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.
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.


METHODS
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.


CONCLUSIONS
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.
Wallborn
Tillmann
T
University Hospital for Children and Adolescents, University of Leipzig, Liebigstrasse 20a, D-04103 Leipzig, Germany.
Wüller
Stefan
S
Klammt
Jürgen
J
Kruis
Tassilo
T
Kratzsch
Jürgen
J
Schmidt
Gabriele
G
Schlicke
Marina
M
Müller
Eva
E
van de Leur
Hildegard Schmitz
HS
Kiess
Wieland
W
Pfäffle
Roland
R
D019943:Amino Acid Substitution; D001724:Birth Weight; D049628:Body Size; D003072:Cognition Disorders / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005091:Exons / Q000235:genetics; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics*; D018698:Glutamic Acid / Q000235:genetics; D006130:Growth Disorders / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007231:Infant, Newborn; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008607:Intellectual Disability / Q000235:genetics; D008831:Microcephaly / Q000235:genetics; D020125:Mutation, Missense; D016133:Polymerase Chain Reaction; D017526:Receptor, IGF Type 1 / Q000235:genetics* / Q000378:metabolism; D014633:Valine / Q000235:genetics
D018972:Insulin-Like Growth Factor Binding Protein 3; D018698:Glutamic Acid; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D014633:Valine