX4 LIM-homeodomain factors in pituitary development

Mullen

Colvin

Hunter

et al. 2007

Molecular and Cellular Endocrinology

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The LHX3 and LHX4 LIM-homeodomain transcription factors play essential roles in pituitary gland and nervous system development. Mutations in the genes encoding these regulatory proteins are associated with combined hormone deficiency diseases in humans and animal models. Patients with these diseases have complex syndromes involving short stature, and reproductive and metabolic disorders. Analyses of the features of these diseases and the biochemical properties of the LHX3 and LHX4 proteins will facilitate a better understanding of the molecular pathways that regulate the development of the specialized hormone-secreting cells of the mammalian anterior pituitary gland.

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Section: Lhx4mentioning

confidence: 97%

“…The human LHX4 gene on chromosome 1 has a similar exon/intron organization to LHX3 but longer introns result in a gene length of >45 kilobases (Machinis et al, 2001;Sloop et al, 2001c). In mice, the Lhx4 (or Gsh4) gene is expressed in the developing hindbrain, cerebral cortex, pituitary gland, and spinal cord (Li et al, 1994;Liu et al, 2002).…”

Section: Lhx4mentioning

confidence: 99%

Roles of the LHX3 and LHX4 LIM-homeodomain factors in pituitary development

Mullen

Colvin

Hunter

et al. 2007

Molecular and Cellular Endocrinology

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“…Through yeast two-hybrid screening, using the synovial sarcoma-associated SSX1 C terminus as a bait, we isolated two cDNAs corresponding to the LHX4 protein, a transcription factor that is known to be involved in pituitary and motor neuron development (Sheng et al, 1997;Sharma et al, 1998;Machinis et al, 2001;Raetzman et al, 2002) and to be deregulated and/ or translocated in human chronic myeloid and acute lymphoblastic leukemias (Wu et al, 1996;Dong et al, 1997;Wu and Minden, 1997;Kawamata et al, 2002;Yamaguchi et al, 2003). In the yeast two-hybrid system, the LHX4 protein interacts equally well with the C terminus of all SSX proteins known to be involved in synovial sarcoma, that is SSX1, SSX2 and SSX4.…”

Section: Discussionmentioning

confidence: 99%

“…During normal development, the LHX4 gene is predominantly expressed in the central nervous system (Liu et al, 2002), and it was proposed that its overexpression may be associated with cellular proliferation and/or anti-apoptosis (Kawamata et al, 2002;Yamaguchi et al, 2003). Indeed, mouse knockout studies revealed that LHX4 deficiency leads to an increased apoptotic rate in Rathke's pouch, resulting in an impaired pituitary development reminiscent of human congenital pituitary hormone deficiency (CPHD; Sheng et al, 1997;Machinis et al, 2001;Raetzman et al, 2002). In addition, LHX4 was shown to have a direct stimulatory effect on for example the prolactin gene promoter.…”

Section: Discussionmentioning

confidence: 99%

The C terminus of the synovial sarcoma-associated SSX proteins interacts with the LIM homeobox protein LHX4

et al. 2007

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As a result of the synovial sarcoma-associated t(X;18) translocation, the SS18 gene on chromosome 18 is fused to either one of the three closely related SSX genes on the X chromosome. The SS18 protein is thought to act as a transcriptional co-activator, whereas the SSX proteins are thought to act as transcriptional corepressors. The main SSX-repression domain is located in its C terminus, a domain that is retained in the respective SS18-SSX fusion proteins. Both the SS18 and SSX proteins lack DNAbinding domains. Previously, we found that the SS18 and SS18-SSX fusion proteins may be tethered to DNA targets via the SS18-interacting protein AF10. Here, we set out to isolate proteins that interact with the SSX C-terminal repression domain using a yeast two-hybrid interaction trap. Of the positive clones isolated, two corresponded to the LIM homeobox protein LHX4, a DNA-binding protein that is involved in transcription regulation. An endogenous interaction was subsequently established in mammalian cells via colocalization and coimmunoprecipitation of the respective proteins. Interestingly, the LHX4 gene was previously found to be deregulated in various human leukemias. In addition, it was previously found that LIM homeobox proteins may bind to and activate the glycoprotein-a (CGA) promoter. Using LHX4 chromatin immunoprecipitation and CGApromoter assays, we found that endogenous LHX4 binds to the CGA promoter and that LHX4-mediated CGA activation is enhanced by the SS18-SSX protein, but not by the SSX protein. Taken together, we conclude that this novel protein -protein interaction may have direct consequences for the (de)regulation of SSX and/or SS18-SSX target genes and, thus, for the development of human synovial sarcomas.

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“…Among them, two closely related genes, LHX3 and LHX4, are believed to share redundant biological properties. To date, there has been only one published report of a mutation of LHX4 [2]. The patient with LHX4 germline splice mutation displayed: CPHD (GH, TSH, ACTH; LH/FSH and PRL were not evaluated), anterior pituitary hypoplasia, ectopic posterior pituitary and extrapituitary manifestations that included a poorly formed sella turcica, a persistent craniopharyngeal canal and pointed cerebellar tonsils suggestive of Chiari malformation.…”

Section: Functional Relationship Between Lhx4 and Pou1f1 In Light Of mentioning

confidence: 99%

Pituitary

Maghnie¹,

Secco²,

Loche³

2006

Yearbook of Pediatric Endocrinology 2006

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Among the wide range of relevant subjects assessed, we found that the most deserving topics in the pituitary field during the timeframe represented were: gene research, clinical trials, pathogenic mechanisms and clinical practice recommendations. We hope that this chapter will serve as a guide to orient endocrine specialists in these exciting and challenging new directions. It is undeniable that these areas have been changing so rapidly in recent years that a practicing physician inevitably finds it difficult to keep up with all of the latest developments. Therefore, a compact review and summary like the present chapter hopes to satisfy updating needs while helping busy physicians save time as well. Mechanism of the yearA comprehensive description of the transcriptome of the hypothalamoneurohypophyseal system in euhydrated and dehydrated rats Hindmarch C, Yao S, Beighton G, Paton J, Murphy D The Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Bristol, UK Proc Natl Acad Sci USA 2006;103:1609-1614 Background: The endocrine hypothalamoneurohypophyseal system (HNS) is crucially involved in water homeostasis through three interdependent mechanisms including thirst, vasopressin (AVP) and the kidneys. Small changes in plasma osmolality lead to AVP secretion promoting water conservation in its major target organ. The functional plasticity of the NHS during dehydration in terms of the gene expression involved in this pathway is not yet clearly understood. Methods: Adult male rats were dehydrated and subsequently tissue collection from the brain and RNA extraction were carried out. The GeneSpring catalog of a list of genes identified as being expressed in the rat NHS which includes large peptidergic magnocellular neurons of the supraoptic (SON) and paraventricular hypothalamic nuclei (PVN) or neurointermediate lobe (NIL) was used. The corresponding gene lists represent comprehensive descriptions of the RNA populations expressed in the different tissue components of the HNS. Combined lists were filtered to identify genes that are putatively upregulated by at least 2-fold after dehydration or putatively downregulated by at least 2-fold after dehydration. Merging of the statistically filtered up-or downregulated gene lists gave the catalogs of transcripts that are abundantly changed in the HNS structures. Results: Marked changes in the HSN steady-state RNA level after dehydration were evident in the SON, PVN and NIL. There were clear transcriptome phenotypic differences between the SON and PVN in the controls compared to the dehydrated tissues. Conclusion: A large number of genes were identified as being expressed in rat HNS tissues after dehydration. The pattern of HNS transcripts with marked differences in gene expression indicates that these genes are candidate regulators and effectors of HNS activity and remodeling.As systems biology gets into problems related to our field, we have to start looking at genomic arrays rather than single genes, at proteomics rather than sin...

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Syndromic Short Stature in Patients with a Germline Mutation in the LIM Homeobox LHX4

Cited by 253 publications

References 24 publications

Roles of the LHX3 and LHX4 LIM-homeodomain factors in pituitary development

Roles of the LHX3 and LHX4 LIM-homeodomain factors in pituitary development

The C terminus of the synovial sarcoma-associated SSX proteins interacts with the LIM homeobox protein LHX4

Pituitary

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