Clinical and functional characteristics of a novel heterozygous mutation of the IGF1R gene and IGF1R haploinsufficiency due to terminal 15q26.2->qter deletion in patients with intrauterine growth retardation and postnatal catch-up growth failure.
BACKGROUND
Mutations in the IGF1R gene result in intrauterine growth retardation and postnatal growth failure.


OBJECTIVE
The objective of this study was to describe the clinical features of subjects with a mutation in the IGF1R gene and to evaluate the molecular and functional characteristics of a novel IGF1R mutation.


METHODS
Three children with unexplained intrauterine growth retardation (birth weight <-1.5 SD score) and persistent short stature (<-2.0 SD score) were included in the study.


METHODS
Auxological and endocrinological profiles were measured. All coding regions, including the intron-exon boundaries of the IGF1R gene, were amplified via PCR and directly sequenced. To study the functional effect of the IGF1R gene mutation on IGF-I signaling, total IGF1R protein expression, and IGF-I-dependent Akt and ERK phosphorylation were assessed by Western blotting.


RESULTS
Two children and their father possessed a novel c.420del (p.A110fsX20) mutation in exon 2 of the IGF1R gene. After recombinant human GH therapy, the growth deficit decreased in these two children. Our data show that IGF-I-induced autophosphorylation of the phosphorylated tyrosine and phosphorylated Akt of IGF1R increased in a dose-dependent manner but did so less efficiently in patients. Array comparative genomic hybridization of chromosome 15 identified a heterozygous deletion of 15q26.2 to 15qter in subject 3.


CONCLUSIONS
The novel heterozygous mutation described in this study reduced IGF1R expression and represents haploinsufficiency of the IGF1R gene. Our results indicate that this mutation in the IGF1R gene leads to abnormalities in the function of IGF1R and also retards intrauterine and subsequent growth in humans.
Choi
Jin-Ho
JH
Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea.
Kang
Minji
M
Kim
Gu-Hwan
GH
Hong
Maria
M
Jin
Hye Young
HY
Lee
Beom-Hee
BH
Park
Jung-Young
JY
Lee
Se-Min
SM
Seo
Eul-Ju
EJ
Yoo
Han-Wook
HW
D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005317:Fetal Growth Retardation / Q000235:genetics* / Q000378:metabolism; D057895:Haploinsufficiency / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D009154:Mutation; D010375:Pedigree; D010766:Phosphorylation; D017526:Receptor, IGF Type 1 / Q000235:genetics* / Q000378:metabolism
D017526:Receptor, IGF Type 1