The first homozygous mutation (S226I) in the highly‐conserved WSXWS‐like motif of the GH receptor causing Laron syndrome: supression of GH secretion by GnRH analogue therapy not restored by dihydrotestosterone administration

Jorge, Alexander A L; Souza, S. C. A. L.; Arnhold, Ivo Jorge Prado; Mendonca, Berenice B.

doi:10.1111/j.1365-2265.2004.01930.x

Cited by 22 publications

(14 citation statements)

References 21 publications

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“…It is noteworthy that basal and stimulated GH levels were in the normal range in contrast to elevated levels usually observed in patients with GHR defects (23,24). The same was observed in other patients with STAT5B defects (4,7).…”

Section: Discussioncontrasting

confidence: 44%

A novel STAT5B mutation causing GH insensitivity syndrome associated with hyperprolactinemia and immune dysfunction in two male siblings

Pugliese-Pires

Tonelli

Dora

et al. 2010

European Journal of Endocrinology

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Background: GH insensitivity (GHI) syndrome caused by STAT5B mutations was recently reported, and it is characterized by extreme short stature and immune dysfunction. Treatment with recombinant human IGF1 (rhIGF1) is approved for patients with GHI, but the growth response to this therapy in patients with STAT5B mutations has not been reported. Objectives: To report the clinical features, molecular findings, and the short-term growth response to rhIGF1 therapy in patients with STAT5B mutation. Subjects and methods: Hormonal and immunological evaluations were performed in two male siblings with GHI associated with atopic eczema, interstitial lung disease, and thrombocytopenic purpura. STAT5B genes were directly sequenced. The younger sibling was treated with rhIGF1 at a dose of 110 mg/kg BID. Results: Both siblings had laboratory findings compatible with GHI associated with hyperprolactinemia. Lymphopenia and reduced number of natural killer cells without immunoglobulin abnormalities were observed. STAT5B sequence revealed a homozygous frameshift mutation (p.L142fsX161) in both siblings. The younger sibling (9.9 years of age) was treated with rhIGF1 at appropriate dosage, and he did not present any significant change in his growth velocity (from 2.3 to 3.0 cm/year after 1.5 years of therapy). The presence of a chronic illness could possibly be responsible for the poor result of rhIGF1 treatment. Further studies in patients with STAT5B defects are necessary to define the response to rhIGF1 treatment in this disorder. Conclusion: GHI associated with immune dysfunction, especially interstitial lung disease, and hyperprolactinemia is strongly suggestive of a mutation in STAT5B in both sexes.

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Section: Discussioncontrasting

confidence: 44%

A novel STAT5B mutation causing GH insensitivity syndrome associated with hyperprolactinemia and immune dysfunction in two male siblings

Pugliese-Pires

Tonelli

Dora

et al. 2010

European Journal of Endocrinology

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“…Laboratorialmente o paciente apresentava níveis elevados de GH com níveis baixos de IGF-I e GHBP, porém com níveis normais de IGFBP-3. O estudo molecular demonstrou a presença de uma mutação em homozigose no exon 7 que leva à troca do aminoácido serina por isoleucina no codon 226 (S226I) (6).…”

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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

Jorge

Filho²,

Lins

et al. 2005

Arq Bras Endocrinol Metab

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Arq Bras Endocrinol Metab vol 49 nº 3 Junho 2005 384 RESUMOEstudamos o gene do receptor de hormônio de crescimento (GHR) de 6 pacientes com síndrome de Laron (SL) provenientes de 4 famílias distintas. Os exons 2 a 10 foram amplificados por pares de primers intrônicos. Os produtos de PCR foram seqüenciados diretamente. Os 6 pacientes possuíam no exon 6, codon 180, a troca GGA>GAA em homozigose. Esta mutação não altera o aminoácido traduzido, porém cria um novo sítio de splice que causa a deleção de 8 aminoácidos do domínio extracelular do GHR. Para avaliar um efeito fundador da mutação E180splice, os membros das 4 famílias foram genotipados para 4 regiões intragênicas polimórficas: a presença ou ausência do exon 3, dois polimorfismos de um único nucleotídeo presentes nos exons 6 e 10 e o sítio polimórfico no intron 9. Todos os pacientes apresentavam o mesmo haplótipo destas 4 regiões. A mutação E180splice foi descrita anteriormente em uma comunidade andina no sul do Equador descendente de espanhóis e também numa família judia de Israel. Nossas famílias compartilham o mesmo haplótipo do intron 9 observado nestes pacientes. Concluímos que a mutação E180splice é uma importante causa de IGH no Brasil e a presença do mesmo haplótipo em nossos pacientes, nos pacientes equatorianos e israelenses com a mutação E180splice é forte indício do efeito fundador desta mutação. ABSTRACT Founder Effect of E180splice Mutation in Growth Hormone Receptor Gene (GHR) Identified in Brazilian Patients With GH Insensitivity.We studied the growth hormone receptor (GHR) gene in 6 patients with Laron syndrome (LS) from 4 unrelated families. Exons 2 to 10 were amplified by PCR using specific intronic pairs of primers. The PCR products were directly sequenced. Our results showed that all 6 patients carried a homozygous GAG>GAA mutation in codon 180 of exon 6. This mutation did not change the translated amino acid, but created an abnormal splice site deleting 8 amino acids from the extracellular domain of GHR. Members of all 4 kindreds with the E180splice mutation were genotyped for 4 polymorphic intragenic sites: The retention or exclusion of exon 3, single nucleotide polymorphisms present in exons 6 and 10, and intron 9 polymorphic site. All 6 patients presented the same haplotype. The E180splice mutation was first described in a population of Spanish descendants from the Andes of Southern Ecuador. This mutation was also found in oriental Jewish patients from Israel. Our families share the same intron-9 haplotype observed in Ecuadorian and Israeli patients. We conclude that the E180splice mutation is an important cause of LS in Brazil and there is probably a founder effect since our patients, Ecuadorian and Israeli patients share the same haplotype in intron 9.

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“…No entanto, o quadro clínico e laboratorial da IGH varia dentro de um espectro que vai da síndrome de Laron a apresentações mais leves que podem ser confundidas com a baixa estatura idiopática (1). As causas mais comuns de IGH são mutações no gene do receptor de GH (GHR; OMIM: *600946), sendo que mais de setenta já foram descritas até o momento (2,3), a maioria herdada de maneira autossômica recessiva (3,4).…”

Section: Discussionunclassified

Deficiência da STAT5B: uma nova síndrome de insensibilidade ao hormônio de crescimento associada a acometimento imunológico

Scalco

Pugliese-Pires

Jorge

2013

Arq Bras Endocrinol Metab

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Uma nova apresentação da insensibilidade ao hormônio de crescimento (IGH), causada por mutações em homozigose no gene STAT5B (transdutor de sinal e ativador de transcrição tipo 5B), foi caracterizada nos últimos anos. Sua particularidade é a associação com quadros de disfunção imunológica grave, sendo o mais característico a pneumonite intersticial linfocítica. A presença concomitante de doenças crônicas imunológicas pode fazer com que a baixa estatura seja erroneamente considerada uma consequência do quadro clínico, levando ao subdiagnóstico dessa forma de IGH. O objetivo desta revisão é divulgar o conhecimento atual sobre essa rara patologia, facilitando o reconhecimento de pacientes com IGH secundária a mutações no gene STAT5B em ambulatórios de endocrinologia e de outras especialidades.

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The first homozygous mutation (S226I) in the highly‐conserved WSXWS‐like motif of the GH receptor causing Laron syndrome: supression of GH secretion by GnRH analogue therapy not restored by dihydrotestosterone administration

Cited by 22 publications

References 21 publications

A novel STAT5B mutation causing GH insensitivity syndrome associated with hyperprolactinemia and immune dysfunction in two male siblings

A novel STAT5B mutation causing GH insensitivity syndrome associated with hyperprolactinemia and immune dysfunction in two male siblings

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

Deficiência da STAT5B: uma nova síndrome de insensibilidade ao hormônio de crescimento associada a acometimento imunológico

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