Heterozygous Mutation within a Kinase-Conserved Motif of the Insulin-Like Growth Factor I Receptor Causes Intrauterine and Postnatal Growth Retardation

Kruis, Tassilo; Klammt, J; Galli‐Τsinopoulou, Assimina; Wallborn, Tillmann; Schlicke, Marina; Müller, Eva; Kratzsch, Jürgen; Körner, Antje; Odeh, Rasha; Kieß, Wieland; Pfäffle, Roland

doi:10.1210/endo.151.2.9996

Cited by 20 publications

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“…Of interest, IGF-1R mutation is a very rare event that has been reported only in a number of cases in heterozygote form (Klammt et al, 2008(Klammt et al, , 2011Kruis et al, 2010;Wallborn et al, 2010). Moreover, these mutations were not associated with neoplasia but rather with growth retardation.…”

Section: Igf-1r Activation Is a Pre-requisite For Malignant Transformmentioning

confidence: 99%

Tumor suppressors govern insulin-like growth factor signaling pathways: implications in metabolism and cancer

Werner

2011

Oncogene

116

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The insulin-like growth factor (IGF) axis mediates growth, differentiation and developmental processes, and is also involved in control of metabolic activities. Deregulation of IGF axis expression and action is linked to a number of pathologies, ranging from metabolic disorders to growth deficits and cancer development. Activation of the IGF signaling pathway is a crucial prerequisite for malignant transformation. In addition, overexpression of the IGF-1 receptor (IGF-1R) constitutes a typical hallmark of most types of cancer. A series of tumor suppressors have been identified whose mechanisms of action involve transcriptional suppression of the IGF-1R gene. These tumor suppressors include the p53/p63/ p73 family, breast cancer gene-1, von-Hippel Lindau protein, Wilms' tumor-1 and others. Comprehensive analyses have identified a complex bidirectional interplay between the IGF and tumor-suppressor signaling pathways. These interactions are of major importance in terms of cancer development and may also predict responsiveness to IGF-1R-targeted therapies. Furthermore, the insulin/IGF system has a pivotal role in the regulation of cancer cell metabolism. Deregulation of IGF axis components by mutated tumor-suppressor proteins may lead to metabolic perturbations, with ensuing pathological consequences.

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Section: Igf-1r Activation Is a Pre-requisite For Malignant Transformmentioning

confidence: 99%

Tumor suppressors govern insulin-like growth factor signaling pathways: implications in metabolism and cancer

Werner

2011

Oncogene

116

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“…A mutação p.G1155A foi descrita por Kruis e cols. em 2010 e encontra-se localizada no éxon 19, havendo troca da glicina pela alanina no códon 1155 (32). Ambas as mutações ocorrem no resíduo de aminoácido altamente conservado, localizado no domínio tirosina-quinase intracelular, ocasionando menor autofosforilação do receptor mutado e, consequentemente, redução na ativação de ERK (pela via MAPK) e AKT (pela via PI3K); porém a expressão do IGF-1R e sua afinidade ao ligante não ficaram comprometidas.…”

Section: Modelos Animais De Defeitos No Sistema Igfs/igf1runclassified

“…Nas crianças foi observado em praticamente todos os casos atraso na idade óssea ao redor de 1 ano em relação à idade cronológica. A puberdade atrasada foi descrita em três pacientes do sexo feminino (16,32), porém muitos estudos não caracterizaram adequadamente o desenvolvimento puberal. Pacientes com deficiência primária de IGF-1 (33) ou com deficiência de subunidade ácido-lábil (37), que cursam com baixos valores circulantes de IGF-1, também apresentam atraso puberal, sugerindo o papel desse hormô-nio no mecanismo que regula o início da puberdade.…”

Section: Características Fenotípicas E Clínicas Dos Carreadores Das Munclassified

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Mutações no gene do receptor do fator de crescimento insulina-símile 1 (IGF1R) como causa de retardo do crescimento pré- e pós-natal

Leal

Canton

Montenegro

et al. 2011

Arq Bras Endocrinol Metab

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SUMÁRIOAproximadamente 10% das crianças nascidas pequenas para a idade gestacional (PIGs) não apresentam recuperação espontânea do crescimento. As causas desse déficit de crescimento pré-natal e sua manutenção após o nascimento ainda não são completamente conhecidas na maioria dos casos. Nos últimos oito anos, diversas mutações inativadoras e deleções do gene IGF1R em heterozigose foram relatadas, indicando o papel de defeitos no eixo IGFs/IGF1R como causa do déficit de crescimento. Postula-se que pelo menos 2,5% das crianças nascidas PIGs possam apresentar defeitos no gene IGF1R. O quadro clínico desses pacientes apresenta grande variabilidade quanto à gravidade do retardo de crescimento e aos parâmetros hormonais. Nos casos mais evidentes, os pacientes apresentam microcefalia, déficit cognitivo leve e valores elevados de IGF-1, associados à baixa estatura de início pré-natal. Esta revisão abordará os aspectos clínicos, moleculares e do tratamento da baixa estatura com hrGH de crianças com mutações no IGF1R. Arq Bras Endocrinol Metab. 2011;55(8):541-9 Descritores Receptor do fator de crescimento insulina-símile 1; mutação; retardo do crescimento intrauterino; transtornos do crescimento; crianças nascidas pequenas para a idade gestacional SUMMARY Approximately 10% of children born small-for-gestational age (SGA) do not show spontaneous growth catch-up. The causes of this deficit in prenatal growth and its maintenance after birth are not completely known, in most cases. Over the past eight years, several heterozygous inactivating mutations and deletions in IGF1R gene have been reported, indicating the role of defects in the IGFs/IGF1R axis as a cause of growth deficit. It has been hypothesized that at least 2.5% of children born SGA may have IGF1R gene defects. The clinical presentation of these patients is highly variable in the severity of growth retardation and hormonal parameters. In the most evident cases, patients have microcephaly, mild cognitive impairment and high levels of IGF-1, associated with short stature of prenatal onset. This review will describe the clinical, molecular and treatment of short stature with hrGH of children with mutations in the IGF1R gene. Arq Bras Endocrinol Metab. 2011;55(8):541-9

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“…IGF-1R has, however, been reported to play a role in invasion and metastasis of breast cancer cells [17][18][19]. Some rare mutations reported in IGF-1R were associated with mere growth retardation without an effect on cancer development or neoplasia [20][21]. Activation of the receptor results in either the activation of the Ras /Raf / MAP kinase pathway leading to cell proliferation or activation of Akt/PKB pathway regulating cell survival, through phosphorylation of IRS-1.…”

Section: Introductionmentioning

confidence: 99%

Nanoparticle-facilitated Intratumoral Delivery of Bcl-2/IGF-1R siRNAs and p53 Gene Synergistically Inhibits Tumor Growth in Immunocompetent Mice

Kunnath¹,

Kamaruzman²,

Chowdhury³

2015

J Nanomed Nanotechnol

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Heterozygous Mutation within a Kinase-Conserved Motif of the Insulin-Like Growth Factor I Receptor Causes Intrauterine and Postnatal Growth Retardation

Cited by 20 publications

References 0 publications

Tumor suppressors govern insulin-like growth factor signaling pathways: implications in metabolism and cancer

Tumor suppressors govern insulin-like growth factor signaling pathways: implications in metabolism and cancer

Mutações no gene do receptor do fator de crescimento insulina-símile 1 (IGF1R) como causa de retardo do crescimento pré- e pós-natal

Nanoparticle-facilitated Intratumoral Delivery of Bcl-2/IGF-1R siRNAs and p53 Gene Synergistically Inhibits Tumor Growth in Immunocompetent Mice

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