Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Novel MYO5B mutation in microvillous inclusion disease of Syrian ancestry.

ABSTRACT: Microvillus inclusion disease (MVID) is a rare autosomal recessive condition characterized by a lack of microvilli on the surface of enterocytes, resulting in severe, life-threatening diarrhea that could lead to mortality within the first year of life. We identify two unrelated families, each with one child presenting with severe MVID from birth. Using trio whole-exome sequencing, we observed that the two families share a novel nonsense variant (Glu1589*) in the MYO5B gene, a type Vb myosin motor protein in which rare damaging mutations were previously described to cause MVID. This founder mutation was very rare in public databases and is likely specific to patients of Syrian ancestry. We present a detailed account of both patients' clinical histories to fully characterize the effect of this variant and expand the genotype-phenotype databases for MVID patients from the Middle East.

SUBMITTER: Hassan K

PROVIDER: S-EPMC8958910 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Novel <i>MYO5B</i> mutation in microvillous inclusion disease of Syrian ancestry.

Hassan Kamal K Robay Amal A Al-Maraghi Aljazi A Nimeri Nuha N Azzam Asmaa Basheer AB Al Shakaki Alya A Hamid Eman E Crystal Ronald G RG Fakhro Khalid A KA

Cold Spring Harbor molecular case studies 20220201 2

Microvillus inclusion disease (MVID) is a rare autosomal recessive condition characterized by a lack of microvilli on the surface of enterocytes, resulting in severe, life-threatening diarrhea that could lead to mortality within the first year of life. We identify two unrelated families, each with one child presenting with severe MVID from birth. Using trio whole-exome sequencing, we observed that the two families share a novel nonsense variant (Glu1589*) in the <i>MYO5B</i> gene, a type Vb myos ...[more]

PMID: 34815247

Similar Datasets

Two cases of microvillous inclusion disease caused by novel mutations in MYO5B gene.

Project description:Microvillous inclusion disease (MVID) typically appears with severe chronic diarrhea in the few days after birth and rapidly causes dehydration and metabolic acidosis. In this context, presenting two novel cases, we underline the crucial importance of mutation analysis for the diagnosis of this disease that may be easily misdiagnosed.

| S-EPMC6293129 | biostudies-literature

Myo5b knockout mice as a model of microvillus inclusion disease.

Project description:Inherited MYO5B mutations have recently been associated with microvillus inclusion disease (MVID), an autosomal recessive syndrome characterized by intractable, life-threatening, watery diarrhea appearing shortly after birth. Characterization of the molecular mechanisms underlying this disease and development of novel therapeutic approaches is hampered by the lack of animal models. In this study we describe the phenotype of a novel mouse model with targeted inactivation of Myo5b. Myo5b knockout mice show perinatal mortality, diarrhea and the characteristic mislocalization of apical and basolateral plasma membrane markers in enterocytes. Moreover, in transmission electron preparations, we observed microvillus atrophy and the presence of microvillus inclusion bodies. Importantly, Myo5b knockout embryos at day 20 of gestation already display all these structural defects, indicating that they are tissue autonomous rather than secondary to environmental cues, such as the long-term absence of nutrients in the intestine. Myo5b knockout mice closely resemble the phenotype of MVID patients and constitute a useful model to further investigate the underlying molecular mechanism of this disease and to preclinically assess the efficacy of novel therapeutic approaches.

| S-EPMC4511872 | biostudies-literature

[Clinical features and MYO5B mutations of a family affected by microvillus inclusion disease].

Project description:Microvillus inclusion disease (MVID) is an autosomal recessive disorder caused by biallelic mutations in the MYO5B or STX3 gene. Refractory diarrhea and malabsorption are the main clinical manifestations. The aim of this study was to investigate the clinical features and MYO5B gene mutations of an infant with MVID. A 21-day-old female infant was referred to the hospital with the complaint of diarrhea for 20 days. On physical examination, growth retardation of the body weight and length was found along with moderately jaundiced skin and sclera. Breath sounds were clear in the two lungs and the heart sounds were normal. The abdomen was distended and the veins in the abdominal wall were observed. The liver and spleen were not palpable. Biochemical analysis revealed raised serum total bile acids, bilirubin, transaminases and γ-glutamyl transpeptidase while decreased levels of serum sodium, chloride, phosphate and magnesium. Blood gas analysis indicated metabolic acidosis. The preliminary diagnosis was congenital diarrhea, and thus parenteral nutrition was given along with other symptomatic and supportive measures. However, diarrhea, metabolic acidosis and electrolyte disturbance were intractable, and the cholestatic indices, including transaminases, γ-glutamyl transpeptidase, bilirubin and total bile acids, remained at increased levels. One month later, the patient was discharged and then lost contact. On genetic analysis, the infant was proved to be a compound heterozygote of the c.310+2Tdup and c.1966C>T(p.R656C) variants of the gene MYO5B, with c.310+2Tdup being a novel splice-site mutation. MVID was thus definitely diagnosed.

| S-EPMC7403068 | biostudies-literature

Diagnosis of microvillous inclusion disease: a case report and literature review with significance for oman.

Project description:Microvillous Inclusion Disease (MVID) is one of the congenital diarrheal disorders (CDD) caused by genetic defects in enterocyte differentiation and polarization. Its prevalence is higher in countries with a high degree of consanguinity. It causes severe, intractable secretory diarrhea leading to permanent and definitive intestinal failure with resultant dependency on parenteral nutrition (PN). Small bowel transplantation is the only curative treatment. The gold standard for diagnosis are the typical morphological abnormalities in small bowel biopsies on light and electron microscopy (EM). In recent times, histochemistry and immunohistochemistry have shown sufficient diagnostic accuracy replacing EM if the facility is unavailable or EM findings are inconclusive. We describe a neonate with CDD who was diagnosed to have MVID on the duodenal biopsy by morphohistochemical and immunophenotypic methods used for the first time in Oman. By utilizing such easy and accessible diagnostic methods, a rare genetic disorder could be diagnosed with certainty and the family could be counseled accordingly. With a high degree of consanguinity in the region, the prevalence of MVID in Oman needs to be identified once these patients are diagnosed by utilizing appropriate investigations. Care of such patients necessitates improving current parenteral nutrition services and addressing the future need for small bowel transplantation (SBTx), in Oman.

| S-EPMC3515048 | biostudies-literature

Novel GLA Mutation Promotes Intron Inclusion Leading to Fabry Disease.

Project description:Fabry disease (FD) is a rare and underdiagnosed X-linked disorder resulting from the deficient activity of the lysosomal hydrolase α-galactosidase A, which leads to storage of complex glycosphingolipids inside of lysosomes in critical organs and tissues, impairing their functions and consequently resulting in a progressive multisystem disease. FD is caused by mutations in the GLA gene, and only 4.6% of described mutations are located in the splice site regions. RNA splicing is an essential step to the formation of functional proteins, and mutations in splice site regions can cause formation of aberrant transcripts leading to disease. Here we report a novel GLA insertion at position c.801+3 in intron 5 (c.801+2_801+3insT) in a Brazilian family with suspicion of FD. The index case, a 46-year-old male, presented undetectable α-galactosidase A activity. Analysis of blood cDNA found two aberrant GLA transcripts. In the first transcript, a novel donor splice site was created promoting formation of an intron inclusion with 37 bp. The splice site was not recognized in the second transcript and the intron 5 was not excised. The wild-type transcript was not formed and both aberrant transcripts lead to a premature stop codon. Despite not being in the canonical site, this new mutation disrupts existing 5' splice site and produces two aberrant transcripts leading to FD.

| S-EPMC6777637 | biostudies-literature

Modeling of a Novel Patient-Based MYO5B Point Mutation Reveals Insights Into MVID Pathogenesis.

Project description: Not available

| S-EPMC10041088 | biostudies-literature

Loss of MYO5B in mice recapitulates Microvillus Inclusion Disease and reveals an apical trafficking pathway distinct to neonatal duodenum.

Project description:Background and aimsInactivating mutations in MYO5B cause severe neonatal diarrhea in Microvillus Inclusion Disease. Loss of active MYO5B causes the formation of pathognomonic inclusions and aberrations in brush border enzymes.MethodsWe developed three mouse models of germline, constitutively intestinal targeted and inducible intestinal targeted deletion of MYO5B. The mice were evaluated for enterocyte cellular morphology.ResultsGermline MYO5B KO mice showed early diarrhea and failure to thrive with evident microvillus inclusions and loss of apical transporters in the duodenum. IgG was present within inclusions. Apical transporters were lost and inclusions were present in the duodenum, but were nearly absent in the ileum. VillinCre;MYO5BF/F mice showed similar pathology and morphological changes in duodenal enterocytes. In contrast, when MYO5B KO was induced with tamoxifen treatment at 8 weeks of age, VillinCreERT2;MYO5BF/F mice developed severe diarrhea with loss of duodenal brush border enzymes, but few inclusions were observed in enterocytes. However, if tamoxifen is administered to 2-day-old VillinCreERT2;MYO5BF/F mice, prominent microvillus inclusions were observed.ConclusionsThe microvillus inclusions that develop after MYO5B loss reveal the presence of an unrecognized apical membrane trafficking pathway in neonatal duodenal enterocytes. However, the diarrheal pathology after MYO5B loss is due to deficits in transporter presentation at the apical membrane in duodenal enterocytes.

| S-EPMC4806369 | biostudies-literature

Lysophosphatidic Acid Increases Maturation of Brush Borders and SGLT1 Activity in MYO5B-deficient Mice, a Model of Microvillus Inclusion Disease.

Project description:Background & aimMyosin VB (MYO5B) is an essential trafficking protein for membrane recycling in gastrointestinal epithelial cells. The inactivating mutations of MYO5B cause the congenital diarrheal disease, microvillus inclusion disease (MVID). MYO5B deficiency in mice causes mislocalization of SGLT1 and NHE3, but retained apical function of CFTR, resulting in malabsorption and secretory diarrhea. Activation of lysophosphatidic acid (LPA) receptors can improve diarrhea, but the effect of LPA on MVID symptoms is unclear. We investigated whether LPA administration can reduce the epithelial deficits in MYO5B-knockout mice.MethodsStudies were conducted with tamoxifen-induced, intestine-specific knockout of MYO5B (VilCreERT2;Myo5bflox/flox) and littermate controls. Mice were given LPA, an LPAR2 agonist (GRI977143), or vehicle for 4 days after a single injection of tamoxifen. Apical SGLT1 and CFTR activities were measured in Üssing chambers. Intestinal tissues were collected, and localization of membrane transporters was evaluated by immunofluorescence analysis in tissue sections and enteroids. RNA sequencing and enrichment analysis were performed with isolated jejunal epithelial cells.ResultsDaily administration of LPA reduced villus blunting, frequency of multivesicular bodies, and levels of cathepsins in intestinal tissues of MYO5B-knockout mice compared with vehicle administration. LPA partially restored the brush border height and the localization of SGLT1 and NHE3 in small intestine of MYO5B-knockout mice and enteroids. The SGLT1-dependent short-circuit current was increased and abnormal CFTR activities were decreased in jejunum from MYO5B-knockout mice given LPA compared with vehicle.ConclusionsLPA may regulate a MYO5B-independent trafficking mechanism and brush border maturation, and therefore be developed for treatment of MVID.

| S-EPMC8240502 | biostudies-literature

MYO5B, STX3, and STXBP2 mutations reveal a common disease mechanism that unifies a subset of congenital diarrheal disorders: A mutation update.

Project description:Microvillus inclusion disease (MVID) is a rare but fatal autosomal recessive congenital diarrheal disorder caused by MYO5B mutations. In 2013, we launched an open-access registry for MVID patients and their MYO5B mutations (www.mvid-central.org). Since then, additional unique MYO5B mutations have been identified in MVID patients, but also in non-MVID patients. Animal models have been generated that formally prove the causality between MYO5B and MVID. Importantly, mutations in two other genes, STXBP2 and STX3, have since been associated with variants of MVID, shedding new light on the pathogenesis of this congenital diarrheal disorder. Here, we review these additional genes and their mutations. Furthermore, we discuss recent data from cell studies that indicate that the three genes are functionally linked and, therefore, may constitute a common disease mechanism that unifies a subset of phenotypically linked congenital diarrheal disorders. We present new data based on patient material to support this. To congregate existing and future information on MVID geno-/phenotypes, we have updated and expanded the MVID registry to include all currently known MVID-associated gene mutations, their demonstrated or predicted functional consequences, and associated clinical information.

| S-EPMC5838515 | biostudies-literature

Evaluating the promise of inclusion of African ancestry populations in genomics.

Project description:The lack of representation of diverse ancestral backgrounds in genomic research is well-known, and the resultant scientific and ethical limitations are becoming increasingly appreciated. The paucity of data on individuals with African ancestry is especially noteworthy as Africa is the birthplace of modern humans and harbors the greatest genetic diversity. It is expected that greater representation of those with African ancestry in genomic research will bring novel insights into human biology, and lead to improvements in clinical care and improved understanding of health disparities. Now that major efforts have been undertaken to address this failing, is there evidence of these anticipated advances? Here, we evaluate the promise of including diverse individuals in genomic research in the context of recent literature on individuals of African ancestry. In addition, we discuss progress and achievements on related technological challenges and diversity among scientists conducting genomic research.

| S-EPMC7042246 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data