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      Novel nonsense mutation (p.Y113X) in the human growth hormone receptor gene in a Brazilian patient with Laron syndrome Translated title: Nova mutação nonsense (p.Y113X) no gene do receptor do hormônio do crescimento em um paciente brasileiro com síndrome de Laron

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          Abstract

          BACKGROUND: To date, about sixty different mutations within GH receptor (GHR) gene have been described in patients with GH insensitivity syndrome (GHI). In this report, we described a novel nonsense mutation of GHR. METHODS: The patient was evaluated at the age of 6 yr, for short stature associated to clinical phenotype of GHI. GH, IGF-1, and GHBP levels were determined. The PCR products from exons 2-10 were sequenced. RESULTS: The patient had high GH (26 µg/L), low IGF-1 (22.5 ng/ml) and undetectable GHBP levels. The sequencing of GHR exon 5 disclosed adenine duplication at nucleotide 338 of GHR coding sequence (c.338dupA) in homozygous state. CONCLUSION: We described a novel mutation that causes a truncated GHR and a loss of receptor function due to the lack of amino acids comprising the transmembrane and intracellular regions of GHR protein, leading to GHI.

          Translated abstract

          INTRODUÇÃO: Até o momento, aproximadamente 60 diferentes mutações envolvendo o gene do receptor do GH (GHR) foram descritas em pacientes com a síndrome de insensibilidade ao GH (GHI). Neste artigo, descrevemos uma nova mutação nonsense do GHR. MÉTODOS: O paciente foi avaliado aos 6 anos de idade para baixa estatura associada ao fenótipo clínico da GHI. Níveis de GH, IGF-1 e GHBP foram determinados. Os produtos de PCR dos éxons 2-10 foram seqüenciados. RESULTADOS: O paciente apresentou níveis elevados de GH (26 µg/L), baixos de IGF-1 (22.5 ng/ml) e indetectáveis de GHBP. O seqüenciamento do éxon 5 do GHR revelou uma duplicação da adenina no nucleotídeo 338 da sequência de codificação do GHR (c.338dupA) em homozigose. CONCLUSÃO: Descrevemos uma nova mutação que causa um GHR truncado e uma perda da função do receptor devido à perda de aminoácidos compreendendo as regiões transmembrana e intracelular do receptor, levando a GHI.

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          Most cited references 51

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          Laron syndrome (primary growth hormone resistance or insensitivity): the personal experience 1958-2003.

           Zvi Laron (2004)
          Clinical and laboratory investigations starting in 1958 of a group of dwarfed children resembling isolated GH deficiency but who had very high serum levels of GH led to the description of the syndrome of primary GH resistance or insensitivity (Laron syndrome) and subsequently to the discovery of its molecular defects residing in the GH receptor and leading to an inability of IGF-I generation. With the biosynthesis of IGF-I in 1986, therapeutic trials started. Continuously more and more patients are being diagnosed in many parts of the world with a variety of molecular defects. This syndrome proved to be a unique model that enables the study of the consequences of GH receptor defects, the physiopathology of GH-IGF-I disruption, and comparison of the GH-independent IGF-I effects. This review presents the personal experience gained from the study follow-up and treatment of the 60 patients followed up for many years in the Israeli cohort.
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            Genetic pituitary dwarfism with high serum concentation of growth hormone--a new inborn error of metabolism?

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              Laron dwarfism and mutations of the growth hormone-receptor gene.

              Laron dwarfism is associated with resistance to growth hormone (GH). To investigate its genetic basis, we used genetic linkage to test whether the disorder results from a defect in the gene for the human GH receptor. Denaturing gradient gel electrophoresis and sequencing of specific GH-receptor-gene fragments allowed us to characterize specific intragenic DNA markers in 35 control subjects of Mediterranean descent, for use in linkage studies. In two Mediterranean families in which the parents were consanguineous and some of the children had Laron dwarfism, the disease trait and DNA polymorphisms were inherited together. Moreover, an analysis of the GH-receptor-gene RNA transcripts in lymphocytes from one of these families allowed us to identify a thymidine-to-cytosine substitution that generated a serine in place of a phenylalanine at position 96 in the extracellular coding domain of the mature protein. This defect probably affects the receptor adversely and is probably responsible for the lack of plasma GH-binding activity in the patients. This mutation was not found in the GH-receptor genomic sequences of seven unrelated subjects with Laron dwarfism who belonged to different population groups. An analysis of the GH-receptor markers in these patients indicated that different gene frameworks (polymorphic sites within the single gene) were associated with the mutant alleles. We conclude that Laron dwarfism is due to abnormalities in the gene for GH receptor, which may differ from family to family.
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                Author and article information

                Contributors
                Role: ND
                Role: ND
                Role: ND
                Role: ND
                Role: ND
                Journal
                abem
                Arquivos Brasileiros de Endocrinologia & Metabologia
                Arq Bras Endocrinol Metab
                Sociedade Brasileira de Endocrinologia e Metabologia (São Paulo )
                1677-9487
                November 2008
                : 52
                : 8
                : 1264-1271
                Affiliations
                [1 ] Universidade de Pernambuco Brasil
                [2 ] Universidade de São Paulo Brazil
                [3 ] University of Florida USA
                Article
                S0004-27302008000800010
                10.1590/S0004-27302008000800010
                Product
                Product Information: website
                Categories
                ENDOCRINOLOGY & METABOLISM

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