-
Cells Apr 2020Cilia are microtubule-based organelles, protruding from the apical cell surface and anchoring to the cytoskeleton. Primary (nonmotile) cilia of the kidney act as... (Review)
Review
Cilia are microtubule-based organelles, protruding from the apical cell surface and anchoring to the cytoskeleton. Primary (nonmotile) cilia of the kidney act as mechanosensors of nephron cells, responding to fluid movements by triggering signal transduction. The impaired functioning of primary cilia leads to formation of cysts which in turn contribute to development of diverse renal diseases, including kidney ciliopathies and renal cancer. Here, we review current knowledge on the role of ciliary genes in kidney ciliopathies and renal cell carcinoma (RCC). Special focus is given on the impact of mutations and altered expression of ciliary genes (e.g., encoding polycystins, nephrocystins, Bardet-Biedl syndrome (BBS) proteins, ALS1, Oral-facial-digital syndrome 1 (OFD1) and others) in polycystic kidney disease and nephronophthisis, as well as rare genetic disorders, including syndromes of Joubert, Meckel-Gruber, Bardet-Biedl, Senior-Loken, Alström, Orofaciodigital syndrome type I and cranioectodermal dysplasia. We also show that RCC and classic kidney ciliopathies share commonly disturbed genes affecting cilia function, including (von Hippel-Lindau tumor suppressor), (polycystin 1, transient receptor potential channel interacting) and polycystin 2, transient receptor potential cation channel). Finally, we discuss the significance of ciliary genes as diagnostic and prognostic markers, as well as therapeutic targets in ciliopathies and cancer.
Topics: Cilia; Humans; Polycystic Kidney Diseases; TRPP Cation Channels
PubMed: 32276433
DOI: 10.3390/cells9040907 -
Journal of Molecular Medicine (Berlin,... Jan 2019Alström syndrome (AS) is characterised by metabolic deficits, retinal dystrophy, sensorineural hearing loss, dilated cardiomyopathy and multi-organ fibrosis.... (Review)
Review
Alström syndrome (AS) is characterised by metabolic deficits, retinal dystrophy, sensorineural hearing loss, dilated cardiomyopathy and multi-organ fibrosis. Elucidating the function of the mutated gene, ALMS1, is critical for the development of specific treatments and may uncover pathways relevant to a range of other disorders including common forms of obesity and type 2 diabetes. Interest in ALMS1 is heightened by the recent discovery of its involvement in neonatal cardiomyocyte cell cycle arrest, a process with potential relevance to regenerative medicine. ALMS1 encodes a ~ 0.5 megadalton protein that localises to the base of centrioles. Some studies have suggested a role for this protein in maintaining centriole-nucleated sensory organelles termed primary cilia, and AS is now considered to belong to the growing class of human genetic disorders linked to ciliary dysfunction (ciliopathies). However, mechanistic details are lacking, and recent studies have implicated ALMS1 in several processes including endosomal trafficking, actin organisation, maintenance of centrosome cohesion and transcription. In line with a more complex picture, multiple isoforms of the protein likely exist and non-centrosomal sites of localisation have been reported. This review outlines the evidence for both ciliary and extra-ciliary functions of ALMS1.
Topics: Alstrom Syndrome; Amino Acid Sequence; Animals; Cell Cycle Proteins; Gene Expression Regulation; Humans; Protein Interaction Maps; Protein Isoforms
PubMed: 30421101
DOI: 10.1007/s00109-018-1714-x -
Orphanet Journal of Rare Diseases Sep 2022Alström syndrome (ALMS) is a rare autosomal recessive genetic disorder that is caused by homozygous or compound heterozygous mutation in the ALMS1 gene. Dilated... (Review)
Review
OBJECTIVE
Alström syndrome (ALMS) is a rare autosomal recessive genetic disorder that is caused by homozygous or compound heterozygous mutation in the ALMS1 gene. Dilated cardiomyopathy (DCM) is one of the well-recognized features of the syndrome ranging from sudden-onset infantile DCM to adult-onset cardiomyopathy, sometimes of the restrictive hypertrophic form with a poor prognosis. We aimed to evaluate severe cardiomyopathy in Alström syndrome in infancy and display susceptible specific mutations of the disease, which may be linked to severe DCM. Secondarily we reviewed published mutations in ALMS1 with cardiomyopathies in the literature.
METHOD
We represent new mutagenic alleles related to severe cardiomyopathy and cardiac outcome in this patient cohort. We evaluated echocardiographic studies of nine Turkish patients diagnosed with Alström syndrome (between 2014 and 2020, at age two weeks to twenty years). Thus, we examined the cardiac manifestations of a single-centre prospective series of nine children with specific ALMS mutations and multisystem involvement. All patients underwent genetic and biochemical testing, electrocardiograms, and echocardiographic imaging to evaluate systolic strain with speckle tracking.
RESULTS
Four of the patients died from cardiomyopathy. Three patients (including three of the four fatalities) with the same mutation (c.7911dupC [p.Asn2638Glnfs*24]) had cardiomyopathy with intra-familial variability in the severity of cardiomyopathy. Global longitudinal strain, a measure of systolic contractile function, was abnormal in all patients that can be measured.
CONCLUSION
Cardiac function in ALMS patients with infantile cardiomyopathy appears to have different clinical spectrums depending on the mutagenic allele. The c.7911dupC (p. Asn2638Glnfs*24) mutation can be related to severe cardiomyopathy. Parents can be informed and consulted about the progression of severe cardiomyopathy in a child carrying this mutagenic allele.
Topics: Adult; Alstrom Syndrome; Cardiomyopathies; Cardiomyopathy, Dilated; Child; Homozygote; Humans; Mutation
PubMed: 36109815
DOI: 10.1186/s13023-022-02483-7 -
Intractable & Rare Diseases Research Nov 2021Alström syndrome is a rare monogenic ciliopathy caused by a mutation to the () gene. Alström syndrome has an autosomal recessive nature of inheritance. Approximately... (Review)
Review
Alström syndrome is a rare monogenic ciliopathy caused by a mutation to the () gene. Alström syndrome has an autosomal recessive nature of inheritance. Approximately 1,200 cases of Alström syndrome have been identified worldwide. Complications of the disease are likely caused by dysfunctional cilia with complications arising early in life. The known complications of Alström syndrome have been reported to impact multiple major organ systems, including the endocrine system, cardiac system, renal system, sensory system, and hepatic system. The symptoms of Alström syndrome have great variability in presentation and intensity but often lead to organ damage. This has resulted in a shortened lifespan for individuals affected by Alström syndrome. Individuals with the disease rare exceed the age of 50. Currently, there are no specific treatments for Alström syndrome that can cure the disease, prevent the complications, or reverse the complications. Current management involves management of symptoms with the goal of improving quality of life and lifespan. This review aims to summarize the current knowledge on the epidemiology, diagnosis, pathophysiology, complications, management, and prognosis of Alström syndrome. In addition to that, this review also aims to raise awareness and encourage research on Alström syndrome as the condition has a huge impact on affected individuals.
PubMed: 34877237
DOI: 10.5582/irdr.2021.01113 -
Diagnostics (Basel, Switzerland) Apr 2021Alström syndrome (ALMS) is an ultra-rare monogenic disease characterized by insulin resistance, multi-organ fibrosis, obesity, type 2 diabetes mellitus (T2DM), and...
Alström syndrome (ALMS) is an ultra-rare monogenic disease characterized by insulin resistance, multi-organ fibrosis, obesity, type 2 diabetes mellitus (T2DM), and hypertriglyceridemia with high and early incidence of non-alcoholic fatty liver disease (NAFLD). We evaluated liver fibrosis quantifying liver stiffness (LS) by shear wave elastography (SWE) and steatosis using ultrasound sonographic (US) liver/kidney ratios (L/K) in 18 patients with ALMS and 25 controls, and analyzed the contribution of metabolic and genetic alterations in NAFLD progression. We also genetically characterized patients. LS and L/K values were significantly higher in patients compared with in controls ( < 0.001 versus = 0.013). In patients, LS correlated with the Fibrosis-4 Index and age, while L/K was associated with triglyceride levels. LS showed an increasing trend in patients with metabolic comorbidities and displayed a significant correlation with waist circumference, the homeostasis model assessment, and glycated hemoglobin A1c. SWE and US represent promising tools to accurately evaluate early liver fibrosis and steatosis in adults and children with ALMS during follow-up. We described a new pathogenic variant of exon 8 in . Patients with ALMS displayed enhanced steatosis, an early increased age-dependent LS that is associated with obesity and T2DM but also linked to genetic alterations, suggesting that could be involved in liver fibrogenesis.
PubMed: 33924909
DOI: 10.3390/diagnostics11050797 -
Prilozi (Makedonska Akademija Na... Jul 2022Alström syndrome (ALMS) is an autosomal recessive disorder characterized by multiple organ involvement, including progressive cone-rod dystrophy, sensorineural hearing...
Alström syndrome (ALMS) is an autosomal recessive disorder characterized by multiple organ involvement, including progressive cone-rod dystrophy, sensorineural hearing loss, childhood obesity, and type 2 diabetes mellitus. Pathogenic variants in the ALMS1 gene are the known cause for the occurrence of this devastating condition. Here we report on a 12 year old boy referred to the University Clinic with early signs of impaired hearing and vision, obesity, and scoliosis. Central vision was first affected, followed by peripheral vision. In addition, his weight began increasing after the age of two years, reaching 78 kg at a height of 157 cm (BMI 31.64). No polydactyly was present. His mental development was normal in spite of his hearing and vision impairments. There was acanthosis nigricans on the neck. ECG and the cardiac ultrasound were normal. At the age of 12 years, his testicles are 12 ml and his pubertal status is P2 A2. OGTT revealed impaired glucose tolerance with elevated insulin concentrations 121ulU/mL (reference range 2,00-29,1 ulU/mL). Renal function was unaffected, liver functions were normal. Uric acid and lipids were within normal plasma concentrations. A Whole Exome Sequencing was performed and a homozygous ALMS1 pathogenic, frameshift gene variant (LRG_741t1(ALMS1):c.4156dup; p.Thr1386AsnfsTer15) was determined as the cause of the disease. Both parents were carriers for the variant. The absence of mental retardation and polydactyly differentiates Alström and Bardet-Biedle syndrome.
Topics: Alstrom Syndrome; Cell Cycle Proteins; Child; Child, Preschool; Diabetes Mellitus, Type 2; Hearing; Humans; Male; Pediatric Obesity
PubMed: 35843912
DOI: 10.2478/prilozi-2022-0028 -
The New England Journal of Medicine May 2015The potential benefit of dual antiplatelet therapy beyond 1 year after a myocardial infarction has not been established. We investigated the efficacy and safety of... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The potential benefit of dual antiplatelet therapy beyond 1 year after a myocardial infarction has not been established. We investigated the efficacy and safety of ticagrelor, a P2Y12 receptor antagonist with established efficacy after an acute coronary syndrome, in this context.
METHODS
We randomly assigned, in a double-blind 1:1:1 fashion, 21,162 patients who had had a myocardial infarction 1 to 3 years earlier to ticagrelor at a dose of 90 mg twice daily, ticagrelor at a dose of 60 mg twice daily, or placebo. All the patients were to receive low-dose aspirin and were followed for a median of 33 months. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke. The primary safety end point was Thrombolysis in Myocardial Infarction (TIMI) major bleeding.
RESULTS
The two ticagrelor doses each reduced, as compared with placebo, the rate of the primary efficacy end point, with Kaplan-Meier rates at 3 years of 7.85% in the group that received 90 mg of ticagrelor twice daily, 7.77% in the group that received 60 mg of ticagrelor twice daily, and 9.04% in the placebo group (hazard ratio for 90 mg of ticagrelor vs. placebo, 0.85; 95% confidence interval [CI], 0.75 to 0.96; P=0.008; hazard ratio for 60 mg of ticagrelor vs. placebo, 0.84; 95% CI, 0.74 to 0.95; P=0.004). Rates of TIMI major bleeding were higher with ticagrelor (2.60% with 90 mg and 2.30% with 60 mg) than with placebo (1.06%) (P<0.001 for each dose vs. placebo); the rates of intracranial hemorrhage or fatal bleeding in the three groups were 0.63%, 0.71%, and 0.60%, respectively.
CONCLUSIONS
In patients with a myocardial infarction more than 1 year previously, treatment with ticagrelor significantly reduced the risk of cardiovascular death, myocardial infarction, or stroke and increased the risk of major bleeding. (Funded by AstraZeneca; PEGASUS-TIMI 54 ClinicalTrials.gov number, NCT01225562.).
Topics: Adenosine; Aged; Aspirin; Cardiovascular Diseases; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Hemorrhage; Humans; Intracranial Hemorrhages; Kaplan-Meier Estimate; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Risk; Secondary Prevention; Ticagrelor
PubMed: 25773268
DOI: 10.1056/NEJMoa1500857 -
Yonago Acta Medica May 2024Alström syndrome is a form of inherited obesity caused by a single gene abnormality and is inherited as an autosomal recessive trait. It is characterised by a variety... (Review)
Review
Alström syndrome is a form of inherited obesity caused by a single gene abnormality and is inherited as an autosomal recessive trait. It is characterised by a variety of clinical manifestations, including progressive visual and hearing impairment, type 2 diabetes mellitus, dilated cardiomyopathy, and hepatic and renal dysfunction, in addition to obesity. Recent insights underline the pivotal involvement of the disease-associated gene () in cilia formation and function, leading to the classification of its clinical manifestations as a ciliopathy. This review delineates the diverse clinical indicators defining the syndrome and elucidates its pathological underpinnings.
PubMed: 38803594
DOI: 10.33160/yam.2024.05.010 -
Molecules and Cells Apr 2022A primary cilium, a hair-like protrusion of the plasma membrane, is a pivotal organelle for sensing external environmental signals and transducing intracellular... (Review)
Review
A primary cilium, a hair-like protrusion of the plasma membrane, is a pivotal organelle for sensing external environmental signals and transducing intracellular signaling. An interesting linkage between cilia and obesity has been revealed by studies of the human genetic ciliopathies Bardet-Biedl syndrome and Alström syndrome, in which obesity is a principal manifestation. Mouse models of cell type-specific cilia dysgenesis have subsequently demonstrated that ciliary defects restricted to specific hypothalamic neurons are sufficient to induce obesity and hyperphagia. A potential mechanism underlying hypothalamic neuron cilia-related obesity is impaired ciliary localization of G protein-coupled receptors involved in the regulation of appetite and energy metabolism. A well-studied example of this is melanocortin 4 receptor (MC4R), mutations in which are the most common cause of human monogenic obesity. In the paraventricular hypothalamus neurons, a blockade of ciliary trafficking of MC4R as well as its downstream ciliary signaling leads to hyperphagia and weight gain. Another potential mechanism is reduced leptin signaling in hypothalamic neurons with defective cilia. Leptin receptors traffic to the periciliary area upon leptin stimulation. Moreover, defects in cilia formation hamper leptin signaling and actions in both developing and differentiated hypothalamic neurons. The list of obesity-linked ciliary proteins is expending and this supports a tight association between cilia and obesity. This article provides a brief review on the mechanism of how ciliary defects in hypothalamic neurons facilitate obesity.
Topics: Animals; Cilia; Humans; Hyperphagia; Hypothalamus; Leptin; Mice; Obesity
PubMed: 35387896
DOI: 10.14348/molcells.2022.2046 -
The Yale Journal of Biology and Medicine Sep 2019A primary challenge in type 2 diabetes (T2D) is the preservation of a functional population of β-cells, which play a central role in regulating blood glucose levels.... (Review)
Review
A primary challenge in type 2 diabetes (T2D) is the preservation of a functional population of β-cells, which play a central role in regulating blood glucose levels. Two congenital disorders, Bardet-Biedl syndrome (BBS) and Alström syndrome (ALMS), can serve as useful models to understand how β-cells are normally produced and regenerated. Both are characterized by obesity, loss of β-cells, and defects in primary cilia - the sensory center of cells. Primary cilia are cellular protrusions present in almost every vertebrate cell. This antenna-like organelle plays a crucial role in regulating several signaling pathways that direct proper development, proliferation, and homeostasis. Mutations in genes expressing ciliary proteins or proteins present at or near the base of the cilium lead to disorders, collectively called ciliopathies. BBS and Alström syndrome are such disorders. Though both BBS and Alström patients are obese, their childhood diabetes rates are vastly different, suggesting distinct pathogenesis underlying these two ciliopathies. Clinical studies suggest that BBS patients are protected against early onset diabetes by sustained or enhanced β-cell function. In contrast, Alström patients are more prone to develop diabetes. They have hyperinsulinemia, yet their β-cells fail to sense glucose and to regulate insulin secretion accordingly. These data suggest a potential role for primary cilia in maintaining a functional β-cell population and that defects in cilia or in ciliary proteins impair development and function of β-cells. Identifying the respective roles of primary cilia and ciliary proteins, such as BBS and ALMS1 may shed light on β-cell biology and uncover potentially novel targets for diabetes therapy.
Topics: Animals; Cilia; Ciliopathies; Humans; Insulin; Insulin-Secreting Cells; Models, Biological
PubMed: 31543709
DOI: No ID Found