Robert Śmigiel
1, Damian Bednarczyk
1, Łukasz Łaczmański
2, Anita Rauch
3,
Christiane Zweier
3, Dariusz Patkowski
4, Izabela Łaczmańska
1Study of a Hirschsprung’s Disease Patient Cohort Using
Multiplex Ligation-Dependent Probe Amplification
Badania wybranych genów u pacjentów z chorobą Hirschsprunga
z użyciem metody MLPA
1 Genetics Department, Wroclaw Medical University, Poland
2 Department of Endocrinology and Diabetology, Wroclaw Medical University, Poland
3 Institute of Human Genetics, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany 4 Pediatric Surgery Department, Wroclaw Medical University, Poland
Abstract
Background. Hirschsprung’s disease is a congenital disorder with an incidence of 1 per 5000 live births, character-ized by the absence of intestinal ganglion cells. The etiology of Hirschsprung’s disease is very heterogeneous (chro-mosomal, monogenic, oligo- and polygenic, as well as multifactorial). Various genes play a role in its etiology, i.e.
RET, EDNRB, EDN3, GDNF, SOX10, and ZEB2; new susceptible loci have also been identified.
Material and Methods. The characterized mutations in these genes are mostly small deletions and point mutations in both coding and non-coding regions. Also microdeletions of exons of the critical genes have been reported. The goal of this study was to screen 71 patients with Hirschsprung’s disease for micro-rearrangements in four genes (RET, ZEB2, EDN3, and GDNF) using the MLPA method.
Results and Conclusions. In one case, deletion of all ZEB2 exons was detected and Mowat-Wilson syndrome was diagnosed. In the rest of the patients, no genomic rearrangements were observed in any of the four genes (Adv Clin Exp Med 2010, 19, 1, 83–88).
Key words: Hirschsprung’s disease, MLPA, deletions, duplications, RET, ZEB2, EDN3,GDNF, Mowat-Wilson syndrome.
Streszczenie
Wprowadzenie. Choroba Hirschsprunga jest wrodzonym schorzeniem jelita występującym z częstością 1 na 5000 żywo urodzonych dzieci, charakteryzuje się brakiem komórek zwojowych w warstwie mięśniowej błony śluzowej oraz w błonie podśluzowej. Etiologia choroby Hirschsprunga jest bardzo heterogenna genetycznie (czynniki chro-mosomowe, monogenowe, oligo- i poligenowe, a także wieloczynnikowość). Zidentyfikowano wiele genów odgry-wających znaczącą rolę w etiologii choroby: RET, EDNRB, EDN3, GDNF, SOX10, ZEB2, są opisywane także nowe, istotne loci. Charakterystyczne mutacje w tych genach to najczęściej małe delecje oraz mutacje punktowe, zarówno regionach kodujących, jak i niekodujących. Opisuje się także mikrodelecje w regionach chromosomowych, gdzie są zlokalizowane geny krytyczne dla choroby Hirschsprunga.
Materiał i metody. Ocena molekularna 71 pacjentów z chorobą Hirschsprunga w kierunku mikrorearanżacji geno-mowych w czterech genach (RET, ZEB2, EDN3 i GDNF) z użyciem metody MLPA. W jednym przypadku wykaza-no delecję wszystkich egzonów genu ZEB2,rozpoznając jednocześnie u pacjenta zespół Mowat i Wilsona.
Wyniki i wnioski. W pozostałych przypadkach nie wykazano istotnych rearanżacji genomowych w czterech bada-nych genach (Adv Clin Exp Med 2010, 19, 1, 83–88).
Słowa kluczowe: choroba Hirschsprunga, MLPA, delecje, duplikacje, RET, ZEB2, EDN3,GDNF, zespół Mowat-Wilson.
Adv Clin Exp Med 2010, 19, 1, 83–88 ISSN 1230-025X
ORIGINAL PAPERS
© Copyright by Wroclaw Medical University
Hirschsprung’s disease (HSCR, OMIM 142623), or aganglionic megacolon, is a birth defect char-acterized by a complete absence of neuronal gan-glion cells in the myenteric and submucosal
R. Śmigiel et al.
84
short-segment form accounts for 80% of cases and is restricted to the rectosigmoid colon. The long-segment form extends proximal to the sig-moid colon and accounts for the remaining 20%. Aganglionosis rarely extends into the entire large intestine (total colonic aganglionosis) or even the entire bowel (total intestinal aganglionosis). The incidence of short-segment disease is four times greater in males than in females, while equal numbers of males and females present with long-segment HSCR [1]. Clinically, HSCR is character-ized by failure to pass stool, a distended abdomen, vomiting, and enterocolitis. Chronic constipation is a major feature of HSCR in childhood [2].
Various genes, such as RET, EDNRB, GDNF,
EDN3 and SOX10, NTN3, ECE1, and ZEB2 are
involved in the etiology of Hirschsprung’s disease. Mutations in these genes may result in dominant, recessive, or multifactorial patterns of inheritance. The complex nature of HSCR could suggest an oligogenic etiology [3–7]. The diverse models of inheritance, the coexistence of numerous genetic disorders, and the detection of numerous chromo-somal aberrations together with the involvement of various genes confirm the genetic heterogeneity of Hirschsprung’s disease [4–8].
Most defects characterized in the genes in - volved in HSCR are small (point) mutations. The aim of this study was to identify genomic
micro-rearrangements in RET, ZEB2, EDN3, and GDNF
involved in Hirschsprung’s disease. To perform this study, multiplex ligation-dependent probe amplification (MLPA), a method designed to detect small deletions and duplications of one or more exons in the genes of interest, was used.
Material and Methods
The study was carried out on a group of 71 patients with Hirschsprung’s disease. The outline of the study was accepted by the University Ethics Committee. The Hirschsprung’s disease patients were classified according to the length of the agangli-onic colon into two groups: long segment (L-HSCR) and short segment (S-HSCR, rectosigmoid). The his-topathological criteria used for inclusion in the study were histological evaluation of the aganglionic tract (absence of neuronal ganglia) and histochemical staining of nerve fibers (ACTC, S-100, and NSE) in suction biopsies of the rectal submucosa [9].
Multiplex Ligation-Dependent
Probe Amplification (MLPA)
DNA was isolated from peripheral blood lymphocytes using the standard proteinase K/
phenol method [10]. MLPA was performed according to the attached manufacturer’s proto-col using a SALSA P169 Hirschsprung MLPA kit (lot 0706; MRC-Holland). Genomic DNA (100 ng)
was denaturated in 5 µl of Tris EDTA (TE) at 98oC
for 5 min and then hybridized with the SALSA
probemix for 16–18 h at 60oC. After sample
hybridization, ligation in Ligase-65 mix (15 min
in 54oC) was performed. Then the samples were
heated for 5 min at 98oC. The last step was
ampli-fication of the obtained ligation products using polymerase chain reaction (PCR) with the SALSA-PCR set of primers (one FAM labeled). SALSA-PCR was
carried out for 35 cycles (30 s at 95oC, 30 s at 60oC,
60 s at 72oC, and a final extension of 20 min at
72oC) in a TC-512 thermocycler (Techne) in 50 µl
of reaction mix.
The fragments were separated on an ABI 310 capillary sequencer with Genescan software version 3.1.2 (Applied Biosystems) using the LIZ 500 size
standard.Data were analyzed using GeneMarker
software version 1.85 (SoftGenetics LLC). Probe ratios between 0.7–1.3 were defined as normal. For statistical analysis, a population normalization test was used, but samples with a wide random spread of signals were excluded.
Results
A short segment of aganglionic gut was found in 61 patients (85.59%) and a long segment in 10 patients (14.1%). Additional major congenital defects were observed in 32% of the patients, such as chromosomal aberrations, single gene muta-tion, urinary tract defects, cardiac defect, alimen-tary defect, deafness, ophthalmologic problems, and intellectual disability.
Seventy-one patients with Hirschsprung dis ease were tested using MLPA.
Micro-rearrangements in four genes (RET, ZEB2, EDN3,
and GDNF) were screened (Fig. 1). Only in one
case, a patient with multiple congenital defects and psychomotor retardation, were deletions of
all exons of the ZEB2 gene found. Mowat-Wilson
syndrome was diagnosed in this patient. In the other 70 cases with long- and short-segment agan-glionosis, no deletions or amplifications were identified in these four genes.
Discussion
inher-itance pattern remain unclear and should be eluci-dated. Several authors noted that although at least eight genes with mutations that could be associated with Hirschsprung’s disease have been identified, mutations at individual loci are neither necessary nor sufficient to cause clinical disease. These eight genes involved in the etiology of Hirschsprung’s
disease are RET, GDNF, EDNRB, EDN3, NTN,
ECE1, SOX10, and ZEB2 (SIP-1) [5–7, 11]. HSCR occurs as an isolated trait in 70% of Hirschsprung patients, while it is associated with a chromosomal anomaly in 12% of cases and occurs with additional congenital anomalies in 18% of cases. While all Mendelian modes of inher-itance have been described for syndromic HSCR, isolated HSCR is a model for oligogenic disorders with low sex-dependent penetrance [6, 12].
The gene most involved in HSCR’s
etiol-ogy is RET, in which mutations are identified in
about 15–20% of patients with sporadic HSCR and 50% of patients with familial HSCR cases
[13–17]. RET, a member of the cadherin
super-family, encodes one of the receptor tyrosine kinases, which are cell-surface molecules that transduce signals for cell growth and differentia-tion and which play a crucial role in neural crest development, i.e. the migration and differentia-tion of specific cells into enteric neurons [13, 14]. Numerous loss-of-function germline mutations
have been found in this gene [13, 18]. Further
studies showed that a common non-coding RET
variant within a conserved enhancer-like sequence in intron 1 is significantly associated with HSCR [12]. Recent advances have shown a new aspect in the etiology of Hirschsprung’s disease. Variants of
several RET polymorphisms are over- or
under-represented in the HSCR population and appear to modify the HSCR phenotype [19–21]. The sever-ity of the clinical manifestation of HSCR correlates with the frequency of the 135A allele and seems to be inversely associated with the frequencies of the 2071A and 2712G alleles [20, 21]. Moreover,
studies of families with HSCR suggest that RET
penetrance is dependent on allele dosage and other modifier loci [5, 22, 23]. Gabriel et al. found new susceptibility loci at 3p21 and 19p12 engaged in Hirschsprung’s disease etiology together with
10q11, where the RET gene is located [23]. Bolk et
al. suggested that Hirschsprung’s disease requires
both RET and a newly identified locus at 9q31
[22]. Emison et al. concluded that RET mutations,
coding and/or non-coding, are probably a neces-sary feature in all cases of HSCR [12]. However,
RET mutations are not sufficient for HSCR and
are dependent on other genetic modifiers (the oli-gogenic model of inheritance) [5–7].
Further mutations in several genes, such as EDNRB, GDNF, NTN, ECE1, and SOX10 (either
Fig. 1. MLPA profiles of RET, EDN3, GDNF and ZEB2 genes (P169) for Hirschsprung disease patient and for control individual
R. Śmigiel et al.
86
isolated or combined with RET mutation), have
been identified in up to 5% of HSCR cases, sup-porting the genetic heterogeneity of this disorder, which may result from a cumulative effect of at least two mutations in different genes [5–7, 17, 22–24].
The EDNRB gene is located on the 13q22 chro-mosomal region and encodes endothelin recep-tors belong to the G protein-coupled receptor
family. EDNRB gene mutations were found also
in Waardendurg syndrome type IV, also called Shah-Waardenburg syndrome, characterized by a sensorineural hearing deficiency and pigmen-tation defects linked with HSCR. Several authors
observed mutations in both RET and ENDRB in
the same HSCR patients [25, 26]. Mutations in EDNRB were also reported to be linked to
muta-tions in EDN3 and SOX10.
EDN3 protein (ligand endothelin 3) is a recep-tor for EDNRB and was shown to be involved in the development of the neural crest. Hirschsprung’s disease is an example of a neurocristopathic disor-der causing disturbances in innervation of the
gas-trointestinal tract. EDN3 gene is located on
chro-mosome 20q13. EDN3 could be mutated in a small
number of patients with HSCR and could be
linked to mutations in EDNRB [27]. Mutations in
the EDN3 gene can result in Shah-Waardenburg
syndrome and congenital central hypoventilation syndrome (CCHS), assigned to neurocristopathies as well [6, 28].
The GDNF gene is located on 5p12-p13 and
encodes glial cell-derived neurotropic factor
(GDNF). Mutations in GDNF were found solely
in sporadic HSCR patients and were also found in
connection with RET mutations [29].
ZEB2 (ZFHX1B, zinc finger homeobox 1b
gene) has been recently described in a patient with
Mowat-Wilson syndrome with multiple congenital
anomalies and mental retardation [30–33]. ZEB2 is
located on chromosome 2q22 and encodes a pro-tein product, Smad interacting propro-tein 1 (SIP1). Expression of SIP1 protein is detected in nearly all human tissues, such as the heart, brain, pla-centa, lung, liver, and skeletal muscle [34]. SIP1 expression is also detected in human fetal tissues, including brain, kidney, liver, and spleen. It is speculated that SIP1 has a crucial role in embry-onic development, also in the development of the enteric nervous system [31, 34]. Several autosomal dominant mutations and different sized heterozy-gous deletions have been described in patients with Mowat-Wilson syndrome leading to allelic loss and resulting loss of function (protein short-ening or inactivation) [35–37]. It is supposed that
cases with deletions of the ZEB2 gene are similar to
those with point mutations with non-allelic
modi-fiers, explaining the clinical variability [36, 37]. Larger deletions have been shown to be associated with a more severe course [37, 38].
To detect deletions and duplications of the exons of the four genes critical to Hirschsprung’s disease, MLPA was used containing 41 probes with
amplification products for all 20 exons of RET gene
[10q11.21], all 5 exons of EDN3 gene [20q13.32],
all 4 exons of GDNF gene [5p13.2], and all 10 exons
of ZEB2 (ZFHX1B) gene [2q22.3]. The analysis of the 70 patients with short- and long-segment as well as sporadic and syndromic Hirschsprung’s disease showed no significant genomic rearrange-ments in the tested genes. These data confirm pre-vious results obtained by a German group [39].
Only in one case was deletion of all ZEB2
exons detected and Mowat-Wilson syndrome was diagnosed [30, 35–37]. Mowat-Wilson syn-drome is characterized by distinctive facial fea-tures, short stature, structural anomalies including Hirschsprung’s disease, genitourinary anomalies, congenital heart defects, agenesis or hypogenesis of the corpus callosum, and eye defects as well as moderate to severe intellectual disability and severe speech impairment. The patient with MWS diagnosed in the MLPA analysis showed Fallot tetralogy, Hirschsprung’s disease, hepatic cell
lesion, α-1 antitrypsin deficiency (ATD), and liver
cirrhosis in the course of ATD as well as delayed psychomotor development, hypotonia, and a vari-ety of dysmorphic features [38].
A chromosomal abnormality is present in approximately 12% of individuals with HSCR [1, 6]. The most common chromosomal abnormality asso-ciated with HSCR is Down’s syndrome (trisomy 21), which occurs in 2–10% of all individuals with HSCR [6–8, 40]. In the present cohort of patients with HSCR, Down’s syndrome was diagnosed in 4 cases (5% of all patients). Although individuals with Down’s syndrome are at a 100-fold higher risk of HSCR than the general population [40], none of the established “HSCR genes” reside on chromo-some 21; thus the association between trisomy 21 and HSCR remains unexplained. Other chromo-somal aberrations include deletions that encom-pass HSCR-associated genes. These are deletion of
the 13q22 region (EDNRB gene), deletion of the
10q11.2 region (RET), and deletion of the 2q22
region (ZEB2) [5–7, 13, 14, 30]. The identification of
individuals with HSCR and such deletions aided in the discovery of these genes and reinforces the hap-lo-insufficiency model of HSCR pathogenesis. Other chromosomal anomalies have been described in individuals with HSCR, but the relevant gene(s) of interest have not been identified.
genes contributing as separate entities or in
com-bination. It has been demonstrated that the RET,
EDN3, GDNF, and ZEB2 genes are involved in
HSCR’s etiology, but changes in these genes are often
insufficient for HSCR and are dependent on different modifiers. Further genetic studies of known and new genes are needed to elucidate the complex nature of Hirschsprung’s disease as an oligogenic disorder.
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Address for correspondence:
Robert Śmigiel Genetics Department Wroclaw Medical University Marcinkowskiego 1
50-368 Wrocław Poland
Tel.: +48 71 784 13 26
E-mail: [email protected]
Conflict of interest: None declared
