scholarly journals A Familial Insulin-Like Growth Factor-I Receptor Mutant Leads to Short Stature: Clinical and Biochemical Characterization

2007 ◽  
Vol 92 (4) ◽  
pp. 1542-1548 ◽  
Author(s):  
Kenjiro Inagaki ◽  
Anatoly Tiulpakov ◽  
Petr Rubtsov ◽  
Polina Sverdlova ◽  
Valentina Peterkova ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Short Stature ◽  
Growth Retardation ◽  
Fold Increase ◽  
Postnatal Growth ◽  
Β Subunit ◽  
Postnatal Growth Retardation ◽  
Mutant Receptor ◽  
Igf I ◽  
Nih 3T3

Abstract Context: IGF-I/IGF-I receptor (IGF-IR) signaling pathways play important roles in longitudinal growth. A novel Arg481Glu (R481Q) mutation in IGF-IR was detected in a family with intrauterine and postnatal growth retardation. Objective: The objective of the study was to explore the mechanism whereby the R481Q mutation may be causative in growth retardation. Patients: A 13-yr-old girl with short stature was studied for functional analysis of the R481Q mutation in the IGF-IR. Results: Two members of a family who showed intrauterine and postnatal growth retardation, with increased serum IGF-I levels, demonstrated a substitution of arginine for glutamine at 481 (R481Q) in the IGF-IR. This mutation results in the formation of an altered fibronectin type III domain within the α-subunit. NIH-3T3 fibroblasts that overexpress the human wild-type or R481Q mutant IGF-IR demonstrated normal cell surface ligand binding by 125I-IGF-I binding assay. However, the fold increase of IGF-I stimulated tyrosine phosphorylation of the IGF-IR β-subunit as well as downstream activation of ERK1/2 and Akt was reduced in cells overexpressing the mutant receptor. Additionally, basal and IGF-I-stimulated levels of cell proliferation were also reduced in cells overexpressing the mutant receptor. Conclusion: Our results demonstrate that NIH-3T3 cells overexpressing a mutant form of the Igf1r gene, in which arginine at 481 is substituted by glutamine, lead to reduced levels of the fold increase of IGF-IR β-subunit phosphorylation as well as ERK1/2 and Akt phosphorylation and was accompanied by decreased cell proliferation. These results are postulated to be the cause of intrauterine and postnatal growth retardation in the described patients.

scholarly journals Mutation at Cleavage Site of Insulin-Like Growth Factor Receptor in a Short-Stature Child Born with Intrauterine Growth Retardation

2005 ◽  
Vol 90 (8) ◽  
pp. 4679-4687 ◽  
Author(s):  
Yuki Kawashima ◽  
Susumu Kanzaki ◽  
Fan Yang ◽  
Tomoe Kinoshita ◽  
Keiichi Hanaki ◽  
...  
Keyword(s):  
Short Stature ◽  
Growth Retardation ◽  
Cleavage Site ◽  
Intrauterine Growth Retardation ◽  
Growth Factor Receptor ◽  
Heterozygous Mutation ◽  
Β Subunit ◽  
Direct Dna Sequencing ◽  
Intrauterine Growth ◽  
Igf I

Context: Mouse knockout models have clearly demonstrated the critical importance of IGF-I and IGF receptor type 1 (IGF-IR) for embryonic growth as well as postnatal growth. Objective: We hypothesized that mutations of IGF-IR gene might predispose to short stature in children born with intrauterine growth retardation (IUGR). Patients: Twenty-four children with unexplained IUGR (birth weight < −1.5 sd) and short stature (<−2.0 sd) were screened for abnormalities of the IGF-IR gene. Methods: Direct DNA sequencing was used to identify IGF-IR gene mutations. Unprocessed IGF-IR proreceptor in fibroblasts was detected by immunoblot analysis. Functions of mutated IGF-IR in fibroblasts were evaluated by IGF-I binding, and IGF-I-stimulated DNA synthesis and β-subunit autophosphorylation. Results: We found the following results: 1) a heterozygous mutation (R709Q) changing the cleavage site from Arg-Lys-Arg-Arg to Arg-Lys-Gln-Arg was identified in a 6-yr-old Japanese girl (case 1) and her mother who also had IUGR with short stature (case 2); 2) fibroblasts from case 2 contained more IGF-IR proreceptor protein (189 ± 26% of normal) and less mature β-subunit protein (63 ± 12%); 3) [125I]IGF-I binding to fibroblasts from case 2 was reduced, compared with normal control (0.61 ± 0.16 × 106vs. 1.14 ± 0.12 × 106 sites per cell; P < 0.05); and 4) both IGF-I-stimulated [3H]thymidine incorporation and IGF-IR β-subunit autophosphorylation were low in fibroblasts from case 2, compared with those of control (P < 0.05). Conclusions: These findings strongly suggest that this mutation leads to failure of processing of the IGF-IR proreceptor to mature IGF-IR and causes short stature and IUGR.

Novel missense mutation in the IGF-I receptor L2 domain results in intrauterine and postnatal growth retardation

2012 ◽  
Vol 77 (2) ◽  
pp. 246-254 ◽  
Author(s):  
Yuki Kawashima ◽  
Katsumi Higaki ◽  
Toshiaki Fukushima ◽  
Fumihiko Hakuno ◽  
Jun-ichi Nagaishi ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Growth Retardation ◽  
Postnatal Growth ◽  
Postnatal Growth Retardation ◽  
Igf I

scholarly journals 12q14 Microdeletions: Additional Case Series with Confirmation of a Macrocephaly Region

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Adrian Mc Cormack ◽  
Cynthia Sharpe ◽  
Nerine Gregersen ◽  
Warwick Smith ◽  
Ian Hayes ◽  
...  
Keyword(s):  
Short Stature ◽  
Developmental Delay ◽  
Growth Retardation ◽  
Case Series ◽  
Postnatal Growth ◽  
Additional Case ◽  
Postnatal Growth Retardation ◽  
Growth Profile ◽  
Severe Short Stature

To date, there have been only a few reports of patients carrying a microdeletion in chromosome 12q14. These patients usually present with pre- and postnatal growth retardation, and developmental delay. Here we report on two additional patients with both genotype and phenotype differences. Similar to previously published cases, one patient has haploinsufficiency of theHMGA2gene and shows severe short stature and developmental delay. The second patient is only one of a handful without the loss of theHMGA2gene and shows a much better growth profile, but with absolute macrocephaly. This patient’s deletion is unique and hence defines a likely macrocephaly locus that contributes to the general phenotype characterising the 12q14 syndrome.

IGF-I Receptor Mutations Resulting in Intrauterine and Postnatal Growth Retardation

2003 ◽  
Vol 349 (23) ◽  
pp. 2211-2222 ◽  
Author(s):  
M. Jennifer Abuzzahab ◽  
Anke Schneider ◽  
Audrey Goddard ◽  
Florin Grigorescu ◽  
Corinne Lautier ◽  
...  
Keyword(s):  
Growth Retardation ◽  
Postnatal Growth ◽  
Postnatal Growth Retardation ◽  
Igf I

scholarly journals A Heterozygous Mutation of the Insulin-Like Growth Factor-I Receptor Causes Retention of the Nascent Protein in the Endoplasmic Reticulum and Results in Intrauterine and Postnatal Growth Retardation

2010 ◽  
Vol 95 (5) ◽  
pp. 2316-2324 ◽  
Author(s):  
Tillmann Wallborn ◽  
Stefan Wüller ◽  
Jürgen Klammt ◽  
Tassilo Kruis ◽  
Jürgen Kratzsch ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Surface ◽  
Growth Retardation ◽  
Postnatal Growth ◽  
Laser Scanning Microscopy ◽  
Cell Surface Receptor ◽  
Cell Surface Expression ◽  
Growth Disorders ◽  
Postnatal Growth Retardation ◽  
Igf I

Abstract Background: Mutations in the IGF-I receptor (IGF1R) gene can be responsible for intrauterine and postnatal growth disorders. Objective: Here we report on a novel mutation in the IGF1R gene in a female patient. The aim of our study was to analyze the functional impact of this mutation. Patient: At birth, the girl’s length was 47 cm [−1.82 sd score (SDS)], and her weight was 2250 g (−2.26 SDS). Clinical examination revealed microcephaly and retarded cognitive development. She showed no postnatal catch-up growth but had relatively high IGF-I levels (+1.83 to +2.17 SDS). Results: Denaturing HPLC screening and direct DNA sequencing disclosed a heterozygous missense mutation resulting in an amino acid exchange from valine to glutamic acid at position 599 (V599E-IGF1R). Using various cell systems, we found that the V599E-IGF1R mutant was not tyrosine phosphorylated and had an impaired downstream signaling in the presence of IGF-I. Flow cytometry and live cell confocal laser scanning microscopy revealed a lack of cell surface expression due to an extensive retention of V599E-IGF1R proteins within the endoplasmic reticulum. Conclusion: The V599E-IGF1R mutation interferes with the receptor’s trafficking path, thereby abrogating proreceptor processing and plasma membrane localization. Diminished cell surface receptor density solely expressed from the patient’s wild-type allele is supposed to lead to insufficient IGF-I signaling. We hypothesize that this mechanism results in intrauterine and postnatal growth retardation of the affected patient. The reported retention of the nascent IGF1R in the endoplasmic reticulum presents a novel mechanism of IGF-I resistance.

scholarly journals A Heterozygous Mutation of the Insulin-Like Growth Factor-I Receptor Causes Retention of the Nascent Protein in the Endoplasmic Reticulum and Results in Intrauterine and Postnatal Growth Retardation

2010 ◽  
Vol 24 (4) ◽  
pp. 873-873
Author(s):  
Tillmann Wallborn ◽  
Stefan Wüller ◽  
Jürgen Klammt ◽  
Tassilo Kruis ◽  
Jürgen Kratzsch ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Surface ◽  
Growth Retardation ◽  
Postnatal Growth ◽  
Laser Scanning Microscopy ◽  
Cell Surface Receptor ◽  
Cell Surface Expression ◽  
Growth Disorders ◽  
Postnatal Growth Retardation ◽  
Igf I

Abstract Background: Mutations in the IGF-I receptor (IGF1R) gene can be responsible for intrauterine and postnatal growth disorders. Objective: Here we report on a novel mutation in the IGF1R gene in a female patient. The aim of our study was to analyze the functional impact of this mutation. Patient: At birth, the girl’s length was 47 cm [−1.82 sd score (SDS)], and her weight was 2250 g (−2.26 SDS). Clinical examination revealed microcephaly and retarded cognitive development. She showed no postnatal catch-up growth but had relatively high IGF-I levels (+1.83 to +2.17 SDS). Results: Denaturing HPLC screening and direct DNA sequencing disclosed a heterozygous missense mutation resulting in an amino acid exchange from valine to glutamic acid at position 599 (V599E-IGF1R). Using various cell systems, we found that the V599E-IGF1R mutant was not tyrosine phosphorylated and had an impaired downstream signaling in the presence of IGF-I. Flow cytometry and live cell confocal laser scanning microscopy revealed a lack of cell surface expression due to an extensive retention of V599E-IGF1R proteins within the endoplasmic reticulum. Conclusion: The V599E-IGF1R mutation interferes with the receptor’s trafficking path, thereby abrogating proreceptor processing and plasma membrane localization. Diminished cell surface receptor density solely expressed from the patient’s wild-type allele is supposed to lead to insufficient IGF-I signaling. We hypothesize that this mechanism results in intrauterine and postnatal growth retardation of the affected patient. The reported retention of the nascent IGF1R in the endoplasmic reticulum presents a novel mechanism of IGF-I resistance.

scholarly journals Metabolic implications of GH treatment in small for gestational age

2007 ◽  
Vol 157 (suppl_1) ◽  
pp. S47-S50 ◽  
Author(s):  
E M Delemarre ◽  
J Rotteveel ◽  
H A Delemarre-van de Waal
Keyword(s):  
Lipid Metabolism ◽  
Gestational Age ◽  
Growth Retardation ◽  
Small For Gestational Age ◽  
Postnatal Growth ◽  
Gh Treatment ◽  
Increased Risk ◽  
Igf I

Fetal growth retardation is associated with decreased postnatal growth, resulting in a lower adult height. In addition, a low birth weight is associated with an increased risk of developing diseases during adulthood, such as insulin resistance, type 2 diabetes mellitus, hypertension, dyslipidemia, and cardiovascular diseases. Children with persistent postnatal growth retardation, i.e., incomplete catchup growth, can be treated with human GH. The GH/IGF-I axis is involved in the regulation of carbohydrate and lipid metabolism. The question of whether treatment with GH in children born small for gestational age (SGA) has long-term implications with respect to glucose/insulin and lipid metabolism has not been answered yet. In this article, the available data are reviewed.

scholarly journals Genetic disorders in the GH–IGF-I axis in mouse and man

2007 ◽  
Vol 157 (suppl_1) ◽  
pp. S15-S26 ◽  
Author(s):  
M J E Walenkamp ◽  
J M Wit
Keyword(s):  
Short Stature ◽  
Genetic Disorders ◽  
Genetic Defect ◽  
Postnatal Growth ◽  
Genetic Defects ◽  
Animal Data ◽  
Organ Systems ◽  
Number Of Patients ◽  
Igf I ◽  
And Function

Animal knockout experiments have offered the opportunity to study genes that play a role in growth and development. In the last few years, reports of patients with genetic defects in GH–IGF-I axis have greatly increased our knowledge of genetically determined causes of short stature. We will present the animal data and human reports of genetic disorders in the GH–IGF-I axis in order to describe the role of the GH–IGF-I axis in intrauterine and postnatal growth. In addition, the effects of the GH–IGF-I axis on the development and function of different organ systems such as brain, inner ear, eye, skeleton, glucose homeostasis, gonadal function, and immune system will be discussed. The number of patients with genetic defects in the GH–IGF-I axis is small, and a systematic diagnostic approach and selective genetic analysis in a patient with short stature are essential to identify more patients. Finally, the implications of a genetic defect in the GH–IGF-I axis for the patient and the therapeutic options will be discussed.

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