A homozygous mutation in HESX1 is associated with evolving hypopituitarism due to impaired repressor-corepressor interaction

Carvalho, Luciani R.; Woods, Kathryn S.; Mendonca, Berenice B.; Marçal, Nathalie; Zamparini, Andrea L.; Stifani, Stefano; Brickman, Joshua M.; Arnhold, Ivo J.P.; Dattani, Mehul

doi:10.1172/jci18589

Cited by 124 publications

(92 citation statements)

References 31 publications

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“…The patients with EPP showed no mutations in the genes studied (HESX1, LHX4, and PROP1) and this is compatible with the rarity of PTF mutations found in patients with EPP (10,15,20,33,34). Perhaps other developmental genes yet to be identified may be involved in the etiology of EPP, or another pathogenic mechanism could be responsible for this abnormality (35,36).…”

Section: Prop1 Mutations In Familial Cphdsupporting

confidence: 76%

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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Section: Prop1 Mutations In Familial Cphdsupporting

confidence: 76%

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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“…Their response to these stimuli was very low: 0.1 ng/mL for patient II.3, and 1.2 and 4.2 ng/mL for patient II. 4 (normal values > 10 ng/mL). IGF-1 values were also markedly low.…”

Section: Disease Phenotypementioning

confidence: 99%

Unusual Phenotypic Features in a Patient with a Novel Splice Mutation in the GHRHR Gene

Hilal

Hajaji

Vié-Luton

et al. 2008

Mol Med

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“…HESX1 does not act in isolation: other molecular mechanisms appear to influence or be influenced by HESX1 function. 80,81 Other transcription factors that are known to affect development in the region of the pituitary gland include LHX3, LHX4, PROP1, PITX1, PITX2, SIX6, TPIT, and PIT-1. PAX2 may interrelate with PAX6 to produce a variety of effects 82 Consequences to the visual system of abnormal development…”

Section: Gene Regulation Of Midline Structuresmentioning

confidence: 99%

Optic nerve axons: life and death before birth

Taylor

2005

Eye

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A homozygous mutation in HESX1 is associated with evolving hypopituitarism due to impaired repressor-corepressor interaction

Cited by 124 publications

References 31 publications

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

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

Unusual Phenotypic Features in a Patient with a Novel Splice Mutation in the GHRHR Gene

Optic nerve axons: life and death before birth

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