Short Stature Caused by a Mutant Growth Hormone

Takahashi, Yutaka; Kaji, Hidesuke; Okimura, Yasuhiko; Goji, Katsumi; Abe, Hiromi; Chihara, Kazuo

doi:10.1056/nejm199602153340704

Cited by 144 publications

(72 citation statements)

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“…(25) relataram o caso de um menino de 4 anos e 11 meses com 81,7cm (6,1 desvios padrões abaixo da média), proporções corporais normais, testa proeminente, nariz em forma de sela e idade óssea de 2 anos. Os níveis basais de GH eram altos (7 e 14ng/mL), com valores de picos após diferentes testes de estímulo variando entre 15 e 38ng/mL.…”

Section: Gh Bioinativo Isoformas Moleculares Do Gh E Gh Mutantesunclassified

Genética molecular do eixo GH-IGF1

Boguszewski

2001

Arq Bras Endocrinol Metab

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RESUMOO hormônio de crescimento (GH, growth hormone), o fator de crescimento insulina símile-1 (IGF1, insulin-like growth factor-1) e uma enorme variedade de moléculas afins formam um eixo regulador do crescimento pré e pós-natal. Os permanentes avanços nas técnicas de biologia molecular têm facilitado a identificação de defeitos genéticos nos diferentes componentes do eixo GH-IGF1 em crianças com baixa estatura. Por outro lado, a aplicação de novos métodos de dosagens hormonais tem revelado a existência de formas inativas de GH ou quantidades aumentadas de formas com menor atividade biológica, cuja presença na circulação poderia justificar o retardo de crescimento em certas crianças com baixa estatura. Clinicamente, os defeitos genéticos no eixo GH-IGF1 podem se manifestar tanto em síndromes de deficiência como de resistência hormonal, enfatizando a importância de se avaliar não apenas a secreção de GH numa criança com baixa estatura, mas também marcadores periféricos de uma possível resistência tecidual ao hormônio. Neste artigo, os principais defeitos genéticos descritos até o presente momento no eixo GH/IGF1 são revisados, com enfoque sobre as repercussões clínicas destes defeitos e a importância da avaliação genética no diagnóstico diferencial da baixa estatura idiopática e da baixa estatura familiar. Na parte final, alguns breves comentários são feitos sobre defeitos genéticos encontrados em dois importantes fatores de transcrição da hipófise, que provocam um quadro clínico de deficiência combinada de hormônios pituitários, incluindo a deficiência de GH. Unitermos: GH; IGF1; Crescimento; Baixa estatura; Genética molecular ABSTRACT Growth hormone (GH), insulin-like growth factor-1 (IGF1) and several related molecules are involved in the growth regulation axis at both pre and postnatal life. The advances in molecular biology techniques have improved the way of identifying genetic defects in different elements of the GH-IGF1 axis in children with short stature. On the other hand, the use of new GH assays have revealed the presence of GH with no biological activity or increased amounts of less active GH isoforms in the circulation, which could potentially be the cause of growth retardation in certain children with short stature. Clinically, the genetic defects might result in either hormone deficiency or resistance, showing the importance of evaluating both GH secretion and GH responsiveness in a short child. In the present article, the main genetic defects within the GH-IGF1 axis are reviewed with focus in their clinical repercussion and their importance in the differential diagnosis of idiopathic and familial short stature. In addition, a short review on the genetic abnormalities found in two of the most important pituitary transcription factors will be presented.

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Section: Gh Bioinativo Isoformas Moleculares Do Gh E Gh Mutantesunclassified

Genética molecular do eixo GH-IGF1

Boguszewski

2001

Arq Bras Endocrinol Metab

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“…The DNA corresponding to GH-1 gene was amplified by polymerase chain reaction (PCR), using pairs of the specific oligonucleotide primers as described previously [1]. The amplification products were extracted and sequenced using a 373A DNA Sequencer.…”

Section: Hormone Assaysmentioning

confidence: 99%

“…cDNA was then synthesized with total RNA [16] and used for PCR to amplify GH-1 cDNA with different sets of the oligonucleotide primers, as described previously [1]. The amplified products were analyzed as described above.…”

Section: Hormone Assaysmentioning

confidence: 99%

“…This disorder is characterized by short stature with high serum immunoreactive GH concentrations, low serum insulin-like growth factor-1(IGF- 1) concentrations, and increases in both serum IGF-1 concentrations and somatic linear growth after exogenous GH administration.…”

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confidence: 99%

“…Very recently, we have reported a child with short stature and a mutant GH caused by a single missense mutation in the GH gene, which itself cannot transduce the GH-signal to the cells but also can blunt the action of wild-type GH because of its greater affinity for the growth hormone binding protein (GHBP) and GH receptor [1] …”

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confidence: 99%

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Short Stature Caused by a Mutant Growth Hormone with an Antagonistic Effect.

et al. 1996

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Abstract.The molecular basis of biologically inactive GH remained unclear until recently. We have very recently reported a child with short stature and a mutant GH caused by a single missense mutation in the GH-1 gene, which itself cannot transduce the GH-signal to the cells but can blunt the action of wild-type GH by virtue of its greater affinity for the GH binding protein (GHBP)/GH receptor. Briefly the clinical features of the patient are: At the age of 4.9 years his height was 81.7 cm (-6.1 SD) and bone age was 2 years. The patient's serum insulin-like growth factor-1(IGF-1) concentration was 34 ng/ml. The basal serum GH concentration ranged from 7.0 to 14.0 ng/ml and peak concentrations after insulin hypoglycemia, arginine and L-dopa were 38.0, 15.0 and 35.0 ng/ml, respectively. A heterozygous single base substitution was identified in the GH-1 gene of the proband, predicted to convert codon 77 from arginine to cysteine.Isoelectric focusing revealed the presence of an abnormal GH peak in addition to a normal GH peak. The affinity of expressed mutant GH to GHBP was approximately 6 times higher than that of wild-type GH. The mutant GH not only failed to stimulate tyrosine phosphorylation by itself, but it also inhibited the activity of wild-type GH when added simultaneously even in a one tenth dose of wild-type GH. The child whom we reported is therefore the first case of short stature caused by mutant GH with an antagonistic effect.

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Growth Hormone

Phillips

2002

Wiley Encyclopedia of Molecular Medicine

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Short Stature Caused by a Mutant Growth Hormone

Cited by 144 publications

References 25 publications

Genética molecular do eixo GH-IGF1

Genética molecular do eixo GH-IGF1

Short Stature Caused by a Mutant Growth Hormone with an Antagonistic Effect.

Growth Hormone

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