J C E M
O N L I N E
B r i e f
R e p o r t — E n d o c r i n e
R e s e a r c h
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
Jin-Ho Choi,* Minji Kang,* Gu-Hwan Kim, Maria Hong, Hye Young Jin,
Beom-Hee Lee, Jung-Young Park, Se-Min Lee, Eul-Ju Seo, and Han-Wook Yoo
Department of Pediatrics (J.-H.C., H.Y.J., H.-W.Y.), Genome Research Center for Birth Defects and
Genetic Diseases (M.K., M.H., J.-Y.P.), and Medical Genetics Clinic and Laboratory (G.-H.K., B.-H.L.,
E.-J.S.), Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul 138736, Korea; and Department of Pediatrics (S.-M.L.), Hanyang University Guri Hospital, Guri, Gyeonggi-do
471-701, Korea
Context: 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.
Subjects: 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. (J Clin Endocrinol Metab 96: E130 –E134, 2011)
ntrauterine growth retardation (IUGR) is often used as a
synonym for small for gestational age, which is defined as
a fetus weighing less than 2 SD below the mean for its gestational age (1). However, IUGR more properly refers to a
I
pathological process that inhibits fetal growth in utero (2).
Although approximately 10% of children born with IUGR
are at risk of short stature as adults (3), the causes of postnatal
growth retardation are not fully understood.
ISSN Print 0021-972X ISSN Online 1945-7197
Printed in U.S.A.
Copyright © 2011 by The Endocrine Society
doi: 10.1210/jc.2010-1789 Received August 2, 2010. Accepted September 24, 2010.
First Published Online October 20, 2010
* J.-H.C. and M.K. contributed equally to this work.
Abbreviations: IGFBP-3, IGF binding protein-3; IGF1R, IGF-I receptor; IUGR, intrauterine
growth retardation; IRS, insulin receptor substrate; rhGH, recombinant human GH; SDS,
SD scores.
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J Clin Endocrinol Metab, January 2011, 96(1):E130 –E134
J Clin Endocrinol Metab, January 2011, 96(1):E130 –E134
Defects in the IGF-I (IGF1) and IGF-I receptor (IGF1R)
genes have been identified in a few patients with IUGR and
postnatal growth failure. Severe deficiency in IGF-I due to
a homozygous deletion or mutation in the IGF1 gene results in intrauterine and postnatal growth failure, microcephaly, mental retardation, and deafness (4 – 6). Heterozygous mutations in the IGF1R gene lead to partial
resistance to IGF-I, and decreased expression of IGF1R
contributes to IUGR with postnatal growth failure, modestly impaired mental development without hearing impairment, and microcephaly associated with normal or
increased levels of serum IGF-I and IGF binding protein
(IGFBP)-3 (7). This clinical picture is similar to that described with partial IGF-I deficiency due to a missense
mutation of the IGF1 gene resulting in IUGR, postnatal
growth failure, microcephaly, mild intellectual impairment, and normal hearing (8). Homozygous IGF1R mutations or deletions in humans have not been described,
probably because of the lethal effects of a total loss of
IGF1R, which would be consistent with the phenotype of
the mouse knockout model (9).
Here we report the identification of a novel heterozygous mutation of IGF1R and IGF1R haploinsufficiency
due to a terminal 15q26.2-⬎qter deletion. Fibroblasts
with a heterozygous mutation and haploinsufficiency of
the IGF1R gene were used to define functional aspects of
reduced IGF1R expression.
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proved by the Institutional Review Board of Asan Medical Center, and written informed consent was obtained from all subjects
or their parents. Height and weight were expressed as SD scores
(SDS) based on normative data from Korean references (10).
Subject 1
A 6.8-yr-old Korean girl who was brought to medical attention due to her proportional short stature, served as a proband.
She was born at 41 wk of gestation with a birth weight of 2450 g
(⫺2.10 SDS). Her height was 102.8 cm (⫺3.56 SDS), and she
weighed 17.7 kg (⫺1.87 SDS). She displayed no dysmorphic
features, and psychomotor development was normal. Her father
was short [150.6 cm (⫺4.19 SDS)] as an adult but not dysmorphic, and her mother was 156 cm tall (⫺0.96 SDS) (Fig. 1A). The
subject’s midparental target height of 146.8 cm (⫺2.94 SDS) was
calculated from the heights of her parents. Her pubertal staging was
Tanner B1P1, and her bone age was 5 yr 9 months, as determined
by the Greulich-Pyle method (11). The subject had a normal female
karyotype (46,XX). Serum free T4 and TSH levels were normal. Her
basal IGF-I level was 196 ng/ml (⫺0.61 SDS), which rose to 337
ng/ml (1.46 SDS) during an IGF-I generation test. Her basal
IGFBP-3 level was 2625 ng/ml (⫺2.52 SDS). The subject was
treated with six injections of recombinant human GH (rhGH) per
week at a dose of 0.44 mg/kg 䡠 wk. Her height SDS increased from
⫺3.56 at baseline to ⫺2.38 after 1 yr of therapy (Fig. 1B).
Subject 2
Subjects and Methods
The proband’s elder brother was also born with IUGR, with a
birth weight of 2550 g (⫺1.96 SDS) at 40 wk of gestation. The
subject was 114.2 cm (⫺3.47 SDS) tall and weighed 21 kg (⫺2.38
SDS) at 9.5 yr. His bone age was 6 yr at a chronological age of 9.8
yr. The subject’s serum levels of IGF-I and IGFBP-3 were 144 ng/ml
(⫺0.85 SDS) and 2394 ng/ml (⫺3.20 SDS), respectively. Significant
increases in IGF-I levels were observed from 144 ng/ml (⫺0.85 SDS)
to 338 ng/ml (0.75 SDS) during an IGF-I generation test.
Subjects
Subject 3
Three children with unexplained IUGR and persistent short
stature were included in the study. The study protocol was ap-
Subject 3 was brought to our outpatient clinic for evaluation
of multiple anomalies at 2.3 yr of life. The subject was born at 34
FIG. 1. Pedigree of a family with IGF-I resistance (A) and growth charts of the proband and elder brother (B). A, The proband (arrow), family
members carrying the heterozygous IGF1R mutation, and the height SDS corresponding to the age of each family member are indicated. Short
stature was noted on the paternal side of the family (two aunts and grandmother designated with an asterisk); however, mutation analysis was
not performed. Two of the five fetuses died in utero. The heights of family members with short stature are noted. B, Subjects 1 and 2 were treated
with rhGH therapy (0.44 and 0.38 mg/kg 䡠 wk, respectively). Height SDS was increased from ⫺3.56 to ⫺2.38 in the proband after 11 months of
rhGH therapy and from ⫺3.42 to ⫺2.78 in the brother after 1 yr of GH therapy. The arrow indicates the inception of GH treatment.
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Choi et al.
Growth Failure due to IGF1R Mutation
wk of gestation, weighing 1578 g. He underwent coarctoplasty
due to coarctation of the aorta with an atrial septal defect and
orchiopexy for a right cryptorchidism. The subject had a proportional short stature [height: 74.9 cm (⫺3.87 SDS), weight: 7.6
kg (⫺5.21 SDS)] and dysmorphic features including microcephaly, bilateral ptosis, strabismus, long palpebral fissure, and clinodactyly. Renal ultrasonography demonstrated multicystic
dysplastic kidney disease on the left side. A normal male karyotype (46,XY) was identified. At age 4.1 yr, the subject presented
with a height of 85.5 cm (⫺4.51 SDS), a weight of 9.7 kg (⫺5.73
J Clin Endocrinol Metab, January 2011, 96(1):E130 –E134
SDS), and a head circumference of 44.7 cm (⫺4.24 SDS). His
serum levels of IGF-I and IGFBP-3 were 192 ng/ml (⫺1.21 SDS)
and 2604 ng/ml (⫺1.90 SDS), respectively.
Mutation analysis of the IGF1R gene
Mutation analysis of the IGF1R genes was undertaken in two
children (subjects 1 and 2) presenting with IUGR and postnatal
growth failure as well as in their father. Genomic DNA was
extracted from peripheral blood leukocytes and amplified by
PCR using 25 primer pairs that flank the coding
regions of the 21 exons of the IGF1R gene. Each
PCR product was directly sequenced using an
ABI3130x1 genetic analyzer (Applied Biosystems,
Foster City, CA).
Functional analysis of the IGF1R
␤-subunit
FIG. 2. IGF-I-stimulated Tyr phosphorylation (P) of IGF1R␤, and downstream
signaling protein Akt activation in response to IGF-I in skin fibroblasts from patients
and the control. IGF-I signaling after stimulation with increasing concentrations of
IGF-I is shown. IGF-I-induced autophosphorylation of Tyr of IGF1R and
phosphorylation of Akt increased in a dose-dependent manner but less efficiently in
patients. Results are expressed as mean ⫾ SD. *, P ⬍ 0.05 vs. normal control. A twotailed, paired Student’s t test was used to determine the statistical significance of
reduced IGF1R expression in patients’ fibroblast cell lines in comparison with control
cell lines. S1, Subject 1; S2, subject 2; S3, subject 3; C, control). A, Western blotting
of fibroblasts from patients and the control after stimulation with varying
concentration of IGF-I for 15 min. B, Densitometric quantification of phosphorylated
fibroblasts from patients and the control after stimulation. IGF-I treatment increased
Tyr phosphorylation of a 97-kDa protein, representing the processed IGF1R ␤subunit in both patients and the control in a dose-dependent manner. However, IGFI-stimulated autophosphorylation of the IGF1R ␤-subunit was significantly reduced in
fibroblasts from patients in comparison with the control, by 20 and 400 ng/ml IGF-I
(P ⬍ 0.05). C, Densitometric quantification of IGF-I-induced activation of PKB/Akt by
IGF1R autophosphorylation in fibroblasts from patients and the control. Data are
expressed as the ratio of phosphor-specific PKB/Akt and total PKB/Akt. Akt
phosphorylation was significantly abrogated in patient cells at concentrations of 20
and 400 ng/ml IGF-I, compared with control fibroblasts (P ⬍ 0.05).
Real-time PCR was performed to assess the
mRNA content of IGF1R in the patients and control subjects. Total RNA was extracted from skin
fibroblasts using the RNeasy minikit according to
the manufacturer’s instructions (QIAGEN Inc.,
Valencia, CA).
Total protein expression and IGF-I-induced phosphorylation of IGF1R, protein kinase B (PKB)/Akt,
and ERK1/2 were measured by immunoblotting. Total protein extracts (70 –90 ␮g) were resolved by SDSPAGE [7.5–10% (vol/vol) bisacrylamide-acrylamide
37.5:1] and transferred to nitrocellulose membranes,
which were then immunoblotted with specific antibodies. Primary antibodies included phospho-tyrosine1131-IGF1R␤ (1:300), Akt (1:1000), and phosphor-Ser473-Akt (1:500) antibodies (Cell Signaling
Technology, Beverly, MA). Goat antirabbit IgG secondary polyclonal antibody (Abcam, Cambridge,
MA) was used at a dilution of 1:300.
IGF-I-induced autophosphorylation of the IGF1R
␤-subunit and the downstream signaling proteins, Akt
and ERK1/2, were measured by Western blotting using specific antibodies. After overnight culturing in
100-mm dishes containing serum-free media, fibroblasts from patients and the control were stimulated
with 0, 1, 20, and 400 ng/ml of recombinant human
IGF-I (Invitrogen Co., Carlsbad, CA) for 15 min at 37
C, as described previously (12). Blots were probed
with an antiphospho-IGF1R ␤-subunit, total IGF1R␤,
antiphospho-PKB/Akt, total PKB/Akt, and antiphospho-ERK1/2 antibodies (Cell Signaling Technology)
(13). The resultant receptor kinase activity was visualized by Western blotting.
Results
Mutation analysis of the IGF1R gene
Mutations in the IGF1R gene were found
in three family members. The IGF1R gene
analysis in subject 1 identified a heterozygous mutation of c.420del (p.Ala110fsX20)
in exon 2, resulting in a frameshift mutation
J Clin Endocrinol Metab, January 2011, 96(1):E130 –E134
with premature termination of the IGF1R protein. Her
father and elder brother, who were also diagnosed with
IUGR and persistent short stature, were also heterozygous
for the same mutation. However, the subject’s mother did
not have this mutation. No other relatives were tested for
the mutation. Array comparative genomic hybridization
analysis of chromosome 15 of subject 3 showed a heterozygous deletion of 15q26.2 to 15qter, comprising the
entire IGF1R gene. This was a segmental monosomy of the
15(q26.23qter) region, which was narrowed down to a
8.58-Mb deletion (data not shown).
Functional analysis of the IGF1R ␤-subunit
Expression of total IGF1R␤ protein was lower in patients than in the control (Fig. 2A). Furthermore, real-time
PCR analysis revealed that IGF1R mRNA was less abundant in fibroblasts from subjects 1 and 2 than in the normal
control (data not shown).
Western blots from cultured skin fibroblasts showed
lower autophosphorylation of IGF1R in patients compared
with the control. The phosphorylation of the processed
IGF1R ␤-subunit, indicated by the intensity of a 97-kDa
band, was enhanced in a dose-dependent manner (Fig. 2B).
However, the autophosphorylation of the IGF1R ␤-subunit
that was stimulated by the addition of 20 and 400 ng/ml
IGF-I in the control was significantly reduced in patients (P ⬍
0.05) (Fig. 2B). Stimulation of the fibroblasts with a range of
IGF-I doses demonstrated reduced of PKB/Akt in patients
compared with the control. The levels of phosphorylated
Akt/Akt were significantly lower in patients after a challenge
with 20 and 400 ng/ml of IGF-I (P ⬍ 0.05) (Fig. 2C). Stimulation with various concentrations of IGF-I showed that
autophosphorylation of IGF1R and activation of the downstream targets ERK1/2 were similar in cells from patients and
the control (data not shown).
Discussion
In this study, we described three subjects who are resistant
to IGF-I and harbor a novel heterozygous IGF1R mutation and another subject with IGF1R haploinsufficiency
due to deletion of the chromosome 15q26.2-⬎qter region.
Nine different human IGF1R mutations associated
with IUGR and postnatal growth failure have been described, each highlighting a distinct aspect of IGF1R function (http://www.hgmd.org/). Patients with IGF1R mutations all manifest IUGR and variable degrees of postnatal
growth retardation. The variability in specific clinical features in individuals with different IGF1R mutations may
be related to specific functions of mutated IGF1R regions
or to variations in genetic background (12).
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In vitro functional analyses showed reduced total
IGF1R protein expression and reduced intracellular PKB/
Akt activation compared with healthy control. The functional studies of each of the heterozygous IGF1R mutations reported so far, including those in this study, indicate
that the patient’s cells needed higher IGF-I concentrations
to achieve levels of Tyr-phosphorylated IGF1R equivalent
to those of the control. This observation indicates that
rhGH and/or IGF-I treatments may thus confer a potential
benefit to these patients (14). The dosage of rhGH used in
patients with IGF1R mutations or haploinsufficiency
ranged from 0.217 to 0.7 mg/kg 䡠 wk (7, 12–16), which is
higher than the recommended dosage for treatment of GH
deficiency (0.175– 0.35 mg/kg 䡠 wk) (17).
Patients with a terminal deletion in 15q26.2 usually manifest IUGR; short stature; developmental delay; facial dysmorphism; and multiple anomalies such as lung hypoplasia,
cardiac anomaly, proximal placed thumb, and clubfeet (13,
18). Clinical findings in subject 3 were similar to previously
reported cases harboring terminal deletions of 15q26.2 (13,
18, 19). This finding allowed us to expand the clinical phenotype of terminal 15q26.2 deletions and to indicate candidate genes for several phenotypic features.
In conclusion, both a novel heterozygous mutation in
the ␣-subunit of the IGF1R and a segmental deletion encompassing the entire IGF1R result in IGF-I resistance,
leading to IUGR and postnatal growth failure. In vitro
studies of fibroblasts from subjects carrying the c.420del
(p.Ala110fsX20) and a terminal 15q26.2-⬎qter deletion
clearly demonstrated reduced IGF1R expression and subsequent IGF-I resistance, as assessed by IGF1R phosphorylation and postreceptor signal transduction. Our findings
indicate that IGF1R mutations should be considered in the
differential diagnosis of familial IUGR patients with persistent short stature.
Acknowledgments
Address all correspondence and requests for reprints to: Han-Wook
Yoo, M.D., Ph.D., Division of Pediatric Endocrinology and Metabolism, Department of Pediatrics, Asan Medical Center Children’s
Hospital, 388-1, Pungnap-Dong, Songpa-Gu, Seoul 138-736,
Korea. E-mail: [email protected].
This work was supported by a grant from the Ministry for Health,
Welfare, and Family Affairs, Republic of Korea (A080588-2).
Disclosure Summary: The authors have nothing to disclose.
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