Clinical features of a form of Hirschsprung's disease caused by a novel genetic abnormality

doi:10.1053/jpsu.2002.34455

Journal of Pediatric Surgery

Volume 37, Issue 8, August 2002, Pages 1117-1122

https://doi.org/10.1053/jpsu.2002.34455 Get rights and content

Abstract

Background/Purpose: The aim of this report is to describe the pattern of similarities among the patients, exemplifying a newly recognized form of Hirschsprung's disease (HSCR) caused by mutations of ZFHX1B encoding Smad interacting protein-1. Methods: Fluorescence in situ hybridization (FISH) using several cDNAs and RP11-BAC clones and mutation gene scanning using direct nucleotide sequencing analysis of polymerase chain reaction (PCR) were conducted. Personal records of the patients also were analyzed retrospectively to confirm the clinical features. Results: All the patients represented isolated cases without any familial tendency. Aganglionic segments were limited to the recto-sigmoid colon in 3 cases and the rectum in one. Chromosomal screening found normal karyotypes in all cases except one, in whom a translocation between chromosomes 2 and 13 was detected. In addition to HSCR, characteristic facial appearance (hypertelorism with strabismus and wide nasal bridge), microcephaly with epilepsy, and severe physical and mental disabilities were found in all the patients. FISH for the patient having the chromosomal abnormality showed that about a 5-Mb cytogenetic deletion flanked at the 2q22 translocation breakpoint. Among 3 genes mapping to this deleted region, 2 nonsense mutations and a 4-base pair deletion were detected in ZFHX1B. Conclusions: The clinical features of the patients have surprising resemblance and constitute a wide spectrum of neurocristopathies. These findings suggest that the ZFHX1B may be a very important gene for normal embryonic neural crest development. These also indicate that the HSCR can be regarded as a congenital malformation with a background of a multigenetic neurocristopathy. It is of great interest that mutations were located at the same spot (exon 8) of ZFHX1B in 3 of 4 cases, probably accounting for the unique clinical features of this newly recognized form of HSCR. J Pediatr Surg 37:1117-1122. Copyright 2002, Elsevier Science (USA). All rights reserved.

Section snippets

Materials and methods

Over the last 31 years, 200 cases of HSCR have been managed in our hospital. One of the authors (M.N.) has been concerned with surgical intervention and follow-up of all of the patients. Four cases (2.0%) were found to develop along a different course from that ordinarily seen with the patient with HSCR. In addition, the patients resembled each other closely in facial appearance and clinical features. The available findings suggested an identical genetic abnormality as the etiology, and a de

Genetic analyses

Fluorescence in situ hybridization (FISH) was first carried out on the 2q22 area for the last patient shown to have the chromosomal abnormality. The results showed about a 5-Mb cytogenetic deletion flanked by D2S129 and D2S151 at the 2q22 translocation breakpoint.¹¹ Among 3 genes mapping to this deleted region (KYNU, PRO 0159, and ZFHX1B), ZFHX1B was selected as a focus for attention as a causative gene of HSCR, because of the previous report that overexpression of ZFHX1B in animal caps

Discussion

The neural crest, originating from cells located in the angle between the superficial ectoderm and the neural tube, migrates ventrolaterally on either side of the spinal cord and gives rise to the dorsal root ganglia of the spinal nerves and the ganglia of the cranial nerves. Neural crest cells also give rise to sympathetic ganglia, chromaffin cells, and melanoblasts in the dermis of the skin. Therefore, developmental errors of the neural crest may well be expressed in various spots of the

Acknowledgements

Genetic analyses were approved by the Human Studies Committee in Aichi Prefectural Colony (Human Service Center). Permission was obtained from the parents of patients for full facial images to be published.

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The enteric nervous system (ENS) is a complex neural network that controls many essential functions in the gastrointestinal tract, including the regulation of intestinal peristalsis. Neural crest cells migrate, proliferate, and differentiate within the intestinal wall to give rise to the neurons and glial cells of the ENS. Failure of this process to occur normally during embryogenesis can lead to severe disorders of intestinal motility, the most common of which is Hirschsprung’s disease. Several proteins have been identified as being essential for normal ENS development, including members of the Ret and endothelin-3 signaling pathways. The analysis of transgenic mice harboring mutations in these critical genes has greatly enhanced our understanding of the molecular regulation of ENS development and of the etiology of intestinal aganglionosis. Building on this fundamental research, much has been learned recently about the genetics underlying the complex inheritance pattern of Hirschsprung’s disease. Continued progress in elucidating the molecular basis of normal and abnormal ENS development will greatly enhance our understanding of congenital enteric neuropathies and improve our ability to diagnose and treat children affected by these disabling conditions.
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Patients with zinc finger homeo box 1B (ZFHX1B) mutations or deletions develop multiple congenital anomalies including Hirschsprung disease, known as Mowat-Wilson syndrome (MWS). In this study, we investigated variations in the enteric neural plexus abnormalities in MWS using morphometry-based histopathologic analysis.
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The variations in myenteric plexus pathologies in MWS appear to be caused by both variations in ZFHX1B abnormalities and epigenetic factors.
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The enteric nervous system (ENS) is derived from neural crest cells that migrate along the gastrointestinal tract to form a network of neurons and glia that are essential for regulating intestinal motility. Despite the number of genes known to play essential roles in ENS development, the molecular etiology of congenital disorders affecting this process remains largely unknown. To determine the role of bone morphogenetic protein (BMP) signaling in ENS development, we first examined the expression of bmp2, bmp4, and bmprII during hindgut development and find these strongly expressed in the ENS. Moreover, functional BMP signaling, demonstrated by the expression of phosphorylated Smad1/5/8, is present in the enteric ganglia. Inhibition of BMP activity by noggin misexpression within the developing gut, both in ovo and in vitro, inhibits normal migration of enteric neural crest cells. BMP inhibition also leads to hypoganglionosis and failure of enteric ganglion formation, with crest cells unable to cluster into aggregates. Abnormalities of migration and ganglion formation are the hallmarks of two human intestinal disorders, Hirschsprung's disease and intestinal neuronal dysplasia. Our results support an essential role for BMP signaling in these aspects of ENS development and provide a basis for further investigation of these proteins in the etiology of neuro-intestinal disorders.
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Citation Excerpt :
In addition, SIP1 was identified in two independent large scale screens to identify genes relevant to cancer (31, 32). Moreover, many mutations in SIP1, the majority of which lead to truncation of the protein, have recently been reported to cause congenital defects sometimes associated with Hirschsprung's disease (33–38). Therefore, in addition to the study of the function of SIP1 in vivo in multiple biological and pathological processes, the elucidation of the mechanism of action of SIP1, preferably at the level of important target genes such as E-cadherin, remains crucial.
δEF1 and SIP1 (or Zfhx1a and Zfhx1b, respectively) are the only known members of the vertebrate Zfh1 family of homeodomain/zinc finger-containing proteins. Similar to other transcription factors, both Smad-interacting protein-1 (SIP1) and δEF1 are capable of repressing E-cadherin transcription through binding to the E2 boxes located in its promoter. In the case of δEF1, this repression has been proposed to occur via interaction with the corepressor C-terminal binding protein (CtBP). In this study, we show by coimmunoprecipitation that SIP1 and CtBP interact in vivo and that an isolated CtBP-binding SIP1 fragment depends on CtBP for transcriptional repression. However, and most importantly, full-length SIP1 and δEF1 proteins do not depend on their interaction with CtBP to repress transcription from the E-cadherin promoter. Furthermore, in E-cadherin-positive kidney epithelial cells, the conditional synthesis of mutant SIP1 that cannot bind to CtBP abrogates endogenous E-cadherin expression in a similar way as wild-type SIP1. Our results indicate that full-length SIP1 can repress E-cadherin in a CtBP-independent manner.

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^☆: This paper was supported by a Grant from Health Science Research for Research on Brain Science, the Ministry of Health, Labor and Welfare, in Japan.

^☆☆: Address reprint requests to Masahiro Nagaya, MD, Department of Pediatric Surgery, Central Hospital, Aichi Prefectural Colony, 713-8 Kamiya, Kasugai, Aichi, 480-0392 Japan.

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Clinical features of a form of Hirschsprung's disease caused by a novel genetic abnormality☆,☆☆

Abstract

Section snippets

Materials and methods

Genetic analyses

Discussion

Acknowledgements

Cell

Biochem Biology Res Commun

J Pediatr Surg

J Pediatr Surg

Pediatr Neurol

Close linkage with the RET protooncogene and boundaries of deletion mutations in autosomal dominant Hirschsprung disease

Hum Mol Genet

Mutations of the RET proto-oncogene in Hirschsprung's disease

Nature

Endothelin-B receptor mutations in patients with isolated Hirschsprung disease from a non-inbred population

Hum Mol Genet

Mutation of the endothelin-3 gene in the Waardenburg-Hirschsprung disease (Shah-Waardenburg syndrome)

Nat Genet

A homozygous mutation in the endothelin-3 gene associated with a combined Waardenburg type 2 and Hirschsprung phenotype (Shah-Waardenburg syndrome)

Nat Genet

Germline mutations in glial cell line-derived neurotrophic factor (GDNF) and RET in a Hirschsprung disease patient

Nat Genet

De novo mutation of GDNF, ligand for the RET/GDNFR-alpha receptor complex, in Hirschsprung disease

Hum Mol Genet

SOX10 mutations in patients with Waardenburg-Hirschsprung disease

Nat Genet

Sox10 mutation disrupts neural crest development in Dom Hirschsprung mouse model

Nat Genet

Mutations in SIP1, encoding Smad interacting protein-1, cause a form of Hirschsprung disease

Nat Genet

The migration of neural crest cells to the wall of the digestive tract in avian embryo

J Embryol Exp Morphol