Mutational and expressional analysis of ERBB3 gene in common solid cancers

ERBB3 is a member of EGFR family receptor tyrosine kinases, genetic alterations of which are common and therapeutically targeted in human cancers. Recently, somatic mutations of ERBB3 gene, including recurrent mutation in exon 3 altering Val104, were reported in gastric cancers (GC) and colorectal cancers (CRC), strongly suggesting its role in the development of GC and CRC. To examine whether the recurrent ERBB3 mutations of exon 3 occur in GC and CRC, and other malignancies as well, we analyzed the ERBB3 in 1677 cancer tissues by a single‐strand conformation polymorphism (SSCP) assay. We identified ERBB3 mutations altering the Val104 mutations in GC (0.5%) and CRC (2.2%). However, we did not find the ERBB3 mutations in the other cancers besides GC and CRC. We observed that an increased intensity of phosphorylated ERBB3 (pERBB3) in GC and CRC. Of note, all of the cancers with ERBB3 mutations displayed an increased intensity of pERBB3 immunostaining. Our data indicate that the recurrent ERBB3 mutations altering Val104 occur predominantly in GC and CRC. Also, the data suggest that ERBB3 is altered in GC and CRC by various ways, including somatic mutations and increased expression that might play roles in tumorigenesis.     

Gut feelings: Studying enteric nervous system development,function, and disease in the zebrafish model system

The enteric nervous system (ENS) is the largest part of the peripheral nervous system and is entirely neural crest–derived. It provides the intrinsic innervation of the gut, controlling different aspects of gut function, such as motility. In this review, we will discuss key points of Zebrafish ENS development, genes, and signaling pathways regulating ENS development, as well as contributions of the Zebrafish model system to better understand ENS disorders. During their migration, enteric progenitor cells (EPCs) display a gradient of developmental states based on their proliferative and migratory characteristics, and show spatiotemporal heterogeneity based on gene expression patterns. Many genes and signaling pathways that regulate the migration and proliferation of EPCs have been identified, but later stages of ENS development, especially steps of neuronal and glial differentiation, remain poorly understood. In recent years, Zebrafish have become increasingly important to test candidate genes for ENS disorders (e.g., from genome‐wide association studies), to identify environmental influences on ENS development (e.g., through large‐scale drug screens), and to investigate the role the gut microbiota play in ENS development and disease. With its unique advantages as a model organism, Zebrafish will continue to contribute to a better understanding of ENS development, function, and disease. Developmental Dynamics 247:268–278, 2018. © 2017 Wiley Periodicals, Inc.     

Hirschsprung''s disease and Ondine''s curse: further evidence for a distinct syndrome

Although Hirschsprung's disease is a relatively common congenital malformation, with an estimated incidence of about 1:5000, Primary Central Hypoventilation Syndrome (Ondine's curse) is exceedingly rare, with about 50 reported cases. We describe a patient with total colonic aganglionosis occurring together with failure of automatic control of respiration, specific facial dysmorphology and characteristic CT scan changes to substantiate further the syndromic nature of this association.     

Overexpression of G100S mutation in PRKAG2 causes Wolff–Parkinson–White syndrome in zebrafish

The Wolff–Parkinson–White (WPW) syndrome was believed to be associated with PRKAG2 gene mutations. In this study, we verified the pathopoiesis of G100S mutation, a novel mutation only discovered in Chinese patients with WPW, in cardiac disorder. Similar to R302Q, when overexpressed PRKAG2 G100S mutant in zebrafish, we observed a thicker heart wall, detected a decreased AMPK enzymatic activity by tissue AMPK kinase activity colorimetric technique, as well as examined an increased glycogen storage in heart wall using the method for periodic acid‐Schiff staining, in comparison with the zebrafish without exogenous PRKAG2 (mock) or with wild‐type PRKAG2 (WT). Taken together, we concluded PRKAG2 G100S mutation might contribute to impair the AMP‐activated protein kinase function, which resulted in increased cardiac glycogen storage, serving as a pathogenesis for WPW syndrome in Chinese.     

A patient with Schinzel-Giedion syndrome and a review of 20 patients

Summary The Schinzel-Giedion syndrome is characterized by severe midface retraction, multiple skull anomalies, clubfeet, and cardian and renal malformations. So far, 20 patients have been reported. This is the first report of the syndrome demonstrated in Oriental patients. In surviving patients, severe growth and developmental deficiency is a common finding.     

The latest FADS: Functional analysis of GLDN patient variants and classification of GLDN‐associated AMC as a type of viable fetal akinesia deformation sequence

Recessive variants in the GLDN gene, which encodes the gliomedin protein and is involved in nervous system development, have recently been associated with Arthrogryposis Multiplex Congenita (AMC), a heterogenous condition characterized by congenital contractures of more than one joint. Two cohorts of patients with GLDN‐associated AMC have previously been described, evolving the understanding of the condition from lethal to survivable with the provision of significant neonatal support. Here, we describe one additional patient currently living with the syndrome, having one novel variant, p.Leu365Phe, for which we provide functional data supporting its pathogenicity. We additionally provide experimental data for four other previously reported variants lacking functional evidence, including p.Arg393Lys, the second variant present in our patient. We discuss unique and defining clinical features, adding calcium‐related findings which appear to be recurrent in the GLDN cohort. Finally, we compare all previously reported patients and draw new conclusions about scope of illness, with emphasis on the finding of pulmonary hypoplasia, suggesting that AMC secondary to GLDN variants may be best fitted under the umbrella of fetal akinesia deformation sequence (FADS).     

Expression analysis of BMP2, BMP5, BMP10 in human colon tissues from Hirschsprung disease patients

Objective: Bone morphogenetic proteins (BMPs) are members of the transforming growth factor β (TGF β) superfamily. BMP2, BMP5 and BMP10 exert their biological functions by interacting with membrane bound receptors belonging to the serine/threonine kinase family. Hirschsprung disease (HSCR) is characterized by the absence of intramural ganglion cells in the nerve plexuses of the distal gut. However, putative Notch function in enteric nervous system (ENS) development and the etiology of HSCR is unknown. Methods: Aganglionic and ganglionic colon segment tissues of 50 HSCR patients were investigated for the expression pattern of BMP2, BMP5 and BMP10 using real-time RT-PCR, Western blot analysis and immunohistochemical staining. Results: The mRNA levels of BMP2, BMP5 and BMP10 in the stenotic colon segment from HSCR patients were significantly higher than those in the normal ones. Similar increased expressions of them in the stenotic colon segments were detected by Western blotting coupled with densitometry analysis. Lastly, immunohistologicl stain showed significant BMP2, 5 and 10 increases in mucous and muscular layers from stenotic colon segments compared to normal segments. Conclusions: BMP2, BMP5 and BMP10 are elevated in the stenotic colon segment of HSCR, and BMPs signaling plays a pivotal role in the development of HSCR.     

Reduced endothelin converting enzyme-1 and endothelin-3 mRNA in the developing bowel of male mice may increase expressivity and penetrance of Hirschsprung disease-like distal intestinal aganglionosis.

Hirschsprung disease (distal intestinal aganglionosis, HSCR) is a multigenic disorder with incomplete penetrance, variable expressivity, and a strong male gender bias. Recent studies demonstrated that these genetic patterns arise because gene interactions determine whether enteric nervous system (ENS) precursors successfully proliferate and migrate into the distal bowel. We now demonstrate that male gender bias in the extent of distal intestinal aganglionosis occurs in mice with Ret dominant-negative mutations (RetDN) that mimic human HSCR. We hypothesized that male gender bias could result from reduced expression of a gene already known to be essential for ENS development. Using quantitative real-time polymerase chain reaction (PCR) we demonstrated reduced levels of endothelin converting enzyme-1 and endothelin-3 mRNA in the male mouse bowel at the time that ENS precursors migrate into the colon. Other HSCR-associated genes are expressed at comparable levels in male and female mice. Testosterone and Mullerian inhibiting substance had no deleterious effect on ENS precursor development, but adding EDN3 peptide to E11.5 male RetDN heterozygous mouse gut explants in organ culture significantly increased the rate of ENS precursor migration through the bowel.     

腹泻型肠易激综合征患者血清抗肠神经元抗体免疫反应特点及其临床意义

目的 通过检测腹泻型肠易激综合征(IBS-D)患者血清中抗肠神经元抗体(AENA),分析与症状的相关性,探讨AENA在IBS发病中的可能作用。方法 纳入符合罗马Ⅲ诊断标准IBS-D患者和健康对照者,采集血清,以豚鼠黏膜下神经丛为底物,间接免疫荧光法检测血清AENA,盲法判断免疫反应染色结果;比较AENA阳性和阴性/弱阳性IBS-D患者临床症状的差别。结果 1)127例IBS-D患者AENA阳性率为85.8%;86名健康对照者阳性率为7.0%。109例AENA阳性的IBS-D患者血清分别为强阳性23.6%、阳性43.3%、弱阳性18.9%,表现为单纯胞质染色、单纯胞核染色、胞质和胞核染色、核膜染色、胞质和核膜染色;6名AENA阳性的健康对照血清均为单纯胞质染色。2)AENA强阳性的IBS-D患者,其肠道症状重于抗体阴性和弱阳性患者,表现为肠道症状计分高分(10分者,58.8%比38.1%)、平素腹痛频发(91.7%比60.0%)、排便前腹痛/腹部不适严重的患者比例数高(24.7%比9.5%);AENA阳性IBS-D患者排便急迫感更常见(87.3%比57.1%)。结论 AENA在IBS发病中可能起一定作用,其有望成为IBS-D的生物学标志。     

Cohen syndrome: fertility in a female patient

In this report we describe fertility in an adult female with Cohen syndrome. She gave birth to a son, now 1.5 years old, with discrete facial stigmata and slight psychomotor retardation.     

Lethal syndrome of slender bones,intrauterine fractures,characteristic facial appearance,and cataracts,resembling Hallermann-Streiff syndrome in two sibs

We report on a family in which 1 male infant who died neonatally and 1 female fetus at 29 weeks of gestation had an identical condition resembling Hallermann-Streiff syndrome. The long bones were slender with a few fractures, the skull was underossified, and the face was characteristic of Hallermann-Streiff syndrome. Bilateral cataracts were identified in the male. We regard the condition in this family as a severe form of Hallermann-Streiff syndrome, which appears to have been lethal, at least in the liveborn male. This syndrome is usually sporadic. Recurrence in sibs suggests the possibility of autosomal-recessive inheritance, or of a dominant mutation with parental mosaicism. © 1995 Wiley-Liss, Inc.     

Long-chain 3-hydroxyacyl-Coenzyme A dehydrogenase (L-CHAD) deficiency in a patient with the Bannayan-Riley-Ruvalcaba syndrome

Bannayan-Riley-Ruvalcaba syndrome (BRRS) is an autosomal dominant condition of macrocephaly in combination with lipomas/hemangiomas, hypotonia, developmental delay, and a lipid myopathy. The etiology of the lipid storage myopathy has been unclear. We describe a black boy with findings of BRRS who also has a defect in long-chain fatty acid oxidation expressed in cultured skin fibroblasts as a deficiency of long-chain-L-3-hydroxyacyl-CoA dehydrogenase (L-CHAD). He also has an abnormal brain MRI and increased size of both lower limbs. We present this child because of his unusual combination of findings, and postulate that L-CHAD deficiency may be the cause of the lipid myopathy in BRRS. © 1994 Wiley-Liss, Inc.     

Zebrafish as a model for long QT syndrome: the evidence and the means of manipulating zebrafish gene expression

Congenital long QT syndrome (LQT) is a group of cardiac disorders associated with the dysfunction of cardiac ion channels. It is characterized by prolongation of the QT-interval, episodes of syncope and even sudden death. Individuals may remain asymptomatic for most of their lives while others present with severe symptoms. This heterogeneity in phenotype makes diagnosis difficult with a greater emphasis on more targeted therapy. As a means of understanding the molecular mechanisms underlying LQT syndrome, evaluating the effect of modifier genes on disease severity as well as to test new therapies, the development of model systems remains an important research tool. Mice have predominantly been the animal model of choice for cardiac arrhythmia research, but there have been varying degrees of success in recapitulating the human symptoms; the mouse cardiac action potential (AP) and surface electrocardiograms exhibit major differences from those of the human heart. Against this background, the zebrafish is an emerging vertebrate disease modelling species that offers advantages in analysing LQT syndrome, not least because its cardiac AP much more closely resembles that of the human. This article highlights the use and potential of this species in LQT syndrome modelling, and as a platform for the in vivo assessment of putative disease-causing mutations in LQT genes, and of therapeutic interventions.     

Analysis of CNTNAP1 gene variants in a Chinese pedigree affected with lethal congenital contracture syndrome type 7CSCD

Objective To explore the genetic basis for a couple who had developed polyhydramnios during three pregnancies and given birth to two liveborns featuring limb contracture, dyspnea and neonatal death. Methods Whole-exome sequencing (WES) was carried out on fetal tissue and peripheral blood samples from the couple. Suspected variants were verified by Sanger sequencing. Results The fclus was found to harbor homozygous nonsense c. 37180T (p. Argl240Ter) variants of theCNTNAPI gene, which were respectively inherited from its mother and father. The variant was unreported previously. According to the guidelines of the American College of Medical Genetics and Genomics, the variant was predicted to be pathogenic (PVS1 + PM2 + PP4). Conclusion The novel homozygous nonsense variants of the CNTN API gene probably underlay the lethal congenital contracture syndrome type 7 (LCCS7) in this pedigree. Above finding has enabled genetic counseling and prenatal diagnosis for the family. © 2022 West China University of Medical Sciences. All rights reserved.     

Female pseudohermaphroditism due to classical 21-hydroxylase deficiency in a girl with Turner syndrome

We report on a rare case of female pseudohermaphroditism due to classical 21-hydroxylase deficiency associated with Turner syndrome (45,X/46,XX). Difficulties in the management of both diseases are briefly discussed. We regard this rare combination as a coincidental occurrence.