Congenital Short Bowel Syndrome Research Articles

CLMP is a tumor suppressor that determines all-trans retinoic acid response in colorectal cancer

CAR-like membrane protein (CLMP) is a tight junction-associated protein whose mutation is associated with congenital short bowel syndrome (CSBS), but its functions in colorectal cancer (CRC) remain unknown. Here, we demonstrate that CLMP is rarely mutated but significantly decreased in CRC patients, and its deficiency accelerates CRC tumorigenesis, growth, and resistance to all-trans retinoic acid (ATRA). Mechanistically, CLMP recruits β-catenin to cell membrane, independent of cadherin proteins. CLMP-mediated β-catenin translocation inactivates Wnt(Wingless and INT-1)/β-catenin signaling, thereby suppressing CRC tumorigenesis and growth in ApcMin/+, azoxymethane/dextran sodium sulfate (AOM/DSS), and orthotopic CRC mouse models. As a direct target of Wnt/β-catenin, cytochrome P450 hydroxylase A1 (CYP26A1)-an enzyme that degrades ATRA to a less bioactive retinoid-is upregulated by CLMP deficiency, resulting in ATRA-resistant CRC that can be reversed by administering CYP26A1 inhibitor. Collectively, our data identify the anti-CRC role of CLMP and suggest that CYP26A1 inhibitor enable to boost ATRA's therapeutic efficiency.

CXADR-Like Membrane Protein Regulates Colonic Epithelial Cell Proliferation and Prevents Tumor Growth

CXADR-like membrane protein (CLMP) is structurally related to coxsackie and adenovirus receptor. Pathogenic variants in CLMP gene have been associated with congenital short bowel syndrome, implying a role for CLMP in intestinal development. However, the contribution of CLMP to regulating gut development and homeostasis is unknown. In this study, we investigated CLMP function in the colonic epithelium using complementary invivo and invitro approaches, including mice with inducible intestinal epithelial cell (IEC)-specific deletion of CLMP (ClmpΔIEC), intestinal organoids, IECs with overexpression, or loss of CLMP and RNA sequencing data from individuals with colorectal cancer. Loss of CLMP enhanced IEC proliferation and, conversely, CLMP overexpression reduced proliferation. Xenograft experiments revealed increased tumor growth in mice implanted with CLMP-deficient colonic tumor cells, and poor engraftment was observed with CLMP-overexpressing cells. ClmpΔIEC mice showed exacerbated tumor burden in an azoxymethane and dextran sulfate sodium-induced colonic tumorigenesis model, and CLMP expression was reduced in human colorectal cancer samples. Mechanistic studies revealed that CLMP-dependent regulation of IEC proliferation is linked to signaling through mTOR-Akt-β-catenin pathways. These results reveal novel insights into CLMP function in the colonic epithelium, highlighting an important role in regulating IEC proliferation, suggesting tumor suppressive function in colon cancer.

Poor outcomes in congenital short bowel syndrome with intestinal malrotation: Experience from a developing country

Journal of Neonatal Surgery is a peer-reviewed and open-access electronic journal. Only a few journals are being published on Neonatal Surgery especially from a developing country, which justifies the need of a new journal on this subject.

The IgSF Cell Adhesion Protein CLMP and Congenital Short Bowel Syndrome (CSBS).

The immunoglobulin-like cell adhesion molecule CLMP is a member of the CAR family of cell adhesion proteins and is implicated in human congenital short-bowel syndrome (CSBS). CSBS is a rare but very severe disease for which no cure is currently available. In this review, we compare data from human CSBS patients and a mouse knockout model. These data indicate that CSBS is characterized by a defect in intestinal elongation during embryonic development and impaired peristalsis. The latter is driven by uncoordinated calcium signaling via gap junctions, which is linked to a reduction in connexin43 and 45 levels in the circumferential smooth muscle layer of the intestine. Furthermore, we discuss how mutations in the CLMP gene affect other organs and tissues, including the ureter. Here, the absence of CLMP produces a severe bilateral hydronephrosis-also caused by a reduced level of connexin43 and associated uncoordinated calcium signaling via gap junctions.

Intestinal epithelial CAR‐Like Membrane Protein promotes mucosal barrier function and prevents colitis‐associated cancer in mice

CAR‐Like Membrane Protein (CLMP) is a transmembrane glycoprotein structurally related to Coxsackie and Adenovirus Receptor. Mutations in CLMP gene have been correlated with the development of an intestinal pediatric disorder termed congenital short bowel syndrome (CSBS). To date, not only is the pathogenesis of CSBS incompletely understood, the role of CLMP in gut homeostasis and disease has not yet been elucidated. We found that CLMP expression is significantly reduced in colorectal cancer (CRC) biopsies and increased in inflammatory bowel disease (IBD) compared to normal mucosa samples. Given the expression pattern of CLMP, we generated mice harboring a tamoxifen inducible intestinal epithelial cell (IEC)‐specific deletion of CLMP as well as model human IEC in which CLMP expression was silenced or upregulated. We then assessed the role of CLMP in regulating intestinal mucosal barrier function, the development of chronic inflammation and colitis‐associated cancer. In this study we report that CLMP protein expression is abundant in differentiated IEC compared to undifferentiated and highly proliferative IEC. CLMP is associated with tight junction controlling the paracellular permeability to solutes and macromolecules. Epithelial CLMP deficiency resulted in enhanced paracellular permeability in vivo and in vitro.These findings indicate an important role for CLMP in regulating epithelial barrier function. Mechanistically, we found that CLMP is involved in homotypic trans‐interactions that facilitate cell‐cell cohesion and promotes cell‐matrix adhesion through integrin beta 1 activity. Lastly, we observed that loss of CLMP in human and mouse IEC resulted in increased cell proliferation. Conversely, CLMP overexpression in IEC resulted in reduced cell proliferation. These results were corroborated in murine models of cancer that included xenograft experiments with CLMP‐deficient tumor cells versus CLMP overexpressing tumor cells and Azoxymethane/Dextran Sulfate Sodium‐induced colitis‐associated cancer. In these models, CLMP deficiency worsened tumor growth. Biochemical analyses revealed CLMP‐dependent regulation of IEC proliferation to be mediated through effects on Akt signaling and beta‐catenin transcriptional activity. Collectively, our findings provide the first report of a key role for CLMP in the positive regulation of intestinal epithelial barrier function and prevention of tumor development.

Congenital Short-Bowel Syndrome Is Associated With a Novel Deletion Mutation in the CLMP Gene: Mutations in CLMP Caused CSBS.

Objective: To describe the clinical presentation and novel mutation in the coxsackie and adenovirus receptor-like membrane protein (CLMP) gene in a Chinese family with congenital short bowel syndrome (CSBS).Methods: We collected clinical data from a Chinese family with inherited CSBS, and performed whole exon sequencing of the children and their parents. The pathogenic sites of candidate genes were targeted, and the detected exon deletions were verified by quantitative PCR.Results: Two siblings in this family presented with bilious vomiting, and were diagnosed with CSBS on laparotomy. Two siblings and their parents underwent complete exome sequencing of the peripheral blood. Both children had CLMP gene exons 3–5 homozygous deletion mutation, while the parents had a heterozygous mutation.Conclusion: This study identified a novel mutation of the CLMP gene in a Chinese family with CSBS. Identification of this mutation can help with genetic counseling and prenatal diagnosis of CSBS.

Congenital short bowel syndrome

Journal of Neonatal Surgery is a peer-reviewed and open-access electronic journal. Only a few journals are being published on Neonatal Surgery especially from a developing country, which justifies the need of a new journal on this subject.

Whole-Exome Sequencing Identified Novel CLMP Mutations in a Family With Congenital Short Bowel Syndrome Presenting Differently in Two Probands.

Congenital short bowel syndrome (CSBS) is a rare condition characterized by an inborn shortening of bowel length with loss of intestinal functions, which often combines malrotation. CXADR-like membrane protein (CLMP) and filamin A (FLNA) gene mutations are the two major causes of this inherited defect. We presented two siblings with the older brother suffering from a laparotomy for bowel obstruction due to malrotation on the 17th day after birth. The younger sister encountered a laparotomy for lactobezoar at 6 months old. CSBS was diagnosed by measurement of the bowel length during the operations. Compound heterozygous CLMP mutations with the paternal allele harboring a long deletion across exon 3–5 and the maternal allele bearing a non-sense mutation of exon 3 (c.235C > T, p.Q79∗) were identified in both cases. They are the first reported familial CSBS caused by novel CLMP mutations in Taiwan.

Congenital short bowel syndrome: a case report and review of the literature

Congenital short bowel syndrome is a rare condition of the newborn, with several reports demonstrating high mortality. For the first time in Russia, we report a case of treatment of a newborn girl with genetically confirmed congenital short bowel syndrome, and also provide a review of the literature on this syndrome. After birth, the child experienced constant vomiting of bile with a progressive decrease in body weight. The laparotomy for congenital adhesions between the loops of the small intestine with severe violations of the evacuation function revealed that the small bowel was 50 cm in length, confirming the diagnosis of congenital short bowel syndrome. The genetic test, using whole exome sequencing, identified a homozygous mutation in the CLMP gene in this patient. A positive result in the postoperative period was achieved using the protocol for the management of patients with short bowel syndrome. Currently, the girl is 11 months old, body weight is 9 kg, development is harmonious. Long-term survival of children with congenital short bowel syndrome is now possible if enteral feeds are introduced early to promote intestinal adaptation, with subsequent weaning off parenteral nutrition.

Congenital Short-Bowel Syndrome: Clinical and Genetic Presentation in China.

Congenital short-bowel syndrome (CSBS) is a rare disorder characterized by retardation of intestinal development. However, it is still not well recognized at present. In this study, the etiological, clinical, and genetic characteristics of CSBS in China were analyzed. Nine infants with CSBS were recruited. Full-thickness biopsy findings were evaluated by histopathology. Whole-exome sequencing was performed to identify mutations in patients and their family members. All patients were followed up at >1 year of age. Six of 9 infants had malrotation, and 2 patients had intestinal atresia. The average total small-bowel length was 51.7 (40-75) cm. Coxsackie and adenovirus receptor-like membrane protein (CLMP) mutations were found in 5 patients and were related to decreases in ileal goblet cells and mucous secretion. Among these 5 patients, 3 shared the same mutation (c. 206G>A p.R69H), 1 patient had an exon 3-5 deletion, and 1 patient had the C.655T>G, p.Cys219Gly, and C.389-2A>C. Another case carried a loss-of-function mutation in filamin A (FLNA). In the other 3 patients, no pathogenic mutations in genes related to intestinal development were found. The rate of catheter-related bloodstream infection was 4.3 per 1000 catheter days, and intestinal failure-associated liver disease (IFALD) was 77.8%. The median follow-up duration was 24.1 months. Eight patients were weaned off parenteral nutrition (PN). Six patients still exhibited malnutrition during follow-up. Infants with CSBS often need long-term PN and remain at risk of SBS-related complications. CLMP and FLNA mutations are associated with CSBS in the Chinese population.

Congenital Short Bowel Syndrome

Congenital short bowel syndrome (SBS) is a rare congen.it.al disease, Only about 37 cases were reported. Infants usually present with failure to 'thrive, recurrent vomiting and or diarrhoea. It is associated with significant mortality and morbidity, High degree of suspicion is necessary to diagnose this condition promptly. Early initiation of parenteral nutrition or surgery may result in a favorable outcome. We treated a case of infant aged eight-weeks presented with recurrent bilious vomiting and failure to thrive. On Laparotomy it was found that the baby had very short small bowel with malrotation. This case was reported and reviewed.
 Journal of Surgical Sciences (2014) Vol. 18 (1) : 35-37

The IgCAM CLMP regulates expression of Connexin43 and Connexin45 in intestinal and ureteral smooth muscle contraction in mice.

ABSTRACTCAR-like membrane protein (CLMP), an immunoglobulin cell adhesion molecule (IgCAM), has been implicated in congenital short-bowel syndrome in humans, a condition with high mortality for which there is currently no cure. We therefore studied the function of CLMP in a Clmp-deficient mouse model. Although we found that the levels of mRNAs encoding Connexin43 or Connexin45 were not or were only marginally affected, respectively, by Clmp deficiency, the absence of CLMP caused a severe reduction of both proteins in smooth muscle cells of the intestine and of Connexin43 in the ureter. Analysis of calcium signaling revealed a disordered cell-cell communication between smooth muscle cells, which in turn induced an impaired and uncoordinated motility of the intestine and the ureter. Consequently, insufficient transport of chyme and urine caused a fatal delay to thrive, a high rate of mortality, and provoked a severe hydronephrosis in CLMP knockouts. Neurotransmission and the capability of smooth muscle cells to contract in ring preparations of the intestine were not altered. Physical obstructions were not detectable and an overall normal histology in the intestine as well as in the ureter was observed, except for a slight hypertrophy of smooth muscle layers. Deletion of Clmp did not lead to a reduced length of the intestine as shown for the human CLMP gene but resulted in gut malrotations. In sum, the absence of CLMP caused functional obstructions in the intestinal tract and ureter by impaired peristaltic contractions most likely due to a lack of gap-junctional communication between smooth muscle cells.

IS-22 Congenital short bowel syndrome : A case successfully treated with home parenteral nuturition(International Session IV)

IS-22 Congenital short bowel syndrome : A case successfully treated with home parenteral nuturition(International Session IV)

Two new mutations of the CLMP gene identified in a newborn presenting congenital short-bowel syndrome

Congenital short-bowel syndrome (CSBS) is a rare neonatal pathology associated with poor prognosis and high mortality rate. We describe a newborn presenting CSBS intestinal malrotation and chronic intestinal pseudo-obstruction syndrome (CIPS), compound heterozygous for two previously unreported heterozygous mutations in Coxsackie and adenovirus receptor-like membrane protein (CLMP) gene, one in intron 1 (c.28+1G>C), the other on exon 4 (c502C>T, p.R168X). Both mutations are predicted to be pathogenic, leading to impaired splicing and the appearance of a premature stop codon, respectively. Our case is remarkable in that it concerns two heterozygous truncating mutations associated with a good clinical prognosis with a favorable cerebral and gastrointestinal outcome and a substantial enteral input at 8 months of age, despite a small intestine measuring only 35cm.

The Long-Term Treatment of Short Bowel Syndrome

Short bowel syndrome (SBS) is the most common cause of intestinal failure in the pediatric population. Functionally, SBS is defined as the spectrum of malabsorption features occurring after extensive surgical resection. Congenital SBS is a rare entity, with an estimated prevalence of 0.02-0.1% among all live births. The mainstay of treatment consists of parenteral nutrition and intestinal rehabilitation, comprising surgical reconstruction. The two main procedures are Longitudinal Intestinal Lengthening and Tailoring procedure (LILT) and Serial Transverse Enteroplasty Procedure (STEP). Transplantation is reserved as treatment of last resort, when intestinal rehabilitation has been unsuccessful. Short bowel syndrome is a debilitating disease, whose management stretches over the course of years. However, with the innovation of surgical techniques such as LILT and STEP, as well as advances in multidisciplinary intestinal rehabilitation centers, long-term survival rates are approaching 90%. In this review we discuss the current and future treatment options for SBS.

Genetic screening of Congenital Short Bowel Syndrome patients confirms CLMP as the major gene involved in the recessive form of this disorder

Congenital short bowel syndrome (CSBS) is an intestinal pediatric disorder, where patients are born with a dramatic shortened small intestine. Pathogenic variants in CLMP were recently identified to cause an autosomal recessive form of the disease. However, due to the rare nature of CSBS, only a small number of patients have been reported to date with variants in this gene. In this report, we describe novel inherited variants in CLMP in three CSBS patients derived from two unrelated families, confirming CLMP as the major gene involved in the development of the recessive form of CSBS.

First STEPs: Serial transverse enteroplasty as a primary procedure in neonates with congenital short bowel

BackgroundSince its introduction as an alternative intestinal lengthening technique, serial transverse enteroplasty (STEP) has been increasingly used as the surgical treatment of choice for patients with refractory short bowel syndrome (SBS). While primary STEP for the treatment of congenital conditions was proposed in the original description of the procedure, emphasis was placed on a delayed or staged approach to these patients. To date, a comprehensive review of the outcomes from this sub-population has not been reported by the International STEP Data Registry. MethodsA retrospective review of the International STEP Data Registry was performed to identify all patients who underwent STEP as a primary operative procedure for the treatment of congenital SBS. Changes in pre- and post-STEP values were assessed using paired t-tests with significance set at p<0.05. Data are presented as mean ± standard deviation. ResultsFifteen patients underwent primary STEP for congenital SBS between September 1, 2004, and April 10, 2012. Thirteen patients had follow-up information available. Causes of congenital SBS included closing gastroschisis, small bowel atresia, and midgut volvulus. Twelve patients had pre- and post-STEP bowel measurements taken. Average pre- and post-STEP bowel lengths were 32 ± 16 cm and 47 ± 22 cm, respectively. Intestinal length was increased by a mean of 15 ± 12 cm for a relative small bowel length increase of 50.4 ± 27.3% (p<0.001). Only one patient required an ostomy at the time of primary STEP. A second patient required a temporary ostomy at 3months of age that was later closed. There was one death from intestinal failure associated liver disease (IFALD). Another patient experienced IFALD progression and required liver and intestinal transplantation. The most commonly reported complication following primary STEP was obstruction or bowel re-dilatation requiring additional operative interventions. Nine patients underwent second STEP procedures under these circumstances. Eight patients remain dependent on parenteral nutrition, while three patients achieved enteral autonomy. ConclusionsPrimary STEP is a feasible and safe surgical option for the treatment of congenital conditions resulting in SBS. Primary STEP establishes early bowel continuity, creates intestinal length from congenitally dilated bowel, and appears to obviate the need for interval stomas and their associated loss of bowel length in neonates with congenital SBS. However, with recent changes in SBS management emphasizing intestinal rehabilitation, additional studies are needed to assess the long-term impact on intestinal adaptation of STEP performed in the neonatal period prior to adoption of this technique.

CLMP Is Essential for Intestinal Development, but Does Not Play a Key Role in Cellular Processes Involved in Intestinal Epithelial Development

Loss-of-function mutations in CLMP have been found in patients with Congenital Short Bowel Syndrome (CSBS), suggesting that its encoded protein plays a major role in intestinal development. CLMP is a membrane protein that co-localizes with tight junction proteins, but its function is largely unknown. We expressed wild-type (WT)-CLMP and a mutant-CLMP (associated with CSBS) in human intestinal epithelial T84 cells that, as we show here, do not produce endogenous CLMP. We investigated the effects of WT-CLMP and mutant-CLMP proteins on key cellular processes that are important for intestinal epithelial development, including migration, proliferation, viability and transepithelial resistance. Our data showed that expression of WT-CLMP or mutant-CLMP does not affect any of these processes. Moreover, our aggregation assays in CHO cells show that CLMP does not act as a strong adhesion molecule. Thus, our data suggest that, in the in vitro model systems we used, the key processes involved in intestinal epithelial development appear to be unaffected by WT-CLMP or mutant-CLMP. Further research is needed to determine the role of CLMP in the development of the intestine.

Congenital short bowel syndrome as the presenting symptom in male patients with FLNA mutations

Autosomal recessive congenital short bowel syndrome is caused by mutations in CLMP. No mutations were found in the affected males of a family with presumed X-linked congenital short bowel syndrome or in an isolated male patient. Our aim was to identify the disease-causing mutation in these patients. We performed mutation analysis of the second exon of FLNA in the two surviving affected males of the presumed X-linked family and in the isolated patient. We identified a novel 2-base-pair deletion in the second exon of FLNA in all these male patients. The deletion is located between two nearby methionines at the N-terminus of filamin A. Previous studies showed that translation of FLNA occurs from both methionines, resulting in two isoforms of the protein. We hypothesized that the longer isoform is no longer translated due to the mutation and that this mutation is therefore not lethal for males in utero. Our findings emphasize that congenital short bowel syndrome can be the presenting symptom in male patients with mutations in FLNA.

CLMP Is Required for Intestinal Development, and Loss-of-Function Mutations Cause Congenital Short-Bowel Syndrome

Short-bowel syndrome usually results from surgical resection of the small intestine for diseases such as intestinal atresias, volvulus, and necrotizing enterocolitis. Patients with congenital short-bowel syndrome (CSBS) are born with a substantial shortening of the small intestine, to a mean length of 50 cm, compared with a normal length at birth of 190-280 cm. They also are born with intestinal malrotation. Because CSBS occurs in many consanguineous families, it is considered to be an autosomal-recessive disorder. We aimed to identify and characterize the genetic factor causing CSBS. We performed homozygosity mapping using 610,000 K single-nucleotide polymorphism arrays to analyze the genomes of 5 patients with CSBS. After identifying a gene causing the disease, we determined its expression pattern in human embryos. We also overexpressed forms of the gene product that were and were not associated with CSBS in Chinese Hamster Ovary and T84 cells and generated a zebrafish model of the disease. We identified loss-of-function mutations in Coxsackie- and adenovirus receptor-like membrane protein (CLMP) in CSBS patients. CLMP is a tight-junction-associated protein that is expressed in the intestine of human embryos throughout development. Mutations in CLMP prevented its normal localization to the cell membrane. Knock-down experiments in zebrafish resulted in general developmental defects, including shortening of the intestine and the absence of goblet cells. Because goblet cells are characteristic for the midintestine in zebrafish, which resembles the small intestine in human beings, the zebrafish model mimics CSBS. Loss-of-function mutations in CLMP cause CSBS in human beings, likely by interfering with tight-junction formation, which disrupts intestinal development. Furthermore, we developed a zebrafish model of CSBS.