Monoallelic expression of normal mRNA in the <i>PIT1</i> mutation heterozygotes with normal phenotype and biallelic expression in the abnormal phenotype

Okamoto, Nobuhiko; Wada, Yoshinao; Ida, Shinobu; Koga, Ryoichi; Ozono, K; Chiyo, Hideaki; Hayashi, Akira; Tatsumi, Koichi

doi:10.1093/hmg/3.9.1565

Cited by 62 publications

(35 citation statements)

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“…Most cases with R271W were sporadic and there were only two familial cases with this mutation. Okamoto et al (11) reported the first family with R271W. They described a patient who was heterozygous for this mutation.…”

Section: Discussionmentioning

confidence: 99%

“…However, surprisingly, in contrast to a previous report that this mutant acted as a dominant inhibitor of wild type Pit-1 to activate the promoter of GH gene (9), R271W did not inhibit the effect of the wild type on the promoter of GH gene as well as PRL gene, and could activate these promoters to a level similar to wild type Pit-1, at least in our experimental conditions. These results, and the existence of healthy carrier with this mutation (11), suggest that further investigation will be needed to clarify how R271W leads to CPHD.…”

Section: Introductionmentioning

confidence: 94%

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The R271W mutant form of Pit-1 does not act as a dominant inhibitor of Pit-1 action to activate the promoters of GH and prolactin genes

Kishimoto

Okimura

Fumoto³

et al. 2003

European Journal of Endocrinology

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Objective: Genetic abnormalities of the pituitary specific transcription factor, Pit-1, have been reported in several patients with GH, prolactin (PRL) and TSH deficiencies. The most common is a mutation altering an arginine to a tryptophan in codon 271 (R271W) in one allele of the Pit-1 gene. According to the previous in vitro expression study, R271W acted as a dominant negative inhibitor of the wild type to activate the GH promoter. However, healthy carriers with this mutation, who should be affected by the dominant negative effect of R271W, have also been reported. The aim of this study was to clarify in more detail the function of this mutant form of Pit-1. Methods: Transcriptional activity of R271W for the expression of Pit-1-associated genes was investigated in COS7 cells with the aid of transient transfection assays. The 1.8 kb rat GH, 0.6 kb rat PRL or 1.9 kb rat PRL 5 0 -flanking regions were inserted upstream of the luciferase reporter gene and were used for functional analysis of R271W. Another reporter gene containing seven Pit-1 responsive elements was also used. The same experiments were also performed using JEG3 and CHO cells. Results: We could not confirm the dominant negative effect of R271W on wild type Pit-1. Furthermore, our expression study revealed that R271W could activate the promoters of GH and PRL genes to levels similar to the wild type. Conclusion: Taken together with the evidence that phenotypically normal cases have been reported with this mutation, our results deny the relationship between R271W and combined pituitary hormone deficiency.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

The R271W mutant form of Pit-1 does not act as a dominant inhibitor of Pit-1 action to activate the promoters of GH and prolactin genes

Kishimoto

Okimura

Fumoto³

et al. 2003

European Journal of Endocrinology

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“…Among 51 Severe Cases, 44 were IGHD (24 male and 20 female) and 3 were GH-1 gene mutations (one case: type IA (6.7 kb deletion); two cases: type II (point mutation of intron 3; IVS3 + 5G ® A, IVS3 + 5G ® C)) [6,7], 2 were Pit-1 gene mutation [8], and 2 were achondroplasia (Table 1). Hypochondroplasia, Turner syndrome, and chronic renal failure were not included, and complications of other diseases causing growth failure were not observed.…”

Section: ) Etiologies and Clinical Characteristics Of 51 Severe Casesmentioning

confidence: 99%

Clinical Characteristics, Etiologies and Pathophysiology of Patients with Severe Short Stature with Severe GH Deficiency: Questionnaire Study on the Data Registered with the Foundation for Growth Science, Japan

Hanew¹,

Tachibana

Yokoya

et al. 2006

Endocr J

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Abstract. In this study, we sent questionnaires to doctors treating severe short stature with severe GH deficiency (GHD) (height SDS (HtSDS) below -4 and all peak GH to provocative stimuli below 2 m/L) (abbreviated as Severe Case), and obtained effective replies of 51 cases. The clinical characteristics, etiologies, and pathophysiology of these patients were examined. Among the 51 Severe Cases no consanguinity was observed, 44 were IGHD (24 males and 20 females), 3 were GH-1 gene deletion, 2 were Pit-1 gene mutation, and 2 were achondroplasia. HtSDS in these Severe Cases was already remarkably low at 12 (-3.0) and 24 months old (-3.9), while their birth weight and birth length were within normal ranges. Among 44 patients with IGHD, 12 were isolated GHD, and the remaining 32 were combined pituitary hormone deficiency (CPHD). Pituitary MRI was undergone in 25 idiopathic GHD, and abnormal findings (pituitary atrophy, interruption of stalk, and ectopic posterior lobe) were observed in 21 patients with CPHD. More than half of these patients had the history of breech delivery. Three patients with GH-1 gene mutation showed normal pituitary MRI, whereas one of two patients with Pit-1 mutation showed pituitary atrophy and narrowing of pituitary stalk. In conclusion, Severe Cases tended to have CPHD, and the incidence of Severe Case was only 0.6% of total IGHD. Although GHD due to genetic disorders is considered to be extremely rare (0.06% of total IGHD), the incidence reaches high levels (9.8%) among Severe Cases. Growth disorders in these Severe Cases seem to occur soon after delivery. Much earlier diagnosis and hGH treatment are desirable to attain better final height in the Severe Cases. GH-1 and Pit-1 gene analyses are crucial, when genetic abnormalities other than achondroplasia are suspected.

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“…A herança pode ser autossômica recessiva, causada por mutações em homozigose ou heterozigose composta, que produzem vários graus de perda de ligação ao DNA ou perda da ativação da transcrição (31,32,(34)(35)(36)40,45). A herança também pode ser autossômica dominante, causada por mutações em heterozigose, porque a proteína mutante tem uma afinidade aumentada pelos sítios promotores de GH e PRL, causando um efeito dominante negativo sobre a proteína normal (33,38,41,46,47). A mutação R271W em heterozigose é de longe a mais freqüente e ocorre em um dinucleotídeo CpG, provável motivo da freqüente recorrência.…”

Section: Pit-1unclassified

Bases Genéticas dos Distúrbios de Crescimento

Marui

Souza

Carvalho

et al. 2002

Arq Bras Endocrinol Metab

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A integridade do eixo GHRH-GH-IGF-I é fundamental para o crescimento normal de um indivíduo. Mutações nos genes responsáveis por cada uma das etapas deste eixo resultam em baixa estatura grave. Podemos dividir os distúrbios de crescimento em: 1. Deficiência de GH associada a deficiências de outros hormônios hipofisários por alterações em fatores de transcrição envolvidos na organogênese hipofisária (HESX1/RPX, LHX3 e LHX4, PROP-1, PIT-1); 2. Deficiência isolada de GH (receptor do GHRH:GHRHR, GH-1, GH bioinativo); e 3. Insensibilidade ao GH (receptor de GH:GHR, gene da IGF-I e receptor da IGF-I:IGFR). Serão discutidos também os genes implicados na baixa estatura da Síndrome de Turner (SHOX) e Síndrome de Noonan (PTPN11). Atualmente estamos analisando no Laboratório de Hormônios e Genética Molecular da Disciplina de Endocrinologia da FMUSP - LIM 42 os genes HESX-1, LHX3, LHX4, PROP-1, GHRHR, GH-1, GHR, SHOX e PTPN11 em pacientes com baixa estatura e características clínicas e laboratoriais que sugerem o envolvimento destes genes.

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Monoallelic expression of normal mRNA in the PIT1 mutation heterozygotes with normal phenotype and biallelic expression in the abnormal phenotype

Cited by 62 publications

References 0 publications

The R271W mutant form of Pit-1 does not act as a dominant inhibitor of Pit-1 action to activate the promoters of GH and prolactin genes

The R271W mutant form of Pit-1 does not act as a dominant inhibitor of Pit-1 action to activate the promoters of GH and prolactin genes

Clinical Characteristics, Etiologies and Pathophysiology of Patients with Severe Short Stature with Severe GH Deficiency: Questionnaire Study on the Data Registered with the Foundation for Growth Science, Japan

Bases Genéticas dos Distúrbios de Crescimento

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