Efeito fundador da mutação E180splice no gene do receptor de hormônio de crescimento identificada em pacientes brasileiros com insensibilidade ao GH

Jorge, Alexander Augusto de Lima; Filho, Hamilton Cabral de Menezes; Lins, Theresa S. Soares; Guedes, Dulce Rondini; Damiani, Durval; Setian, Nuvarte; Arnhold, Ivo Jorge Prado; Mendonça, Berenice Bilharinho

doi:10.1590/s0004-27302005000300009

Cited by 12 publications

(2 citation statements)

References 13 publications

(15 reference statements)

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“…This implies that the GHR 6Ψ patient cohort share a common genetic background. This is comparable to the p.E180 splice GHR mutation found predominantly in individuals from Ecuador, Brazil and Chile, where a shared genetic background flanking the splice mutation was identified (56,57). First degree relatives who are heterozygous carriers of the p.E180 mutation are modestly shorter than non-carrier relatives (58).…”

Section: Discussionsupporting

confidence: 60%

GHR gene transcript heterogeneity may explain phenotypic variability in GHR pseudoexon (6Ψ) patients

Chatterjee

Cottrell

Rose

et al. 2020

Endocrine Connections

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Objectives The homozygous GH receptor (GHR) pseudoexon (6Ψ) mutation leads to growth hormone insensitivity (GHI) with clinical and biochemical heterogeneity. We investigated whether transcript heterogeneity (6Ψ-GHR to WT-GHR transcript ratio) and/or concurrent defects in other short stature (SS) genes contribute to this. Methods 6Ψ-GHR and WT-GHR mRNA transcripts of four 6Ψ patients (height SDS −4.2 to −3.1) and one control fibroblast were investigated by RT-PCR. Transcripts were quantified by qRT-PCR and delta delta CT analysis and compared using ANOVA with Bonferroni correction. In eleven 6Ψ patients, 40 genes known to cause GHI/SS were analysed by targeted next generation sequencing. Results RT-PCR confirmed 6Ψ-GHR transcript in the 6Ψ patients but not in the control. 6Ψ-GHR transcript levels were comparable in patients 1 and 3 but significantly different among all other patients. The mean 6Ψ:WT transcript ratios ranged from 29–71:1 for patients 1–4 and correlated negatively with height SDS (R = −0.85; P < 0.001). Eight deleterious variants in six genes were detected, but the number of gene hits did not correlate with the degree of SS in individual 6Ψ patients. Conclusion Variable amounts of 6Ψ- and WT-GHR transcripts were identified in 6Ψ patients but no 6Ψ transcript was present in the control. Higher 6Ψ:WT-GHR transcript ratio correlated with SS severity and may explain the phenotypic variability. Analysis of known SS genes suggested that phenotypic variation is independent of the genetic background. This is the first report of transcript heterogeneity producing a spectrum of clinical phenotypes in different individuals harbouring an identical homozygous genetic mutation.

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Section: Discussionsupporting

confidence: 60%

GHR gene transcript heterogeneity may explain phenotypic variability in GHR pseudoexon (6Ψ) patients

Chatterjee

Cottrell

Rose

et al. 2020

Endocrine Connections

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“…A avaliação complementar de 4 regiões intragênicas neste gene em todos os pacientes e familiares permitiu confirmar que todos apresentavam haplótipos idênticos (4).…”

Section: Gil Guerra Júniorunclassified

Cristãos-novos no nordeste e os anões de Orobó (PE): a genética molecular ligada à história do Brasil

Júnior

2005

Arq Bras Endocrinol Metab

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Portanto, em Pernambuco, os cristãos-novos ou tornaram-se senhores de engenho, ou permaneceram como mercadores, ou se transformaram em rendeiros na cobrança dos dízimos, ou, ainda, grande parte deles se dedicou ao comércio de exportação de açúcares, indústria que se encontrava em franco desenvolvimento na capitania (2).No final do século XVI, quando da primeira visitação do Santo Ofí-cio ao Brasil (1593-1595), já era considerável o número de cristãos-novos em Pernambuco. Numa amostragem com base nos depoimentos, pode-se estimar em 14% da população desta capitania nesta época (1,2).Depois da expulsão dos holandeses em 1654, a comunidade judaica pernambucana voltou a sofrer perseguição religiosa por parte dos portugueses e abandonou o Brasil. Das 150 famílias que deixaram o Recife com destino a Amsterdã, um grupo de 23 judeus acabou tendo sua embarcação -o navio Valk -interceptada por piratas espanhóis e aprisionada na Jamaica. Logo em seguida o grupo foi libertado pela tripulação de um navio francês que seguia para a América do Norte e deixado, em setembro de 1654, em Nova Amsterdã, um vilarejo de 1.500 habitantes na época. Foi esse grupo de judeus saído do Recife que fundou a primeira comunidade judaica norte-americana e ajudou a construir o que atualmente é a cidade de Nova Iorque (3).

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The E180splice mutation in the GHR gene causing Laron syndrome: Witness of a Sephardic Jewish exodus from the Iberian Peninsula to the New World?

Gonçalves

Fridman

Pinto

et al. 2014

American J of Med Genetics Pt A

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Laron syndrome (LS) is a genetic disorder caused by mutations in the growth hormone receptor (GHR) gene. The most frequent GHR mutation is E180splice (rs121909360), which was initially found in an inbred population of Spanish descent in Ecuador and subsequently in Israel, Brazil, Chile, and the United States. The aim of the present study is to determine if the E180splice mutation arose from a common origin. We studied 22 patients with LS from Ecuador, Israel (of Moroccan origin), Brazil, Chile, and the United States (of Mexican origin) who were homozygous for the E180splice mutation and compared them to control individuals for markers surrounding the GHR, intragenic polymorphisms, and Y-chromosome STR. An identical haplotype was found in all but one of the subjects carrying the E180splice mutation: D5S665: 150/150; D5S2082: 192/192; D5S2087: 246/246; rs6179 G/G; and rs6180 C/C. One patient differed from the others only at D5S2082 (168/192). This haplotype is rare (~1%) in control individuals and confirmed that the E180splice-associated haplotype was not derived from independent origins but represented recombination from a common ancestor. The analysis of paternal lineage markers showed that 50% belong to haplogroup R1b (found in Portugal and Spain) and 40% to haplogroups J and E (typical in the Middle East and in Eastern European Jews). The germline E180Splice mutation appears to have originated from a single common ancestor. The presence of Y-chromosome markers associated with Sephardic populations in persons harboring the E180splice mutation provides genetic evidence in support of the historical tracking of the exodus of this specific population.

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Efeito fundador da mutação E180splice no gene do receptor de hormônio de crescimento identificada em pacientes brasileiros com insensibilidade ao GH

Cited by 12 publications

References 13 publications

GHR gene transcript heterogeneity may explain phenotypic variability in GHR pseudoexon (6Ψ) patients

GHR gene transcript heterogeneity may explain phenotypic variability in GHR pseudoexon (6Ψ) patients

Cristãos-novos no nordeste e os anões de Orobó (PE): a genética molecular ligada à história do Brasil

The E180splice mutation in the GHR gene causing Laron syndrome: Witness of a Sephardic Jewish exodus from the Iberian Peninsula to the New World?

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