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 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.

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.

A model of intrauterine growth retardation caused by chronic maternal undernutrition in the rat: effects on the somatotrophic axis and postnatal growth

1996 ◽  
Vol 150 (2) ◽  
pp. 231-242 ◽  
Author(s):  
S M Woodall ◽  
B H Breier ◽  
B M Johnston ◽  
P D Gluckman
Keyword(s):  
Growth Retardation ◽  
Intrauterine Growth Retardation ◽  
Postnatal Growth ◽  
Maternal Plasma ◽  
Intrauterine Growth ◽  
Maternal Undernutrition ◽  
Body Weights ◽  
Igf I ◽  
Ad Libitum ◽  
Somatotrophic Axis

Abstract While it is well established that severe maternal undernutrition during pregnancy causes intrauterine growth retardation (IUGR), there has been relatively little study of the endocrine consequences and postnatal development of growth-retarded offspring. We have developed a model in the rat of IUGR by nutritional restriction of the mother throughout gestation and have examined the effects of fetal growth retardation on the endocrine and metabolic status during the perinatal period. Timed matings were performed in Wistar rats and dams were randomly assigned to one of two dietary treatment groups. Food was available ad libitum throughout pregnancy to a control group (ad libitum group) and a restricted group was fed 30% of the ad libitum intake (restricted fed group). After birth, food was available ad libitum in both groups and litter size was adjusted to eight pups per litter. Dams lost a significant amount of body weight throughout gestation due to undernutrition but were able to catch up to the ad libitum group by day 10 postnatally. Litter size was not affected by maternal undernutrition. Maternal plasma IGF-I levels were significantly reduced in the restricted fed group throughout gestation (P<0·001) but were not different postnatally. Maternal plasma IGF-binding proteins (IGFBPs)-1, -2 and -3 were significantly (P<0·05) increased in the restricted fed dams. The mean body weights of fetuses in late gestation from the restricted fed dams were significantly lower (P<0·001) in comparison with fetuses from control dams. Placental weights were also significantly (P<0·01) reduced in the restricted fed compared with control dams. Body weights were significantly lower in the offspring of restricted fed dams than control dams from birth (P<0·01) until 90 days of age (P<0·05). Nose–rump length was reduced in the fetuses of the restricted fed group at day 22 of gestation (P<0·001) until weaning (P<0·05). Plasma IGF-I levels were significantly reduced in the pups of restricted fed dams from day 22 of gestation (P<0·01) until postnatal day 9 (P<0·05) but were not significantly different at the later time-points. Plasma insulin levels were significantly reduced in the pups of restricted fed dams at birth (P<0·05) but not at later time-points. Plasma IGFBP-1 and -2 levels were significantly increased in the offspring from restricted fed dams at day 22 of gestation, at birth and at day 9 postnatally (P<0·05). 125I-Bovine GH specific binding to liver membranes was significantly lower (P<0·05) in offspring from restricted fed dams at 21 days of age but not at 90 days of age. These data demonstrate that nutritional deprivation in the pregnant rat leads to IUGR and postnatal growth failure and to changes in allometric growth patterns and endocrine parameters of the somatotrophic axis postnatally. Journal of Endocrinology (1996) 150, 231–242

Sign in / Sign up

Export Citation Format

Share Document