A pathogenic deletion in Forkhead Box L1 (FOXL1) identifies the first otosclerosis (OTSC) gene

AbstractOtosclerosis is a bone disorder of the otic capsule and common form of late-onset hearing impairment. Considered a complex disease, little is known about its pathogenesis. Over the past 20 years, ten autosomal dominant loci (OTSC1-10) have been mapped but no genes identified. Herein, we map a new OTSC locus to a 9.96 Mb region within the FOX gene cluster on 16q24.1 and identify a 15 bp coding deletion in Forkhead Box L1 co-segregating with otosclerosis in a Caucasian family. Pre-operative phenotype ranges from moderate to severe hearing loss to profound sensorineural loss requiring a cochlear implant. Mutant FOXL1 is both transcribed and translated and correctly locates to the cell nucleus. However, the deletion of 5 residues in the C-terminus of mutant FOXL1 causes a complete loss of transcriptional activity due to loss of secondary (alpha helix) structure. FOXL1 (rs764026385) was identified in a second unrelated case on a shared background. We conclude that FOXL1 (rs764026385) is pathogenic and causes autosomal dominant otosclerosis and propose a key inhibitory role for wildtype Foxl1 in bone remodelling in the otic capsule. New insights into the molecular pathology of otosclerosis from this study provide molecular targets for non-invasive therapeutic interventions.

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A Pathogenic Deletion in Forkhead Box L1 (FOXL1) Identifies the First Otosclerosis (OTSC) Gene

10.21203/rs.3.rs-539887/v1 ◽

2021 ◽

Author(s):

Nelly Abdelfatah ◽

Ahmed A. Mostafa ◽

Curtis R. French ◽

Lance P. Doucette ◽

Cindy Penney ◽

...

Keyword(s):

Complex Disease ◽

Autosomal Dominant ◽

Late Onset ◽

Alpha Helix ◽

Therapeutic Interventions ◽

Otic Capsule ◽

Non Invasive ◽

Forkhead Box ◽

C Terminus ◽

Caucasian Family

Abstract Otosclerosis is a bone disorder of the otic capsule and common form of late-onset hearing impairment. Considered a complex disease, little is known about its pathogenesis. Over the past 20 years, ten autosomal dominant loci (OTSC1-10) have been mapped but no genes identified. Herein, we map a new OTSC locus to a 9.96 Mb region within the FOX gene cluster on 16q24.1 and identify a 15 bp coding deletion in Forkhead Box L1 co-segregating with otosclerosis in a Caucasian family. Phenotype ranges from moderate to severe hearing loss resolved by stapedectomy, to profound sensorineural loss requiring a cochlear implant. Mutant FOXL1 is both transcribed and translated and correctly locates to the cell nucleus. However, the deletion of 5 residues in the C-terminus of mutant FOXL1 causes a complete loss of transcriptional activity due to loss of secondary (alpha helix) structure. FOXL1 (rs764026385) was identified in a second unrelated case on a shared background. We conclude that FOXL1 (rs764026385) is pathogenic and causes autosomal dominant otosclerosis and propose a key inhibitory role for wildtype Foxl1 in bone remodelling in the otic capsule. New insights into the molecular pathology of otosclerosis from this study provide molecular targets for non-invasive therapeutic interventions.

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Late onset autosomal dominant hypophosphatemic rickets; confirmation of the diagnosis with genomic analysis

Bone Abstracts ◽

10.1530/boneabs.1.pp5 ◽

2013 ◽

Author(s):

Symeon Tournis ◽

Ioannis Stathopoulos ◽

Kalliopi Lampropoulou-Adamidou ◽

Theodora Koromila ◽

Nikolaos Chatzistamatas ◽

...

Keyword(s):

Autosomal Dominant ◽

Late Onset ◽

Genomic Analysis ◽

Hypophosphatemic Rickets ◽

Autosomal Dominant Hypophosphatemic Rickets

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The role of microRNAs in gliomas – Therapeutic implications

Current Molecular Pharmacology ◽

10.2174/1874467213666200730115837 ◽

2020 ◽

Vol 13 ◽

Author(s):

Theodora Katsila ◽

Dimitrios Kardamakis

Keyword(s):

Complex Disease ◽

Malignant Gliomas ◽

Kappa Statistic ◽

Individual Variability ◽

Response To Treatment ◽

Disease Phenotype ◽

Therapeutic Implications ◽

Non Invasive ◽

Gene Environment ◽

Sas Macro

Background: Malignant gliomas constitute a complex disease phenotype that demands optimum decisionmaking. Despite being the most common type of primary brain tumors, gliomas are highly heterogeneous when their pathophysiology and response to treatment are considered. Such inter-individual variability also renders differential and early diagnosis extremely difficult. Recent evidence highlight that the gene-environment interplay becomes of fundamental importance in oncogenesis and progression of gliomas. Objective: To unmask key features of the gliomas disease phenotype and map the inter-individual variability of patients, we explore genotype-to-phenotype associations. Emphasis is put on microRNAs as they regulate gene expression, have been implicated in the pathogenesis of gliomas and may serve as theranostics, empowering non-invasive strategies (circulating free or in exosomes). Method: We mined text and omic datasets (as of 2019) and conducted a mixed-method content analysis. A novel framework was developed to meet the aims of our analysis, interrogating data in terms of content and context. We relied on literature data from PubMed/Medline and Scopus, as they are considered the largest abstract and citation databases of peer-reviewed literature. To avoid selection biases, both publicly available and private texts have been assessed. Both percent agreement and Cohen's kappa statistic have been calculated to avoid biases by SAS macro MAGREE with multicategorical ratings. Results: Gliomas serve as a paradigm for multifaceted datasets, despite data sparsity and scarcity. miRNAs and miRNAbased therapeutics are ready for prime time. Exosomal miRNAs empower non-invasive strategies, surpassing circulating free miRNAs, when accuracy and precision are considered. Conclusion: miRNAs holds promise as theranostics.

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Tau and TDP-43 synergy: a novel therapeutic target for sporadic late-onset Alzheimer’s disease

GeroScience ◽

10.1007/s11357-021-00407-0 ◽

2021 ◽

Author(s):

Caitlin S. Latimer ◽

Nicole F. Liachko

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Late Onset ◽

Hippocampal Sclerosis ◽

Model Organism ◽

Amyloid Β ◽

Underlying Disease ◽

Therapeutic Interventions ◽

Disease Biology ◽

Rapid Cognitive Decline

AbstractAlzheimer’s disease (AD) is traditionally defined by the presence of two types of protein aggregates in the brain: amyloid plaques comprised of the protein amyloid-β (Aβ) and neurofibrillary tangles containing the protein tau. However, a large proportion (up to 57%) of AD patients also have TDP-43 aggregates present as an additional comorbid pathology. The presence of TDP-43 aggregates in AD correlates with hippocampal sclerosis, worse brain atrophy, more severe cognitive impairment, and more rapid cognitive decline. In patients with mixed Aβ, tau, and TDP-43 pathology, TDP-43 may interact with neurodegenerative processes in AD, worsening outcomes. While considerable progress has been made to characterize TDP-43 pathology in AD and late-onset dementia, there remains a critical need for mechanistic studies to understand underlying disease biology and develop therapeutic interventions. This perspectives article reviews the current understanding of these processes from autopsy cohort studies and model organism-based research, and proposes targeting neurotoxic synergies between tau and TDP-43 as a new therapeutic strategy for AD with comorbid TDP-43 pathology.

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Non-Invasive Biomarkers for Earlier Detection of Pancreatic Cancer—A Comprehensive Review

Cancers ◽

10.3390/cancers13112722 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2722

Author(s):

Greta Brezgyte ◽

Vinay Shah ◽

Daria Jach ◽

Tatjana Crnogorac-Jurcevic

Keyword(s):

Clinical Setting ◽

Selection Index ◽

Reporting Quality ◽

Standard Of Care ◽

Therapeutic Interventions ◽

Ductal Adenocarcinoma ◽

Index Test ◽

Delayed Presentation ◽

Non Invasive ◽

Study Selection

Pancreatic ductal adenocarcinoma (PDAC) carries a deadly diagnosis, due in large part to delayed presentation when the disease is already at an advanced stage. CA19-9 is currently the most commonly utilized biomarker for PDAC; however, it lacks the necessary accuracy to detect precursor lesions or stage I PDAC. Novel biomarkers that could detect this malignancy with improved sensitivity (SN) and specificity (SP) would likely result in more curative resections and more effective therapeutic interventions, changing thus the present dismal survival figures. The aim of this study was to systematically and comprehensively review the scientific literature on non-invasive biomarkers in biofluids such as blood, urine and saliva that were attempting earlier PDAC detection. The search performed covered a period of 10 years (January 2010—August 2020). Data were extracted using keywords search in the three databases: MEDLINE, Web of Science and Embase. The Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool was applied for study selection based on establishing the risk of bias and applicability concerns in Patient Selection, Index test (biomarker assay) and Reference Standard (standard-of-care diagnostic test). Out of initially over 4000 published reports, 49 relevant studies were selected and reviewed in more detail. In addition, we discuss the present challenges and complexities in the path of translating the discovered biomarkers into the clinical setting. Our systematic review highlighted several promising biomarkers that could, either alone or in combination with CA19-9, potentially improve earlier detection of PDAC. Overall, reviewed biomarker studies should aim to improve methodological and reporting quality, and novel candidate biomarkers should be investigated further in order to demonstrate their clinical usefulness. However, challenges and complexities in the path of translating the discovered biomarkers from the research laboratory to the clinical setting remain and would have to be addressed before a more realistic breakthrough in earlier detection of PDAC is achieved.

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An Adult Mouse Model of Dilated Cardiomyopathy Caused by Inducible Cardiac-Specific Bis Deletion

International Journal of Molecular Sciences ◽

10.3390/ijms22031343 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1343

Author(s):

Hye Hyeon Yun ◽

Soon Young Jung ◽

Bong Woo Park ◽

Ji Seung Ko ◽

Kyunghyun Yoo ◽

...

Keyword(s):

Heart Failure ◽

Dilated Cardiomyopathy ◽

Late Onset ◽

Small Heat Shock Protein ◽

Left Ventricular ◽

Therapeutic Interventions ◽

Ventricular Contractility ◽

Knock Out ◽

Multifunctional Protein ◽

Cell Death Suppressor

BCL-2 interacting cell death suppressor (BIS) is a multifunctional protein that has been implicated in cancer and myopathy. Various mutations of the BIS gene have been identified as causative of cardiac dysfunction in some dilated cardiomyopathy (DCM) patients. This was recently verified in cardiac-specific knock-out (KO) mice. In this study, we developed tamoxifen-inducible cardiomyocyte-specific BIS-KO (Bis-iCKO) mice to assess the role of BIS in the adult heart using the Cre-loxP strategy. The disruption of the Bis gene led to impaired ventricular function and subsequent heart failure due to DCM, characterized by reduced left ventricular contractility and dilatation that were observed using serial echocardiography and histology. The development of DCM was confirmed by alterations in Z-disk integrity and increased expression of several mRNAs associated with heart failure and remodeling. Furthermore, aggregation of desmin was correlated with loss of small heat shock protein in the Bis-iCKO mice, indicating that BIS plays an essential role in the quality control of cardiac proteins, as has been suggested in constitutive cardiac-specific KO mice. Our cardiac-specific BIS-KO mice may be a useful model for developing therapeutic interventions for DCM, especially late-onset DCM, based on the distinct phenotypes and rapid progressions.

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P–331 The #Enzian classification: A comprehensive non-invasive and surgical description system for endometriosis

Human Reproduction ◽

10.1093/humrep/deab130.330 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

J Keckstein ◽

H Gernot

Keyword(s):

Classification System ◽

Working Group ◽

Complex Disease ◽

Diagnostic Methods ◽

Anatomical Location ◽

Ovarian Endometriosis ◽

Deep Endometriosis ◽

Non Invasive ◽

Complete Mapping

Abstract Study question Is there a classification for a complete mapping of endometriosis, including anatomical location, size of the lesions, and degree of involvement that can be used with both, diagnostics and surgery? Summary answer #Enzian classification improves in both, non-invasive diagnostic methods and surgical therapy for endometriosis as a universally usable classification system for all aspects of the disease. What is known already The most commonly used r-ASRM classification has certain limitations due to its incomplete description of DE, the complexity of the classification, and lack of reproducibility. In contrast, the Enzian classification, which has been implemented in the last decade, has proved to be the most suitable for the description of DE. However, since it does not include peritoneal and ovarian lesions and lacks a description of tubo-ovarian adhesions, it has not gained full acceptance. A combination of classification with different systems such as r-ASRM, EFI score and Enzian, may complicate classification of the disease due to overlaps and time-consuming documentation. Study design, size, duration The result is a consensus of a panel of renowned clinicians (working group), gynaecological surgeons and sonographers with extensive expertise in diagnosis and therapy of endometriosis. A first draft was written in 2019 by a joint effort of the first and last author and sent to all working group members. Taking all comments into account, a revised draft was then sent to all coauthors and repeated until a consensus was reached (9 revisions). Participants/materials, setting, methods Criteria used to invite the experts to participate in this consensus process included their having significant peer-reviewed publications in the field of diagnosis and management of endometriosis. Main results and the role of chance Our current proposal is the first of its kind to universally describe superficial and deep endometriosis, ovarian endometriosis, adenomyosis and adhesions by using a classification system that can be applied by gynaecologists, surgeons, sonographers and radiologists following the same principles. The correlation between preoperative and surgical staging, on the basis of the Enzian scheme, allows for consistent and clear classification of endometriosis, especially DE. Endometriosis can be mapped completely with one single classification system enabling the use of one common language. Limitations, reasons for caution This classification system is anatomically logical and should be easy to use. Further studies are ongoing and are needed to provide proof for the applicability, reproducibility and accuracy of the #Enzian classification for the description of endometriosis. Wider implications of the findings: #Enzian classification now enabled better coverage of various endometriosis localizations. The possibility of using this system preoperatively as well as postoperatively within the framework of diagnostics offers clinicians a significant improvement in the care of patients with such a complex disease. Trial registration number Not applicable

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