scholarly journals Congenital Diarrhea and Cholestatic Liver Disease: Phenotypic Spectrum Associated with MYO5B Mutations

2021 ◽  
Vol 10 (3) ◽  
pp. 481
Author(s):  
Denise Aldrian ◽  
Georg F. Vogel ◽  
Teresa K. Frey ◽  
Hasret Ayyıldız Civan ◽  
Aysel Ünlüsoy Aksu ◽  
...  
Keyword(s):  
Liver Disease ◽  
Protein Trafficking ◽  
Intestinal Transplantation ◽  
Disease Diagnosis ◽  
Cholestatic Liver Disease ◽  
Residual Function ◽  
Intractable Diarrhea ◽  
Phenotype Data ◽  
Functional Consequences ◽  
Histopathologic Findings

Myosin Vb (MYO5B) is a motor protein that facilitates protein trafficking and recycling in polarized cells by RAB11- and RAB8-dependent mechanisms. Biallelic MYO5B mutations are identified in the majority of patients with microvillus inclusion disease (MVID). MVID is an intractable diarrhea of infantile onset with characteristic histopathologic findings that requires life-long parenteral nutrition or intestinal transplantation. A large number of such patients eventually develop cholestatic liver disease. Bi-allelic MYO5B mutations are also identified in a subset of patients with predominant early-onset cholestatic liver disease. We present here the compilation of 114 patients with disease-causing MYO5B genotypes, including 44 novel patients as well as 35 novel MYO5B mutations, and an analysis of MYO5B mutations with regard to functional consequences. Our data support the concept that (1) a complete lack of MYO5B protein or early MYO5B truncation causes predominant intestinal disease (MYO5B-MVID), (2) the expression of full-length mutant MYO5B proteins with residual function causes predominant cholestatic liver disease (MYO5B-PFIC), and (3) the expression of mutant MYO5B proteins without residual function causes both intestinal and hepatic disease (MYO5B-MIXED). Genotype-phenotype data are deposited in the existing open MYO5B database in order to improve disease diagnosis, prognosis, and genetic counseling.

scholarly journals MYO5B Novel Homozygous Variant c.2090+3A>T Causes Intron Retention and is Related To Severe Cholestasis and Intractable Diarrhea

2021 ◽  
Author(s):  
Yu Zheng ◽  
Yuming Peng ◽  
Shuju Zhang ◽  
Yu Peng ◽  
Hongmei Zhao ◽  
...  
Keyword(s):  
Protein Trafficking ◽  
Intron Retention ◽  
Failure To Thrive ◽  
Corneal Opacity ◽  
Underlying Mechanism ◽  
Hepatic Cyst ◽  
Cholestatic Liver Disease ◽  
Final Choice ◽  
Intractable Diarrhea ◽  
Homozygous Variant

Abstract Background Myosin Vb (MYO5B) plays an important role in protein trafficking and recycling. Biallelic mutated MYO5B has been found related to microvillus inclusion disease (MVID) or predominant cholestatic liver disease or mixed the two diseases. This study aims to clarify the splicing alteration and associated clinical or pathological features of a newly identified homozygous variant, and thus to provide supporting information for disease mechanism and clinical treatment. Results Here we identified a novel homozygous variant c.2090 + 3A > T by exome sequencing in a female patient. Minigene assay using recombined vectors and cell transfection found 185bp intention of intron 17 in the mRNA, which was predicted a pre-termination of myoVb (p.Arg697fs*47) at the end of the head motor domain. Further bowel biopsies via immunohistochemistry and the electron microscope detected decreased microvillus and local lesion of microvillus inclusion in the mucosa of duodena. The patient presented intractable diarrhea alleviated from severe in early life to mild later. She also had congenital cholestasis, liver cirrhosis, cholelithiasis, hepatic cyst, corneal opacity, and failure to thrive. Medicines were supplied to alleviate symptoms, maintain her intestines and nutrition. Liver transplantation would be the final choice. Conclusions Our study reported a novel homozygous variant that altered splicing and further supported the underlying mechanism that led to complicated enterohepatic phenotypes. The results expanded clinical practice in understanding the genotype-phenotype correlation of MYO5B and associated disease management.

scholarly journals A Link between Intrahepatic Cholestasis and Genetic Variations in Intracellular Trafficking Regulators

Biology ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 119
Author(s):  
Qinghong Li ◽  
Yue Sun ◽  
Sven C. D. van IJzendoorn
Keyword(s):  
Liver Disease ◽  
Golgi Apparatus ◽  
Protein Trafficking ◽  
Intrahepatic Cholestasis ◽  
Intracellular Trafficking ◽  
Bile Secretion ◽  
Cholestatic Liver Disease ◽  
Gene Variants ◽  
Recycling Endosomes ◽  
Complex Process

Intrahepatic cholestasis is characterized by the accumulation of compounds in the serum that are normally secreted by hepatocytes into the bile. Genes associated with familial intrahepatic cholestasis (FIC) include ATP8B1 (FIC1), ABCB11 (FIC2), ABCB4 (FIC3), TJP2 (FIC4), NR1H4 (FIC5) and MYO5B (FIC6). With advanced genome sequencing methodologies, additional mutated genes are rapidly identified in patients presenting with idiopathic FIC. Notably, several of these genes, VPS33B, VIPAS39, SCYL1, and AP1S1, together with MYO5B, are functionally associated with recycling endosomes and/or the Golgi apparatus. These are components of a complex process that controls the sorting and trafficking of proteins, including those involved in bile secretion. These gene variants therefore suggest that defects in intracellular trafficking take a prominent place in FIC. Here we review these FIC-associated trafficking genes and their variants, their contribution to biliary transporter and canalicular protein trafficking, and, when perturbed, to cholestatic liver disease. Published variants for each of these genes have been summarized in table format, providing a convenient reference for those who work in the intrahepatic cholestasis field.

scholarly journals A218 A CASE REPORT OF PSEUDOHYPONATREMIA IN CHOLESTATIC LIVER DISEASE

2021 ◽  
Vol 4 (Supplement_1) ◽  
pp. 250-252
Author(s):  
M Shpoliansky ◽  
B Kamath
Keyword(s):  
Liver Disease ◽  
Liver Transplant ◽  
Measurement Techniques ◽  
Growth Failure ◽  
Urine Osmolality ◽  
Normal Serum ◽  
Plasma Sodium ◽  
Cholestatic Liver Disease ◽  
Aqueous Fraction ◽  
Direct Potentiometry

Abstract Background True hyponatremia in the setting of cholestatic liver disease may signify cirrhosis with fluid overload, and is therefore an ominous sign of deteriorating liver function. In pediatric liver transplant candidates, it is associated with increased waitlist mortality. Pseudohyponatremia however, is a falsely low measurement of plasma sodium when measured by indirect potentiometry. Pseudohyponatremia secondary to hypercholesterolemia is a phenomenon that occurs due to a reduced aqueous fraction of the plasma when levels of cholesterol or triglycerides are greatly elevated. Severe hypercholesterolemia due to Lipoprotein X accumulation may be the cause of pseudohyponatremia in biliary obstruction or cholestasis. Aims To describe a case of pseudohyponatremia secondary to hypercholesterolemia in an infant with Alagille syndrome (ALGS) and cholestatic liver disease. Methods This 7 month-old male with ALGS (confirmed JAGGED1 mutation) and severe cholestasis, failure to thrive, and pruritus, developed new-onset progressive hyponatremia as low as 121 mmol/L at an outside institution. He was therefore transferred to our center for liver transplant assessment due to concerns of progressive liver dysfunction and for management of the hyponatremia. Results Upon admission, the patient was jaundiced but euvolemic, with no evidence of ascites or peripheral edema. Laboratory work drawn at our institution showed conjugated bilirubin of 180 mmol/L, ALT 300 U/L, AST 250 U/L, and GGT 1200 U/L. INR was 1.1 and albumin of 35 g/L. The cholesterol was elevated above 16.8 mmol/L, with high triglycerides 2.68 mmol/L, and the serum appeared visibly lipemic. The sodium level was 138 mmol/L as measured by direct potentiometry due to the visible lipemia. The osmolality of 288 mmol/kg was normal with a normal osmolar gap. Urine osmolality and sodium were also normal. He underwent routine evaluation and was listed for a liver transplant due to the profound cholestasis and growth failure. Conclusions Pseudohyponatremia is an important entity to recognize when caring for patients with cholestatic liver disease and hyponatremia. Both direct potentiometry and indirect potentiometry are currently used for sodium testing in blood in biochemistry laboratories. These measurement techniques show good agreement as long as protein and lipid concentrations in blood are normal, however, hyperlipidemia is a well-recognized cause for error in sodium estimation. It is therefore imperative to evaluate apparent hyponatremia correctly, especially when the patient appears euvolemic clinically and by normal serum osmolality. In this clinical setting, pseudohyponatremia is the likely cause and a workup should be carried out to identify possible underlying etiologies, the most probable being hypercholesterolemia. Failure to recognize this phenomenon may lead to unnecessary and potentially harmful treatments and interventions. Funding Agencies None

scholarly journals Heme Oxygenase-1 Induction by Cobalt Protoporphyrin Ameliorates Cholestatic Liver Disease in a Xenobiotic-Induced Murine Model

2021 ◽  
Vol 22 (15) ◽  
pp. 8253
Author(s):  
Jung-Yeon Kim ◽  
Yongmin Choi ◽  
Jaechan Leem ◽  
Jeong Eun Song
Keyword(s):  
Oxidative Stress ◽  
Liver Disease ◽  
Heme Oxygenase ◽  
Murine Model ◽  
Liver Diseases ◽  
Transforming Growth Factor ◽  
Heme Oxygenase 1 ◽  
Cholestatic Liver Disease ◽  
Hepatocyte Apoptosis ◽  
Cobalt Protoporphyrin

Cholestatic liver diseases can progress to end-stage liver disease and reduce patients’ quality of life. Although their underlying mechanisms are still incompletely elucidated, oxidative stress is considered to be a key contributor to these diseases. Heme oxygenase-1 (HO-1) is a cytoprotective enzyme that displays antioxidant action. It has been found that this enzyme plays a protective role against various inflammatory diseases. However, the role of HO-1 in cholestatic liver diseases has not yet been investigated. Here, we examined whether pharmacological induction of HO-1 by cobalt protoporphyrin (CoPP) ameliorates cholestatic liver injury. To this end, a murine model of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet feeding was used. Administration of CoPP ameliorated liver damage and cholestasis with HO-1 upregulation in DDC diet-fed mice. Induction of HO-1 by CoPP suppressed the DDC diet-induced oxidative stress and hepatocyte apoptosis. In addition, CoPP attenuated cytokine production and inflammatory cell infiltration. Furthermore, deposition of the extracellular matrix and expression of fibrosis-related genes after DDC feeding were also decreased by CoPP. HO-1 induction decreased the number of myofibroblasts and inhibited the transforming growth factor-β pathway. Altogether, these data suggest that the pharmacological induction of HO-1 ameliorates cholestatic liver disease by suppressing oxidative stress, hepatocyte apoptosis, and inflammation.

Evaluation of the role of bile acids and serotonin as markers of pruritus in children with chronic cholestatic liver disease

2021 ◽  
Author(s):  
Nehal El Koofy ◽  
Noha Yassin ◽  
Sawsan Okasha ◽  
Hany William ◽  
Wafaa Elakel ◽  
...  
Keyword(s):  
Liver Disease ◽  
Bile Acids ◽  
Cholestatic Liver Disease
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