LHX3 transcription factor mutations associated with combined pituitary hormone deficiency impair the activation of pituitary target genes

Sloop, Kyle W.; Parker, Gretchen E.; Hanna, Kimberly R.; Wright, Heather A.; Rhodes, Simon J.

doi:10.1016/s0378-1119(01)00369-9

Cited by 67 publications

(54 citation statements)

References 35 publications

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“…Pituitary morphology in these patients was variable with patients displaying hypoplastic or enlarged pituitaries. Molecular analyses of these mutations revealed that the LHX3 proteins encoded by these mutant genes have compromised abilities to trans-activate pituitary hormone gene promoters (Howard and Maurer, 2001;Sloop et al, 2001b). A third human LHX3 mutation involves a single-base pair deletion in exon II producing a truncated protein lacking all functional domains and having no predicted function (Bhangoo et al, 2006).…”

Section: Lhx3mentioning

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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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: Lhx3mentioning

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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“…One hundred nanograms of human genomic DNA were used as template in a 100 uL PCR mixture containing 20 mM Tris-HCl (pH 8.4), 50 mM KCl, 1.5 mM MgCl2, 0.2 mM deoxy-NTPs, 2.5 U Taq polymerase (PCR Reagent System, Life-Technologies) and 0.1 nM of upstream and downstream specific primers. The sequence of the PCR primers and the PCR thermal cycling program have been described elsewhere (9,14,15,19,31). PCR products were analyzed in 1.8% agarose gel and purified using a PCR Product Purification Kit (Life Technologies, USA).…”

Section: Genomic Analysismentioning

confidence: 99%

“…At times, the hypopituitarism may present as an isolated anterior pituitary hormone deficiency (usually GH deficiency), which gradually evolves to CPHD (5,7,8). HESX1 mutations cause either isolated GH deficiency or CPHD, associated or not with other anomalies such as septo-optic dysplasia and agenesis of the corpus callosum (5,9,10); LHX3 mutations lead to GH, TSH, PRL, and gonadotrophin deficiencies, associated with short cervical spine and limited neck rotation (11)(12)(13)(14); LHX4 mutations cause GH, TSH, and ACTH deficiencies and cerebellar abnormalities (15). Defects in PIT1 gene cause GH, TSH, and PRL deficiencies, and in PROP1 cause deficiencies in pituitary hormones produced by PIT1 dependent cell lineages (somatotrophs, thyrotrophs, lactotrophs), as well as evolving gonadotrophin and corticotrophin deficiencies (3,8,(16)(17)(18)(19).…”

mentioning

confidence: 99%

Molecular analysis of PROP1, PIT1, HESX1, LHX3, and LHX4 shows high frequency of PROP1 mutations in patients with familial forms of combined pituitary hormone deficiency

Vieira

Boldarine

Abucham

2007

Arq Bras Endocrinol Metab

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Combined Pituitary Hormone Deficiency (CPHD) is a prevalent disease in Neuroendocrinology services. The genetic form of CPHD may originate from mutations in pituitary transcription factor (PTF) genes and the pituitary image in these cases may give a clue of what PTF is most probably mutated: defects in LHX4 are usually associated with ectopic posterior pituitary (EPP); defects in LHX3, PIT1, and PROP1, with normally placed posterior pituitary (NPPP); HESX1 mutations are associated with both. Objective: To identify mutations in PTF genes in patients with idiopathic hypopituitarism followed in our service, based on the presence or absence of EPP on sellar MRI. Methods: Forty patients with idiopathic hypopituitarism (36 families, 9 consanguineous), followed in the Neuroendocrinology Outpatient Clinic of UNIFESP, Brazil, were submitted to sequencing analyses of PTF genes as follows: LHX3, HESX1, PIT1, and PROP1 were sequenced in patients with NPPP (26/40) and HESX1 and LHX4 in patients with EPP (14/40). Results: We identified only PROP1 mutations in 9 out of 26 patients with CPHD and NPPP (35%). Since eight of them came from 4 consanguineous families, the prevalence of PROP1 mutations was higher when only consanguineous families were considered (44%, 4/9). At the end of the study, we decided to sequence PROP1 in patients with EPP, just to confirm that they were not candidates for PROP1 mutations. Deficiência Combinada de Hormônios Hipofisários (DCHH) é uma doença prevalente em todos os serviços de Neuroendocrinologia. A DCHH de origem genética pode resultar de mutações nos genes de fatores de transcrição hipofisários (FTH), e a ressonância magnética (RM) de sela desses pacientes pode indicar qual FTH tem maior probabilidade de estar mutado: mutações no LHX4 estão geralmente associadas a neuro-hipófise ectópica (NHE); mutações no LHX3, PIT1 e PROP1, a neuro-hipófise tópica (NHT); mutações no HESX1 podem estar associadas a NHE e NHT. Objetivo: Identificar mutações nos FTH em pacientes acompanhados em nosso serviço, portadores de hipopituitarismo idiopático, selecionando os genes a serem estudados de acordo com a presença ou ausência de NHE à RM sela. Métodos: Os genes dos FTH foram seqüenciados em 40 pacientes com hipopituitarismo idiopático (36 famílias, 9 consangüíneas), acompanhados na unidade de Neuroendocrinologia da UNIFESP, SP, Brasil: LHX3, HESX1, PIT1 e PROP1 foram seqüenciados nos pacientes com NHT (26/40) e HESX1 e LHX4, nos pacientes com NHE (14/40). Resultados: Somente mutações PROP1 foram identificadas em 9 de 26 pacientes (35%) com NHT, 8 deles provenientes de 4 famílias consangüíneas (4/9, 44%). Uma vez que mutações no PROP1 foram tão freqüentes, decidimos, ao final do estudo, seqüenciá-lo também nos pacientes com NHE. Nenhum paciente com NHE apresentou mutações no PROP1 ou em outro FTH. Conclusão: Mutações no gene PROP1 foram encontradas em 22,5% (9/40) de todos os pacientes, em 35% (9/26) dos pacientes com NHT e em 44% (4/9) se considerarmos somente as famílias consangüíneas. Portanto, pacien...

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“…The construction of LHX3 cDNA expression plasmids in pcDNA3-based vectors (Invitrogen, Carlsbad, CA) has been described (Sloop et al, 1999;Sloop et al, 2001b;Pfaeffle et al, 2007). Expression constructs for ISL1, NeuroM, and E47 were generous gifts from Dr. Gordon Gill (University of California San Diego), Dr. Teri Belecky-Adams (IUPUI), and Dr. Stephen Konieczny (Purdue University), respectively.…”

Section: Plasmid Construction and Site-directed Mutagenesismentioning

confidence: 99%

“…Studies of knockout mice and humans with recessive LHX3 gene mutations have established that LHX3 is required during development of the pituitary gland and the nervous system (Sheng et al, 1996;Sheng et al, 1997;Sharma et al, 1998;Netchine et al, 2000;Sloop et al, 2001b;Bhangoo et al, 2006;Pfaeffle et al, 2007). Human patients with LHX3 gene mutations have combined pituitary hormone deficiency (CPHD) diseases featuring losses of growth hormone (GH), prolactin (PRL), thyroid-stimulating-hormone (TSH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH).…”

Section: Introductionmentioning

confidence: 99%

Mutations in the LHX3 gene cause dysregulation of pituitary and neural target genes that reflect patient phenotypes

Savage

Hunter

Clark-Sturm

et al. 2007

Gene

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The LHX3 LIM-homeodomain transcription factor is required for correct development of the mammalian pituitary gland and spinal motoneurons. Mutations in the LHX3 gene underlie complex diseases featuring combined anterior pituitary hormone deficiency and, in specific cases, loss of neck rotation considered to result from nervous system abnormalities. The molecular basis for LHX3 protein actions in both normal and aberrant pituitary and nervous system development is poorly understood. In this study, the gene regulatory abilities of mutant LHX3 proteins associated with distinct types of diseases (LHX3a A210V, LHX3a E173Ter, and LHX3a W224Ter) were investigated. The capacity of these proteins to activate pituitary hormone and transcription factor gene promoters, nervous system target genes, and to localize to the nucleus of pituitary cells was measured. Consistent with the symptoms of patients with these mutations, the abnormal proteins displayed diminished capacities to activate the promoters of genes expressed in the pituitary gland. On nervous system promoters, several mutant proteins retained some activity. The ability of the mutant proteins to concentrate in the nucleus of pituitary cells was correlated with the retention of defined nuclear localization signals in the protein sequence, except for the E173Ter protein which unexpectedly localizes to the nucleus, likely due to the insertion of cryptic nuclear localization signals by a frame shift caused by the mutation. This study extends the molecular characterization of the severe neuroendocrine diseases associated with LHX3 gene mutations.

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LHX3 transcription factor mutations associated with combined pituitary hormone deficiency impair the activation of pituitary target genes

Cited by 67 publications

References 35 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

Molecular analysis of PROP1, PIT1, HESX1, LHX3, and LHX4 shows high frequency of PROP1 mutations in patients with familial forms of combined pituitary hormone deficiency

Mutations in the LHX3 gene cause dysregulation of pituitary and neural target genes that reflect patient phenotypes

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