ENG mutations in MADH4/BMPR1A mutation negative patients with juvenile polyposis

Article (PDF Available)inClinical Genetics 71(1):91-2 · February 2007with16 Reads
DOI: 10.1111/j.1399-0004.2007.00734.x · Source: PubMed

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Available from: Sathivel Chinnathambi, May 13, 2016
Clin Genet 2007: 71: 91–92
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#2007 The Authors
Journal compilation #2007 Blackwell Munksgaard
doi: 10.1111/j.1399-0004.2007.00734.x
Letter to the Editor
ENG mutations in MADH4/BMPR1A
mutation negative patients with
juvenile polyposis
To the Editor:
Juvenile polyposis (JP, OMIM 174900) is an
autosomal dominant syndrome in which affected
individuals may develop colonic hamartomatous
polyps, upper gastrointestinal (GI) polyps, and
a pre-disposition to GI cancer (1–3). Two pre-
disposing genes for JP have been identified thus
far, with MADH4 and BMPR1A each account-
ing for approximately 20% of cases (4–6).
Some patients with JP also have hereditary
hemorrhagic telangiectasia (HHT) (7, 8). The
genes pre-disposing to HHT are ENG (HHT1,
OMIM 131195) (9) and ACVR1 (HHT2, OMIM
601284) (10, 11). Both genes are members of the
transforming growth factor beta (TGF-b) super-
family, like MADH4 and BMPR1A. Gallione
et al. found MADH4 germline mutations in seven
families with both JP and HHT but no mutations
of ENG or ACVR1 (12). We previously found no
ACVR1 mutations in 32 patients with JP without
HHT, MADH4 mutation, or BMPR1A mutation
(6). Sweet recently reported that 2 of 14 patients
with JP had germline ENG mutations and
suggested a role for this gene in the causation of
JP (13). The objective of this study was to examine
the prevalence of ENG mutations in patients
meeting the diagnostic criteria for JP who did not
have germline mutations of MADH4 or BMPR1A.
All exons and intron–exon boundaries of
MADH4 and BMPR1A were sequenced in
probands with JP and sporadic cases (6), and in
31 mutation-negative cases, all exons and intron–
exon boundaries of ENG were amplified and
sequenced. When sequence variants were found,
these exons were amplified from a panel of 132
randomly selected individuals and subjected to
restriction enzyme digestion, allowing detection
of the mutant or wild-type sequence.
The results of ENG sequencing are shown in
Table 1. One patient with multiple juvenile
polyps diagnosed at age of 8 was homozygous
for a 14C.T (T5M) substitution. Markers
D9S934 and D9S1825 were both heterozygous
(9 and 3 Mb centromeric to ENG, respectively)
and D9S2157 was homozygous in this patient
(5 Mb telomeric to ENG). A second patient
with multiple juvenile polyps diagnosed at the
age of 5 was heterozygous for the 14C.T (T5M)
mutation. Three of 132 controls digested with
SphI also manifested this change. A third patient
with multiple juvenile polyps diagnosed at age 9
had a 1096G.C mutation (D366H), which was
not found in control samples digested with HgaI.
The patients with JP with ENG mutations did
not have clinical manifestations, a family history
of HHT, or upper GI polyps and had a mean age
of 7.4 years (vs 14.4 years for those without ENG
The 14C.T(T5M) substitution has been
described in patients with HHT and is believed
to be a polymorphism rather than a disease-
causing mutation (14, 15), with an approximately
2% incidence in controls (16, 17). The
1096G.C(D366H) substitution has also been
described as a polymorphism in families with
HHT (18, 19), with an allele frequency of 0.3–1%
of controls (16, 17).
Sweet et al. found two ENG mutations in 14
patients with JP found to be negative for
MADH4,BMPR1A and PTEN mutations (13).
Both patients had an early onset of disease (at
ages 3 and 5 years) and no stigmata of HHT. One
patient with JP had the change 1538A.G
(K531R) and the other 1711C.T(R571C),
which were not found in 105 controls, and have
not been described in patients with HHT (15).
Sweet et al. concluded that these children had a
new, genetically defined form of JP. Gallione
et al. found that seven probands with both JP
and HHT had germline MADH4 mutations,
while none had ENG or ACVR1 mutations and
suggested that the overlap of JP and HHT
phenotypes could be because of the varied effects
of perturbing the TGF-bpathway in different
cell types (20). The findings of the current study
do not confirm the suggestion that ENG is
a pre-disposition gene for JP, and the absence of
disease-causing mutations in a larger subset of
patients with JP suggests that routine screening
for ENG mutations in genetic testing is pre-
mature. The finding of mutations in additional
patients with JP and the cosegregation of these
mutations with the disease phenotype in families
with JP would clearly help confirm the role of
ENG as a JP-causing gene.
This work was supported by a generous grant from the Carver
Charitable Trust and National Institutes of Health Grant
JR Howe
JL Haidle
G Lal
J Bair
C Song
B Pechman
S Chinnathambi
HT Lynch
Department of Surgery, University of Iowa Roy J.
and Lucille A. Carver College of Medicine,
Iowa City, IA,
Genetic Counselor, Hubert H. Humphrey
Cancer Center, Minneapolis, MN, and
Department of Preventive Medicine,
Creighton University School of Medicine,
Omaha, NE, USA
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the gene encoding bone morphogenetic protein receptor 1A
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tions. J Med Genet 2004: 41 (7): 484–491.
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activin receptor-like kinase 1 gene in hereditary haemor-
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giectasia – juvenile polyposis syndrome. Am J Hum Genet
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14. Shovlin CL, Hughes JM, Scott J et al. Characterization of
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disease. J Med Genet 2006: 43 (2): 97–110.
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James R. Howe
Department of Surgery
200 Hawkins Drive
University of Iowa Hospitals and Clinics
Iowa City
IA 52242-1086
Tel.: 1(319)356-1727
Fax: 1(319)356-1218
e-mail: james-howe@uiowa.edu
Table 1. Nucleotide changes in ENG coding sequence
found in patients with juvenile polyposis
Number of
patients Exon Nucleotide
Amino acid
change Normal
2/31 1 14C.T T5M 3/132
1/31 2 120C.T None (G40G) 1/134
4/31 2 207G.A None (L69L) 32/131
4/31 8 1029C.T None (T343T) Not done
1/31 8 1060C.T None (L354L) Not done
1/31 8 1096G.C D366H 0/132
No restriction endonuclease sites present.
Letter to the Editor
    • "The low frequency of ENG mutations found in JP patients raised concerns about whether ENG is a susceptibility gene for JP. Thus, a subsequent report aimed to examine the prevalence of ENG mutations in JP patients who did not have germline mutations in MADH4 and BMPRIA failed to confirm the role of ENG as a gene predisposing to JP[57]. "
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