scholarly journals Identification of a Rare Exon 19 Skipping Mutation in ALMS1 Gene in Alström Syndrome Patients From Two Unrelated Saudi Families

2021 ◽  
Vol 9 ◽  
Author(s):  
Omar I. Saadah ◽  
Babajan Banaganapalli ◽  
Naglaa M. Kamal ◽  
Ahmed N. Sahly ◽  
Hadeel A. Alsufyani ◽  
...  
Keyword(s):  
Healthy Population ◽  
Alström Syndrome ◽  
Whole Exome ◽  
Clinical Presentations ◽  
Pattern Stability ◽  
Alstrom Syndrome ◽  
Disease Variant ◽  
And Function ◽  
Clinical Phenotyping ◽  
Exon 19

Background: Alström syndrome (AS) is a very rare childhood disorder characterized by cardiomyopathy, progressive hearing loss and blindness. Inherited genetic variants of ALMS1 gene are the known molecular cause of this disease. The objective of this study was to characterize the genetic basis and understand the genotype–phenotype relationship in Saudi AS patients.Methods: Clinical phenotyping and whole-exome sequencing (WES) analysis were performed on six AS patients belonging to two unrelated consanguineous Saudi families. Sanger sequencing was performed to determine the mode of inheritance of ALMS1 variant in first-degree family relatives and also to ensure its rare prevalence in 100 healthy population controls.Results: We identified that Alström patients from both the families were sharing a very rare ALMS1, 3′-splice site acceptor (c.11873−2 A>T) variant, which skips entire exon-19 and shortens the protein by 80 amino acids. This disease variant was inherited by AS patients in autosomal recessive mode and is not yet reported in any population-specific genetic databases. AS patients carrying this mutation showed heterogeneity in clinical presentations. Computational analysis of the mutant centroid structure of ALMS1 mRNA revealed that exon-19 skipping enlarges the hairpin loop and decreases the free energy, eventually affecting its folding pattern, stability, and function. Hence, we propose c.11873–2A as an AS causative potential founder mutation in Saudi Arabia because it is found in two families lacking a common lineage.Conclusions: We conclude that WES analysis potentially helps in clinical phenotyping, early diagnosis, and better clinical management of Alström patients showing variable clinical expressivity.

scholarly journals Whole exome sequencing identifies rare biallelic ALMS1 missense and stop gain mutations in familial Alström syndrome patients

2020 ◽  
Vol 27 (1) ◽  
pp. 271-278 ◽  
Author(s):  
Naglaa M. Kamal ◽  
Ahmed N. Sahly ◽  
Babajan Banaganapalli ◽  
Omran M. Rashidi ◽  
Preetha J. Shetty ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Alström Syndrome ◽  
Whole Exome ◽  
Alstrom Syndrome

Whole exome sequencing identified two homozygous ALMS1 mutations in an Iranian family with Alström syndrome

Gene ◽  
2020 ◽  
Vol 727 ◽  
pp. 144228 ◽  
Author(s):  
Shahram Torkamandi ◽  
Somaye Rezaei ◽  
Reza Mirfakhraei ◽  
Masomeh Askari ◽  
Samira Piltan ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Alström Syndrome ◽  
Whole Exome ◽  
Iranian Family ◽  
Alstrom Syndrome

scholarly journals Recessive ciliopathy mutations in primary endocardial fibroelastosis: a rare neonatal cardiomyopathy in a case of Alstrom syndrome

2021 ◽  
Author(s):  
Yan Zhao ◽  
Lee-kai Wang ◽  
Ascia Eskin ◽  
Xuedong Kang ◽  
Viviana M. Fajardo ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genomic Analysis ◽  
Genetic Contribution ◽  
Endocardial Fibroelastosis ◽  
Rna Seq ◽  
Live Births ◽  
Alström Syndrome ◽  
Whole Exome ◽  
Alstrom Syndrome

Abstract Among neonatal cardiomyopathies, primary endocardial fibroelastosis (pEFE) remains a mysterious disease of the endomyocardium that is poorly genetically characterized, affecting 1/5000 live births and accounting for 25% of the entire pediatric dilated cardiomyopathy (DCM) with a devastating course and grave prognosis. To investigate the potential genetic contribution to pEFE, we performed integrative genomic analysis, using whole exome sequencing (WES) and RNA-seq in a female infant with confirmed pathological diagnosis of pEFE. Within regions of homozygosity in the proband genome, WES analysis revealed novel parent-transmitted homozygous mutations affecting three genes with known roles in cilia assembly or function. Among them, a novel homozygous variant [c.1943delA] of uncertain significance in ALMS1 was prioritized for functional genomic and mechanistic analysis. Loss of function mutations of ALMS1 have been implicated in Alstrom syndrome (AS) [OMIM 203800], a rare recessive ciliopathy that has been associated with cardiomyopathy. The variant of interest results in a frameshift introducing a premature stop codon. RNA-seq of the proband’s dermal fibroblasts confirmed the impact of the novel ALMS1 variant on RNA-seq reads and revealed dysregulated cellular signaling and function, including the induction of epithelial mesenchymal transition (EMT) and activation of TGFβ signaling. ALMS1 loss enhanced cellular migration in patient fibroblasts as well as neonatal cardiac fibroblasts, while ALMS1-depleted cardiomyocytes exhibited enhanced proliferation activity. Herein, we present the unique pathological features of pEFE compared to DCM and utilize integrated genomic analysis to elucidate the molecular impact of a novel mutation in ALMS1 gene in an AS case. Our report provides insights into pEFE etiology and suggests, for the first time to our knowledge, ciliopathy as a potential underlying mechanism for this poorly understood and incurable form of neonatal cardiomyopathy. Key message Primary endocardial fibroelastosis (pEFE) is a rare form of neonatal cardiomyopathy that occurs in 1/5000 live births with significant consequences but unknown etiology. Integrated genomics analysis (whole exome sequencing and RNA sequencing) elucidates novel genetic contribution to pEFE etiology. In this case, the cardiac manifestation in Alstrom syndrome is pEFE. To our knowledge, this report provides the first evidence linking ciliopathy to pEFE etiology. Infants with pEFE should be examined for syndromic features of Alstrom syndrome. Our findings lead to a better understanding of the molecular mechanisms of pEFE, paving the way to potential diagnostic and therapeutic applications.

Abstract MP212: Integrated Genomics Analysis Identifies Recessive Ciliopathy Mutations In Primary Endocardial Fibroelastosis: A Rare Neonatal Cardiomyopathy

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Zubin Mehta ◽  
Yan Zhao ◽  
Kang Xuedong ◽  
Juan C Alejos ◽  
Nancy Halnon ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Dermal Fibroblasts ◽  
Neonatal Rat ◽  
Endocardial Fibroelastosis ◽  
Rna Seq ◽  
Mesenchymal Transition ◽  
Alström Syndrome ◽  
Whole Exome ◽  
Alstrom Syndrome

Background: Among neonatal cardiomyopathies, primary endocardial fibroelastosis (pEFE) remains a mysterious disease of the endomyocardium, affecting 1/5000 live births and accounting for 25% of the entire pediatric dilated cardiomyopathy (DCM) population with a devastating course and grave prognosis. Objective: We aimed to investigate potential genetic contributions to pEFE etiology. Methods: We performed integrative genomic analysis in 8 infants with confirmed pathological diagnosis of pEFE using whole exome sequencing (WES), RNA-seq and functional genomics studies. Patient-derived fibroblasts, neonatal rat ventricular myocytes and neonatal rat cardiac fibroblasts were used for cellular assays. Real-time cell migration and proliferation analyses were performed using xCELLigence technology. Results: Whole exome sequencing detected novel and deleterious de novo single nucleotide variants, or inherited homozygous rare variants in 11 cilia-related genes in seven out of the eight affected probands. In particular, a novel homozygous variant [c.1938delA] in ALMS1 was identified in a female proband, pEFE4. This variant resulted in a frameshift introducing a premature stop codon and complete absence of the ALMS1 protein in the proband fibroblasts and explanted heart. Loss of function mutations of ALMS1 have been implicated in Alstrom syndrome [OMIM 203800], a rare recessive ciliopathy. RNA-sequencing of the proband’s dermal fibroblasts revealed significantly dysregulated cellular signaling and function, including the induction of epithelial mesenchymal transition (EMT), potentially mediated by TGFβ signaling activation. The proband fibroblasts exhibited enhanced migration activity. Herein, we present the unique pathological features of pEFE compared to DCM and utilize integrated WES with RNA-seq analysis to elucidate the molecular mechanisms by which the novel causal ALMS1 variant contributes to the unique pathology of pEFE in a female infant with Alstrom syndrome. Conclusions: Our report provides insights into pEFE etiology and suggests, for the first time to our knowledge, ciliopathy as a potential underlying mechanism for this poorly understood and incurable form of neonatal cardiomyopathy.

Five novel ALMS1 gene mutations in six patients with Alström syndrome

2018 ◽  
Vol 31 (6) ◽  
pp. 681-687 ◽  
Author(s):  
Suna Kılınç ◽  
Didem Yücel-Yılmaz ◽  
Aylin Ardagil ◽  
Süheyla Apaydın ◽  
Diana Valverde ◽  
...  
Keyword(s):  
Early Diagnosis ◽  
Autosomal Recessive ◽  
Gene Mutations ◽  
Compound Heterozygous ◽  
Novel Mutations ◽  
Alström Syndrome ◽  
Mutational Screening ◽  
Clinical Presentations ◽  
Alstrom Syndrome ◽  
Over Time

Abstract Background: Alström syndrome is a rare autosomal recessive inherited disorder caused by mutations in the ALMS1 gene. Methods: We describe the clinical and five novel mutational screening findings in six patients with Alström syndrome from five families in a single center with distinct clinical presentations of this condition. Results: Five novel mutations in ALMS1 in exon 8 and intron 17 were identified, one of them was a compound heterozygous: c.2259_2260insT, p.Glu754*; c.2035C>T p.Arg679*; c.2259_2260insT, p.Glu754*; c.5969C>G, p.Ser1990*; c.6541C>T, p. Gln2181*/c.11666-2A>G, splicing. One patient had gallstones, this association, to our knowledge, has not been reported in Alström syndrome previously. Conclusions: Early diagnosis of Alström syndrome is often difficult in children and adolescents, because many of the clinical features develop over time. Early diagnosis can initiate an effective managemen of this condition, and it will help to reduce future damage.

Liver fibrosis is common in Alstrom syndrome and can be identified using non-invasive tests

2014 ◽  
Author(s):  
Jonathan Hazlehurst ◽  
Matthew Armstrong ◽  
Jayne Hodgkiss ◽  
Rachel Crowley ◽  
Tarekegn Geberhiwot ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Non Invasive ◽  
Alström Syndrome ◽  
Alstrom Syndrome

scholarly journals Alterations in ZnT1 expression and function lead to impaired intracellular zinc homeostasis in cancer

2019 ◽  
Vol 5 (1) ◽  
Author(s):  
Adrian Israel Lehvy ◽  
Guy Horev ◽  
Yarden Golan ◽  
Fabian Glaser ◽  
Yael Shammai ◽  
...  
Keyword(s):  
Malignant Tumors ◽  
Zinc Homeostasis ◽  
Healthy Population ◽  
Missense Mutations ◽  
Protein Alignment ◽  
Loss Of Function ◽  
Intracellular Zinc ◽  
Dismal Prognosis ◽  
Zinc Levels ◽  
And Function

Abstract Zinc is vital for the structure and function of ~3000 human proteins and hence plays key physiological roles. Consequently, impaired zinc homeostasis is associated with various human diseases including cancer. Intracellular zinc levels are tightly regulated by two families of zinc transporters: ZIPs and ZnTs; ZIPs import zinc into the cytosol from the extracellular milieu, or from the lumen of organelles into the cytoplasm. In contrast, the vast majority of ZnTs compartmentalize zinc within organelles, whereas the ubiquitously expressed ZnT1 is the sole zinc exporter. Herein, we explored the hypothesis that qualitative and quantitative alterations in ZnT1 activity impair cellular zinc homeostasis in cancer. Towards this end, we first used bioinformatics to analyze inactivating mutations in ZIPs and ZNTs, catalogued in the COSMIC and gnomAD databases, representing tumor specimens and healthy population controls, respectively. ZnT1, ZnT10, ZIP8, and ZIP10 showed extremely high rates of loss of function mutations in cancer as compared to healthy controls. Analysis of the putative functional impact of missense mutations in ZnT1-ZnT10 and ZIP1-ZIP14, using homologous protein alignment and structural predictions, revealed that ZnT1 displays a markedly increased frequency of predicted functionally deleterious mutations in malignant tumors, as compared to a healthy population. Furthermore, examination of ZnT1 expression in 30 cancer types in the TCGA database revealed five tumor types with significant ZnT1 overexpression, which predicted dismal prognosis for cancer patient survival. Novel functional zinc transport assays, which allowed for the indirect measurement of cytosolic zinc levels, established that wild type ZnT1 overexpression results in low intracellular zinc levels. In contrast, overexpression of predicted deleterious ZnT1 missense mutations did not reduce intracellular zinc levels, validating eight missense mutations as loss of function (LoF) mutations. Thus, alterations in ZnT1 expression and LoF mutations in ZnT1 provide a molecular mechanism for impaired zinc homeostasis in cancer formation and/or progression.

scholarly journals Disease-Induced Changes in Salivary Gland Function and the Composition of Saliva

2021 ◽  
pp. 002203452110048
Author(s):  
G.B. Proctor ◽  
A.M. Shaalan
Keyword(s):  
Salivary Gland ◽  
Sjögren Syndrome ◽  
Healthy Population ◽  
Sjogren Syndrome ◽  
Salivary Gland Function ◽  
Salivary Gland Dysfunction ◽  
Gland Function ◽  
And Function ◽  
The Impact ◽  
Saliva Composition

Although the physiological control of salivary secretion has been well studied, the impact of disease on salivary gland function and how this changes the composition and function of saliva is less well understood and is considered in this review. Secretion of saliva is dependent upon nerve-mediated stimuli, which activate glandular fluid and protein secretory mechanisms. The volume of saliva secreted by salivary glands depends upon the frequency and intensity of nerve-mediated stimuli, which increase dramatically with food intake and are subject to facilitatory or inhibitory influences within the central nervous system. Longer-term changes in saliva secretion have been found to occur in response to dietary change and aging, and these physiological influences can alter the composition and function of saliva in the mouth. Salivary gland dysfunction is associated with different diseases, including Sjögren syndrome, sialadenitis, and iatrogenic disease, due to radiotherapy and medications and is usually reported as a loss of secretory volume, which can range in severity. Defining salivary gland dysfunction by measuring salivary flow rates can be difficult since these vary widely in the healthy population. However, saliva can be sampled noninvasively and repeatedly, which facilitates longitudinal studies of subjects, providing a clearer picture of altered function. The application of omics technologies has revealed changes in saliva composition in many systemic diseases, offering disease biomarkers, but these compositional changes may not be related to salivary gland dysfunction. In Sjögren syndrome, there appears to be a change in the rheology of saliva due to altered mucin glycosylation. Analysis of glandular saliva in diseases or therapeutic interventions causing salivary gland inflammation frequently shows increased electrolyte concentrations and increased presence of innate immune proteins, most notably lactoferrin. Altering nerve-mediated signaling of salivary gland secretion contributes to medication-induced dysfunction and may also contribute to altered saliva composition in neurodegenerative disease.

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