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

Aldrian, Denise; Vogel, Georg F.; Frey, Tom; Civan, Hasret Ayyıldız; Aksu, Aysel Ünlüsoy; Avitzur, Yaron; Boluda, Esther Ramos; Çakır, Murat; Demir, Arzu Meltem; Deppisch, Caroline; H-C., Duba; Düker, Gesche; Gerner, Patrick; Hertecant, Jozef; Hornová, J; Kathemann, Simone; Köeglmeier, Jutta; Koutroumpa, A; Lanzersdorfer, Roland; Lev-Tzion, Raffi; Lima, Rosa; Mansour, Sahar; Meissl, Manfred; Melek, Jan; Miqdady, Mohamad; Montoya, Jorge Hernán; Posovszky, Carsten; Rachman, Yelena; Siahanidou, Tania; Tabbers, Merit M.; Uhlig, Holm H.; Ünal, Sevim; Wirth, S; Ruemmele, Frank M; Hess, Michael W.; Huber, Lukas A.; Müller, Thomas; Sturm, Ekkehard; Janecke, Andreas R.

doi:10.3390/jcm10030481

Cited by 24 publications

(44 citation statements)

References 41 publications

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“…For EM we analyzed duodenal samples from 2 patients with functional dyspepsia (one of them shown in Figures S1a–c and S4c,f ) and liver samples from one patient with Friedreich’s ataxia (shown in respective text figures), from one patient with alpha-1 antitrypsin deficiency (not shown), and from a healthy donor liver. All three patients MYO5B mutations with were genetically described recently [ 44 ].…”

Section: Resultsmentioning

confidence: 99%

“…Patient #1 is 35-year-old Caucasian male with compound heterozygous MYO5B-mutations: c.242A>G (p.His81Arg) and c.4798C>T (Gln1600*) [ 44 ]. Parental consanguinity is not known.…”

Section: Resultsmentioning

confidence: 99%

“…Patient #2 is a 12-year-old Arab female, daughter of consanguineous parents, with homozygous MYO5B-mutations: c1669G>T (p.Val557Leu) [ 44 ]. Disease onset was reported at 11 months of age with diarrhea and cholestasis.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, the emerging field on MYO5B associated PFIC (MYO5B-PFIC) has focused on liver function and morphology of PFIC6 patients. Concerning MVID, typical intestinal symptoms were not present in several MYO5B-PFIC patients [ 39 , 42 , 44 ]. A detailed subcellular and ultrastructural characterization of the intestine in MYO5B-PFIC patients is lacking as yet.…”

Section: Introductionmentioning

confidence: 99%

“…The specific added value for ultrastructural pathology and more generally for disease-relevant immuno-histochemistry at EM-level is highlighted here by a careful study on the corresponding disease characteristics of MVID and PFIC. Thorough investigations were performed on samples from a unique disease case of a patient with MYO5B mutations, complemented by selected data from two other relevant cases (all recently described: [ 44 ]). The case documented in detail here is remarkable because the adult patient presents only episodically with symptoms of the digestive system.…”

Section: Introductionmentioning

confidence: 99%

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Advanced Microscopy for Liver and Gut Ultrastructural Pathology in Patients with MVID and PFIC Caused by MYO5B Mutations

Hess

Krainer

Filipek

et al. 2021

JCM

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Mutations in the actin motor protein myosinVb (myo5b) cause aberrant apical cargo transport and the congenital enteropathy microvillus inclusion disease (MVID). Recently, missense mutations in myo5b were also associated with progressive familial intrahepatic cholestasis (MYO5B-PFIC). Here, we thoroughly characterized the ultrastructural and immuno-cytochemical phenotype of hepatocytes and duodenal enterocytes from a unique case of an adult MYO5B-PFIC patient who showed constant hepatopathy but only periodic enteric symptoms. Selected data from two other patients supported the findings. Advanced methods such as cryo-fixation, freeze-substitution, immuno-gold labeling, electron tomography and immuno-fluorescence microscopy complemented the standard procedures. Liver biopsies showed mislocalization of Rab11 and bile canalicular membrane proteins. Rab11-positive vesicles clustered around bile canaliculi and resembled subapical clusters of aberrant recycling endosomes in enterocytes from MVID patients. The adult patient studied in detail showed a severe, MVID-specific enterocyte phenotype, despite only a mild clinical intestinal presentation. This included mislocalization of numerous proteins essential for apical cargo transport and morphological alterations. We characterized the heterogeneous population of large catabolic organelles regarding their complex ultrastructure and differential distribution of autophagic and lysosomal marker proteins. Finally, we generated duodenal organoids/enteroids from biopsies that recapitulated all MVID hallmarks, demonstrating the potential of this disease model for personalized medicine.

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Section: Resultsmentioning

confidence: 99%

“…Patient #1 is 35-year-old Caucasian male with compound heterozygous MYO5B-mutations: c.242A>G (p.His81Arg) and c.4798C>T (Gln1600*) [ 44 ]. Parental consanguinity is not known.…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Advanced Microscopy for Liver and Gut Ultrastructural Pathology in Patients with MVID and PFIC Caused by MYO5B Mutations

Hess

Krainer

Filipek

et al. 2021

JCM

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Cholestatic liver diseases of genetic etiology: Advances and controversies

et al. 2022

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With the application of modern investigative technologies, cholestatic liver diseases of genetic etiology are increasingly identified as the root cause of previously designated “idiopathic” adult and pediatric liver diseases. Here, we review advances in the field enhanced by a deeper understanding of the phenotypes associated with specific gene defects that lead to cholestatic liver diseases. There are evolving areas for clinicians in the current era specifically regarding the role for biopsy and opportunities for a “sequencing first” approach. Risk stratification based on the severity of the genetic defect holds promise to guide the decision to pursue primary liver transplantation versus medical therapy or nontransplant surgery, as well as early screening for HCC. In the present era, the expanding toolbox of recently approved therapies for hepatologists has real potential to help many of our patients with genetic causes of cholestasis. In addition, there are promising agents under study in the pipeline. Relevant to the current era, there are still gaps in knowledge of causation and pathogenesis and lack of fully accepted biomarkers of disease progression and pruritus. We discuss strategies to overcome the challenges of genotype–phenotype correlation and draw attention to the extrahepatic manifestations of these diseases. Finally, with attention to identifying causes and treatments of genetic cholestatic disorders, we anticipate a vibrant future of this dynamic field which builds upon current and future therapies, real‐world evaluations of individual and combined therapeutics, and the potential incorporation of effective gene editing and gene additive technologies.

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The genetics of monogenic intestinal epithelial disorders

2022

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Monogenic intestinal epithelial disorders, also known as congenital diarrheas and enteropathies (CoDEs), are a group of rare diseases that result from mutations in genes that primarily affect intestinal epithelial cell function. Patients with CoDE disorders generally present with infantile-onset diarrhea and poor growth, and often require intensive fluid and nutritional management. CoDE disorders can be classified into several categories that relate to broad areas of epithelial function, structure, and development. The advent of accessible and low-cost genetic sequencing has accelerated discovery in the field with over 45 different genes now associated with CoDE disorders. Despite this increasing knowledge in the causal genetics of disease, the underlying cellular pathophysiology remains incompletely understood for many disorders. Consequently, clinical management options for CoDE disorders are currently limited and there is an urgent need for new and disorder-specific therapies. In this review, we provide a general overview of CoDE disorders, including a historical perspective of the field and relationship to other monogenic disorders of the intestine. We describe the genetics, clinical presentation, and known pathophysiology for specific disorders. Lastly, we describe the major challenges relating to CoDE disorders, briefly outline key areas that need further study, and provide a perspective on the future genetic and therapeutic landscape.

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

Cited by 24 publications

References 41 publications

Advanced Microscopy for Liver and Gut Ultrastructural Pathology in Patients with MVID and PFIC Caused by MYO5B Mutations

Advanced Microscopy for Liver and Gut Ultrastructural Pathology in Patients with MVID and PFIC Caused by MYO5B Mutations

Cholestatic liver diseases of genetic etiology: Advances and controversies

The genetics of monogenic intestinal epithelial disorders

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