Distinct disease phenotypes linked to different combinations of GAA mutations in a large late-onset GSDII sibship

Familial hypertrophic cardiomyopathy (HCM) is the leading cause of sudden cardiac death in the young, and is the most common inherited heart defect affecting 1 in 500 individuals worldwide. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have been demonstrated to model aspects of HCM, but only one iPSC model has been reported for a single HCM mutation in one gene. Here we compare disease phenotypes across a library of patient-specific HCM iPSC-CMs carrying distinct mutations to assess the range of phenotypes that may present in iPSC-CMs derived from different patient cohorts. iPSCs were generated from three patient cohorts carrying known hereditary mutations for HCM in TNNI3, TNNT2, and MYH7 and family-matched controls. Disease phenotypes in patient-specific iPSC-CMs were modeled using immunostaining, Ca2+ imaging, multielectrode array, and video analysis of contractile motion. HCM iPSC-CMs displayed a range of disease phenotypes as assessed by cell size, Ca2+ homeostasis, electrophysiology, and contractile arrhythmia. Different HCM mutations resulted in distinct disease phenotype presentation. Importantly, identical mutations demonstrated similar readouts across multiple lines and clones whereas distinct mutations exhibited differential disease phenotypes. These findings indicate disease-specific iPSC-CMs present with a range of phenotypes for HCM that vary by specific mutation and that iPSC libraries are important for cellular characterization of diseases such as HCM. Figure 1. Derivation and disease phenotype modeling of iPSC-CMs generated from patients carrying distinct familial HCM mutations and family-matched controls.

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Analysis of disease-causing GATA1 mutations in murine gene complementation systems

Blood ◽

10.1182/blood-2013-03-488080 ◽

2013 ◽

Vol 121 (26) ◽

pp. 5218-5227 ◽

Cited By ~ 28

Author(s):

Amy E. Campbell ◽

Lorna Wilkinson-White ◽

Joel P. Mackay ◽

Jacqueline M. Matthews ◽

Gerd A. Blobel

Keyword(s):

Gene Complementation ◽

Disease Phenotypes ◽

Key Points ◽

Distinct Disease

Key Points Disease-causing mutations in GATA1 impair binding to the cofactors FOG1 or TAL1 but not DNA. Different substitutions at the same residue selectively disrupt FOG1 or TAL1 binding leading to distinct disease phenotypes.

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Glutamatergic and GABAergic neurons mediate distinct neurodevelopmental phenotypes of STXBP1 encephalopathy

10.1101/2021.07.13.452234 ◽

2021 ◽

Author(s):

Joo Hyun Kim ◽

Wu Chen ◽

Eugene S Chao ◽

Hongmei Chen ◽

Mingshan Xue

Keyword(s):

Broad Spectrum ◽

Neurotransmitter Release ◽

Gabaergic Neurons ◽

Disease Mechanism ◽

Gabaergic Neurotransmission ◽

Epileptic Encephalopathies ◽

Disease Phenotypes ◽

Pathogenic Variants ◽

Distinct Disease ◽

Inhibitory Signaling

Heterozygous pathogenic variants in syntaxin-binding protein 1 (STXBP1, also known as MUNC18-1) cause STXBP1 encephalopathy and are among the most frequent causes of developmental and epileptic encephalopathies and intellectual disabilities. STXBP1 is an essential protein for presynaptic neurotransmitter release, and its haploinsufficiency impairs glutamatergic and GABAergic neurotransmission. However, the mechanism underlying the broad spectrum of neurological phenotypes is poorly understood. Here we show that glutamatergic and GABAergic neurons mediate distinct disease features with few overlaps. Glutamatergic and GABAergic neurons-specific Stxbp1 haploinsufficient mice exhibit different subsets of the cognitive and seizure phenotypes observed in the constitutive Stxbp1 haploinsufficient mice. Developmental delay and most of the motor and psychiatric phenotypes are only recapitulated by GABAergic Stxbp1 haploinsufficiency. Thus, the contrasting roles of excitatory and inhibitory signaling in STXBP1 encephalopathy identify GABAergic dysfunction as a main disease mechanism and reveal the possibility to selectively modulate disease phenotypes by targeting specific neurotransmitter systems.

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Features of late-onset systemic lupus erythematosus

Romanian Journal of Rheumatology ◽

10.37897/rjr.2021.3.6 ◽

2021 ◽

Vol 30 (3) ◽

pp. 121-124

Author(s):

Alexandra Constantinescu ◽

◽

Claudia Cobilinschi ◽

Elena Gradinaru ◽

Ioana Saulescu ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Late Onset ◽

Systemic Lupus ◽

Diagnostic Challenge ◽

Disease Subtype ◽

Distinct Disease ◽

Physician Awareness ◽

Chronic Autoimmune Disease ◽

Onset Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease, characterized by multiorgan involvement, most commonly targeting the skin, joints and kidneys. Late-onset disease occurs in patients over the age of 50 and represents a diagnostic challenge, as it is less frequently encountered and it may exhibit a more unusual clinical and paraclinical picture. The aim of this paper is to highlight two cases of SLE diagnosed in female patients of considerably advanced ages, 81 and 72 years respectively, in order to enhance physician awareness with regard to this distinct disease subtype.

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Genetic and epigenetic study of an Alzheimer’s disease family with monozygotic triplets

Brain ◽

10.1093/brain/awz289 ◽

2019 ◽

Vol 142 (11) ◽

pp. 3375-3381 ◽

Cited By ~ 1

Author(s):

Ming Zhang ◽

Allison A Dilliott ◽

Roaa Khallaf ◽

John F Robinson ◽

Robert A Hegele ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Early Onset ◽

Late Onset ◽

Accelerated Ageing ◽

Disease Phenotypes ◽

Apoe Ε4 ◽

Ε4 Allele ◽

Disease Family

Zhang, Dilliott et al. examine a unique family with early- and late-onset Alzheimer’s disease phenotypes, as well as disease-discordant monozygotic triplets. The triplets and the patient with early-onset disease are carriers of the APOE ε4-allele plus rare substitutions in other genes. Epigenetic analyses suggest accelerated ageing in the early-onset patient.

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Behçet: the syndrome

Rheumatology ◽

10.1093/rheumatology/kez626 ◽

2020 ◽

Vol 59 (Supplement_3) ◽

pp. iii101-iii107 ◽

Cited By ~ 1

Author(s):

Alessandra Bettiol ◽

Domenico Prisco ◽

Giacomo Emmi

Keyword(s):

Systemic Vasculitis ◽

Current Evidence ◽

Patient Specific ◽

Behçet’S Syndrome ◽

Behçet's Syndrome ◽

Disease Phenotypes ◽

Genetic Features ◽

Distinct Disease ◽

Behcet’S Syndrome ◽

Behcet's Syndrome

Abstract Behçet’s syndrome (BS) is a systemic vasculitis characterized by a relapsing and remitting course. It can involve the skin, mucosa, joints, vessels (arteries and/or veins), eyes, and nervous and gastrointestinal systems, and so is referred to as a syndrome rather than as a unique and nosologically distinct condition. These involvements may present alone or co-exist in the same patient. Although all the possible combinations of the above-mentioned manifestations may occur, clusters of commonly co-existing involvements (also referred to as ‘disease phenotypes’) have been suggested, namely ‘mucocutaneous and articular’, ‘peripheral vascular and extra-parenchymal neurological’ and ‘parenchymal neurological and ocular’ phenotypes have been described. Patient-specific demographic and genetic features have been described as positively or negatively associated with specific disease phenotypes. This review will focus on the different clinical features of Behçet’s syndrome, summarizing current evidence on the distinct disease manifestations as well as the major phenotypes.

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Resolving phenotypic and prognostic differences in interstitial lung disease related to systemic sclerosis by computed tomography-based radiomics

10.1101/2020.06.09.20124800 ◽

2020 ◽

Author(s):

J. Schniering ◽

M. Maciukiewicz ◽

H. S. Gabrys ◽

M. Brunner ◽

C. Blüthgen ◽

...

Keyword(s):

Computed Tomography ◽

Systemic Sclerosis ◽

Interstitial Lung Disease ◽

Lung Disease ◽

Progression Free Survival ◽

Autoimmune Disorder ◽

Free Survival ◽

Disease Phenotypes ◽

Computed Tomography Scans ◽

Distinct Disease

AbstractRadiomic features are quantitative data calculated from routine medical images and have shown great potential for disease phenotyping and risk stratification in cancer. Patients with systemic sclerosis (SSc), a multi-organ autoimmune disorder, have a similarly poor prognosis (10-year survival of 66%), due to interstitial lung disease (ILD) as the primary cause of death. Here, we present the analysis of 1,355 stable radiomic features extracted from computed tomography scans from 156 SSc-ILD patients, which describe distinct disease phenotypes and show prognostic power in two independent cohorts. We derive and externally validate a first quantitative radiomic risk score, qRISSc that accurately predicts progression-free survival in SSc-ILD and outperforms current clinical stratification measures. Correlation analysis with lung proteomics, histology and gene expression data in a cross-species approach demonstrates that qRISSc reverse translates into mice and captures the fibrotic remodeling process in experimental ILD.

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Selective cleavage of nucleolar autoantigen B23 by granzyme B in differentiated vascular smooth muscle cells: Insights into the association of specific autoantibodies with distinct disease phenotypes

Arthritis & Rheumatism ◽

10.1002/art.11485 ◽

2004 ◽

Vol 50 (1) ◽

pp. 233-241 ◽

Cited By ~ 26

Author(s):

Danielle B. Ulanet ◽

Nicholas A. Flavahan ◽

Livia Casciola-Rosen ◽

Antony Rosen

Keyword(s):

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Smooth Muscle Cells ◽

Vascular Smooth Muscle Cells ◽

Granzyme B ◽

Muscle Cells ◽

Disease Phenotypes ◽

Distinct Disease

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The Role of the U5 snRNP in Genetic Disorders and Cancer

Frontiers in Genetics ◽

10.3389/fgene.2021.636620 ◽

2021 ◽

Vol 12 ◽

Author(s):

Katherine A. Wood ◽

Megan A. Eadsforth ◽

William G. Newman ◽

Raymond T. O’Keefe

Keyword(s):

Genetic Variants ◽

Genetic Disorders ◽

Mrna Splicing ◽

Splicing Factors ◽

Macromolecular Complex ◽

Disease Phenotypes ◽

Ribonucleoprotein Complexes ◽

Genes Encoding ◽

Distinct Disease ◽

Human Disorders

Pre-mRNA splicing is performed by the spliceosome, a dynamic macromolecular complex consisting of five small uridine-rich ribonucleoprotein complexes (the U1, U2, U4, U5, and U6 snRNPs) and numerous auxiliary splicing factors. A plethora of human disorders are caused by genetic variants affecting the function and/or expression of splicing factors, including the core snRNP proteins. Variants in the genes encoding proteins of the U5 snRNP cause two distinct and tissue-specific human disease phenotypes – variants in PRPF6, PRPF8, and SNRP200 are associated with retinitis pigmentosa (RP), while variants in EFTUD2 and TXNL4A cause the craniofacial disorders mandibulofacial dysostosis Guion-Almeida type (MFDGA) and Burn-McKeown syndrome (BMKS), respectively. Furthermore, recurrent somatic mutations or changes in the expression levels of a number of U5 snRNP proteins (PRPF6, PRPF8, EFTUD2, DDX23, and SNRNP40) have been associated with human cancers. How and why variants in ubiquitously expressed spliceosome proteins required for pre-mRNA splicing in all human cells result in tissue-restricted disease phenotypes is not clear. Additionally, why variants in different, yet interacting, proteins making up the same core spliceosome snRNP result in completely distinct disease outcomes – RP, craniofacial defects or cancer – is unclear. In this review, we define the roles of different U5 snRNP proteins in RP, craniofacial disorders and cancer, including how disease-associated genetic variants affect pre-mRNA splicing and the proposed disease mechanisms. We then propose potential hypotheses for how U5 snRNP variants cause tissue specificity resulting in the restricted and distinct human disorders.

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