The Experts below are selected from a list of 6252 Experts worldwide ranked by ideXlab platform
Gayle B. Collin - One of the best experts on this subject based on the ideXlab platform.
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Spectral-domain optical coherence tomography findings in Alström Syndrome
Ophthalmic genetics, 2017Co-Authors: Gad Dotan, Gayle B. Collin, Juergen K Naggert, Jan D. Marshall, Vikas Khetan, Elizabeth Affel, Denise Armiger-george, Alex V. LevinAbstract:Background: Alstrom syndrome is a multi-system recessive disorder caused by mutations in ALMS1 gene. The aim of this study was to characterize morphological retinal changes in Alstrom patients usin...
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Alström Syndrome: Mutation Spectrum of ALMS1.
Human mutation, 2015Co-Authors: Jan D. Marshall, Gayle B. Collin, Gabriella Milan, Francesca Favaretto, Jean Muller, Stephen F. Kingsmore, Darrell L. Dinwiddie, Emily G. Farrow, Neil A. Miller, Pietro MaffeiAbstract:Alstrom Syndrome (ALMS), a recessive, monogenic ciliopathy caused by mutations in ALMS1, is typically characterized by multisystem involvement including early cone-rod retinal dystrophy and blindness, hearing loss, childhood obesity, type 2 diabetes mellitus, cardiomyopathy, fibrosis, and multiple organ failure. The precise function of ALMS1 remains elusive, but roles in endosomal and ciliary transport and cell cycle regulation have been shown. The aim of our study was to further define the spectrum of ALMS1 mutations in patients with clinical features of ALMS. Mutational analysis in a world-wide cohort of 204 families identified 109 novel mutations, extending the number of known ALMS1 mutations to 239 and highlighting the allelic heterogeneity of this disorder. This study represents the most comprehensive mutation analysis in patients with ALMS, identifying the largest number of novel mutations in a single study worldwide. Here, we also provide an overview of all ALMS1 mutations identified to date.
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The phenotypic and molecular genetic spectrum of Alström syndrome in 44 Turkish kindreds and a literature review of Alström syndrome in Turkey
Journal of Human Genetics, 2015Co-Authors: Ayşegül Ozantürk, Gayle B. Collin, Jan D. Marshall, Selma Düzenli, Robert P Marshall, Şükrü Candan, Tülay Tos, İhsan Esen, Mustafa Taşkesen, Atilla ÇayırAbstract:Alström syndrome (ALMS) is an autosomal recessive disease characterized by multiple organ involvement, including neurosensory vision and hearing loss, childhood obesity, diabetes mellitus, cardiomyopathy, hypogonadism, and pulmonary, hepatic, renal failure and systemic fibrosis. Alström Syndrome is caused by mutations in ALMS1 , and ALMS1 protein is thought to have a role in microtubule organization, intraflagellar transport, endosome recycling and cell cycle regulation. Here, we report extensive phenotypic and genetic analysis of a large cohort of Turkish patients with ALMS. We evaluated 61 Turkish patients, including 11 previously reported, for both clinical spectrum and mutations in ALMS1 . To reveal the molecular diagnosis of the patients, different approaches were used in combination, a cohort of patients were screened by the gene array to detect the common mutations in ALMS1 gene, then in patients having any of the common ALMS1 mutations were subjected to direct DNA sequencing or next-generation sequencing for the screening of mutations in all coding regions of the gene. In total, 20 distinct disease-causing nucleotide changes in ALMS1 have been identified, eight of which are novel, thereby increasing the reported ALMS1 mutations by 6% (8/120). Five disease-causing variants were identified in more than one kindred, but most of the alleles were unique to each single patient and identified only once (16/20). So far, 16 mutations identified were specific to the Turkish population, and four have also been reported in other ethnicities. In addition, 49 variants of uncertain pathogenicity were noted, and four of these were very rare and probably or likely deleterious according to in silico mutation prediction analyses. ALMS has a relatively high incidence in Turkey and the present study shows that the ALMS1 mutations are largely heterogeneous; thus, these data from a particular population may provide a unique source for the identification of additional mutations underlying Alström Syndrome and contribute to genotype–phenotype correlation studies.
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GLUT4 defects in adipose tissue are early signs of metabolic alterations in ALMS1GT/GT, a mouse model for obesity and insulin resistance.
PloS one, 2014Co-Authors: Francesca Favaretto, Gayle B. Collin, Jan D. Marshall, Pietro Maffei, Gabriella Milan, Roberto Vettor, Fabio Stasi, Juergen K NaggertAbstract:Dysregulation of signaling pathways in adipose tissue leading to insulin resistance can contribute to the development of obesity-related metabolic disorders. Alstrom Syndrome, a recessive ciliopathy, caused by mutations in ALMS1, is characterized by progressive metabolic alterations such as childhood obesity, hyperinsulinemia, and type 2 diabetes. Here we investigated the role of ALMS1 disruption in AT expansion and insulin responsiveness in a murine model for Alstrom Syndrome. A gene trap insertion in ALMS1 on the insulin sensitive C57BL6/Ei genetic background leads to early hyperinsulinemia and a progressive increase in body weight. At 6 weeks of age, before the onset of the metabolic disease, the mutant mice had enlarged fat depots with hypertrophic adipocytes, but without signs of inflammation. Expression of lipogenic enzymes was increased. Pre-adipocytes isolated from mutant animals demonstrated normal adipogenic differentiation but gave rise to mature adipocytes with reduced insulin-stimulated glucose uptake. Assessment of whole body glucose homeostasis revealed glucose intolerance. Insulin stimulation resulted in proper AKT phosphorylation in adipose tissue. However, the total amount of glucose transporter 4 (SLC4A2) and its translocation to the plasma membrane were reduced in mutant adipose depots compared to wildtype littermates. Alterations in insulin stimulated trafficking of glucose transporter 4 are an early sign of metabolic dysfunction in Alstrom mutant mice, providing a possible explanation for the reduced glucose uptake and the compensatory hyperinsulinemia. The metabolic signaling deficits either reside downstream or are independent of AKT activation and suggest a role for ALMS1 in GLUT4 trafficking. Alstrom mutant mice represent an interesting model for the development of metabolic disease in which adipose tissue with a reduced glucose uptake can expand by de novo lipogenesis to an obese state.
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mutations in alstrom protein impair terminal differentiation of cardiomyocytes
Nature Communications, 2014Co-Authors: Lincoln T Shenje, Gayle B. Collin, Peter Andersen, Marc K Halushka, Cecillia Lui, Laviel Fernandez, Nuria Amatalarcon, Wendy S Meschino, Ernest Cutz, Kenneth T E ChangAbstract:Cardiomyocyte cell division and replication in mammals proceed through embryonic development and abruptly decline soon after birth. The process governing cardiomyocyte cell cycle arrest is poorly understood. Here we carry out whole-exome sequencing in an infant with evidence of persistent postnatal cardiomyocyte replication to determine the genetic risk factors. We identify compound heterozygous ALMS1 mutations in the proband, and confirm their presence in her affected sibling, one copy inherited from each heterozygous parent. Next, we recognize homozygous or compound heterozygous truncating mutations in ALMS1 in four other children with high levels of postnatal cardiomyocyte proliferation. ALMS1 mRNA knockdown increases multiple markers of proliferation in cardiomyocytes, the percentage of cardiomyocytes in G2/M phases, and the number of cardiomyocytes by 10% in cultured cells. Homozygous ALMS1-mutant mice have increased cardiomyocyte proliferation at 2 weeks postnatal compared with wild-type littermates. We conclude that deficiency of Alstrom protein impairs postnatal cardiomyocyte cell cycle arrest.
Jan D. Marshall - One of the best experts on this subject based on the ideXlab platform.
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Spectral-domain optical coherence tomography findings in Alström Syndrome
Ophthalmic genetics, 2017Co-Authors: Gad Dotan, Gayle B. Collin, Juergen K Naggert, Jan D. Marshall, Vikas Khetan, Elizabeth Affel, Denise Armiger-george, Alex V. LevinAbstract:Background: Alstrom syndrome is a multi-system recessive disorder caused by mutations in ALMS1 gene. The aim of this study was to characterize morphological retinal changes in Alstrom patients usin...
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Alström Syndrome: Mutation Spectrum of ALMS1.
Human mutation, 2015Co-Authors: Jan D. Marshall, Gayle B. Collin, Gabriella Milan, Francesca Favaretto, Jean Muller, Stephen F. Kingsmore, Darrell L. Dinwiddie, Emily G. Farrow, Neil A. Miller, Pietro MaffeiAbstract:Alstrom Syndrome (ALMS), a recessive, monogenic ciliopathy caused by mutations in ALMS1, is typically characterized by multisystem involvement including early cone-rod retinal dystrophy and blindness, hearing loss, childhood obesity, type 2 diabetes mellitus, cardiomyopathy, fibrosis, and multiple organ failure. The precise function of ALMS1 remains elusive, but roles in endosomal and ciliary transport and cell cycle regulation have been shown. The aim of our study was to further define the spectrum of ALMS1 mutations in patients with clinical features of ALMS. Mutational analysis in a world-wide cohort of 204 families identified 109 novel mutations, extending the number of known ALMS1 mutations to 239 and highlighting the allelic heterogeneity of this disorder. This study represents the most comprehensive mutation analysis in patients with ALMS, identifying the largest number of novel mutations in a single study worldwide. Here, we also provide an overview of all ALMS1 mutations identified to date.
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The phenotypic and molecular genetic spectrum of Alström syndrome in 44 Turkish kindreds and a literature review of Alström syndrome in Turkey
Journal of Human Genetics, 2015Co-Authors: Ayşegül Ozantürk, Gayle B. Collin, Jan D. Marshall, Selma Düzenli, Robert P Marshall, Şükrü Candan, Tülay Tos, İhsan Esen, Mustafa Taşkesen, Atilla ÇayırAbstract:Alström syndrome (ALMS) is an autosomal recessive disease characterized by multiple organ involvement, including neurosensory vision and hearing loss, childhood obesity, diabetes mellitus, cardiomyopathy, hypogonadism, and pulmonary, hepatic, renal failure and systemic fibrosis. Alström Syndrome is caused by mutations in ALMS1 , and ALMS1 protein is thought to have a role in microtubule organization, intraflagellar transport, endosome recycling and cell cycle regulation. Here, we report extensive phenotypic and genetic analysis of a large cohort of Turkish patients with ALMS. We evaluated 61 Turkish patients, including 11 previously reported, for both clinical spectrum and mutations in ALMS1 . To reveal the molecular diagnosis of the patients, different approaches were used in combination, a cohort of patients were screened by the gene array to detect the common mutations in ALMS1 gene, then in patients having any of the common ALMS1 mutations were subjected to direct DNA sequencing or next-generation sequencing for the screening of mutations in all coding regions of the gene. In total, 20 distinct disease-causing nucleotide changes in ALMS1 have been identified, eight of which are novel, thereby increasing the reported ALMS1 mutations by 6% (8/120). Five disease-causing variants were identified in more than one kindred, but most of the alleles were unique to each single patient and identified only once (16/20). So far, 16 mutations identified were specific to the Turkish population, and four have also been reported in other ethnicities. In addition, 49 variants of uncertain pathogenicity were noted, and four of these were very rare and probably or likely deleterious according to in silico mutation prediction analyses. ALMS has a relatively high incidence in Turkey and the present study shows that the ALMS1 mutations are largely heterogeneous; thus, these data from a particular population may provide a unique source for the identification of additional mutations underlying Alström Syndrome and contribute to genotype–phenotype correlation studies.
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GLUT4 defects in adipose tissue are early signs of metabolic alterations in ALMS1GT/GT, a mouse model for obesity and insulin resistance.
PloS one, 2014Co-Authors: Francesca Favaretto, Gayle B. Collin, Jan D. Marshall, Pietro Maffei, Gabriella Milan, Roberto Vettor, Fabio Stasi, Juergen K NaggertAbstract:Dysregulation of signaling pathways in adipose tissue leading to insulin resistance can contribute to the development of obesity-related metabolic disorders. Alstrom Syndrome, a recessive ciliopathy, caused by mutations in ALMS1, is characterized by progressive metabolic alterations such as childhood obesity, hyperinsulinemia, and type 2 diabetes. Here we investigated the role of ALMS1 disruption in AT expansion and insulin responsiveness in a murine model for Alstrom Syndrome. A gene trap insertion in ALMS1 on the insulin sensitive C57BL6/Ei genetic background leads to early hyperinsulinemia and a progressive increase in body weight. At 6 weeks of age, before the onset of the metabolic disease, the mutant mice had enlarged fat depots with hypertrophic adipocytes, but without signs of inflammation. Expression of lipogenic enzymes was increased. Pre-adipocytes isolated from mutant animals demonstrated normal adipogenic differentiation but gave rise to mature adipocytes with reduced insulin-stimulated glucose uptake. Assessment of whole body glucose homeostasis revealed glucose intolerance. Insulin stimulation resulted in proper AKT phosphorylation in adipose tissue. However, the total amount of glucose transporter 4 (SLC4A2) and its translocation to the plasma membrane were reduced in mutant adipose depots compared to wildtype littermates. Alterations in insulin stimulated trafficking of glucose transporter 4 are an early sign of metabolic dysfunction in Alstrom mutant mice, providing a possible explanation for the reduced glucose uptake and the compensatory hyperinsulinemia. The metabolic signaling deficits either reside downstream or are independent of AKT activation and suggest a role for ALMS1 in GLUT4 trafficking. Alstrom mutant mice represent an interesting model for the development of metabolic disease in which adipose tissue with a reduced glucose uptake can expand by de novo lipogenesis to an obese state.
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alstrom syndrome cardiac magnetic resonance findings
International Journal of Cardiology, 2013Co-Authors: Francesco Corbetti, Juergen K Naggert, Jan D. Marshall, Gabriella Milan, Renato Razzolini, Vera Bettini, Francesco Tona, Pietro MaffeiAbstract:Abstract Background Alstrom Syndrome (ALMS) is an extremely rare multiorgan disease caused by mutations in ALMS1 . Dilated cardiomyopathy (DCM) is a common finding but only one series has been investigated by Cardiac Magnetic Resonance (CMR). Methods Eight genetically proven ALMS patients (ages 11–41) underwent CMR performed by standard cine steady state, T1, T2 and late gadolinium enhancement (LGE) sequences. Ejection fraction (EF), Diastolic Volume (EDV) and Systolic Volume normalized for body surface area (ESV), and mass indices were determined, as well as EDV/Mass ratio, an index expressing the adequacy of cardiac mass to heart volume. Regional fibrosis was assessed by LGE; diffuse fibrosis was measured by a TI scout sequence acquired at 5, 10 and 15min after gadolinium by comparing inversion time values (TI) at null time in ALMS and control group. Results In one patient severe DCM was present with diffuse LGE. There were seven cases without clinical DCM. In these patients, EF was at lower normal limits or slightly reduced and ESV index increased; six patients had decreased mass index and EDV/Mass ratio. Mild regional non ischemic fibrosis was detected by LGE in three cases; diffuse fibrosis was observed in all cases, as demonstrated by shorter TI values in ALMS in comparison with controls (5min: 152±12 vs 186±16, p 0.0002; 10min: 175±8 vs 204±18, p 0.0012; 15min: 193±9 vs 224±16, p 0.0002). Conclusions Cardiac involvement in ALMS is characterized by progressive DCM, associated with systolic dysfunction, myocardial fibrosis and reduced myocardial mass.
Pablo A. Ortiz - One of the best experts on this subject based on the ideXlab platform.
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Role of Alström syndrome 1 in the regulation of blood pressure and renal function.
JCI insight, 2018Co-Authors: Ankita Bachhawat Jaykumar, Juergen K Naggert, Keyona N King-medina, Paulo S. Caceres, Tang-dong Liao, Indrani Datta, Dipak Maskey, Mariela Mendez, William H. Beierwaltes, Pablo A. OrtizAbstract:Elevated blood pressure (BP) and renal dysfunction are complex traits representing major global health problems. Single nucleotide polymorphisms identified by genome-wide association studies have identified the Alstrom syndrome 1 (ALMS1) gene locus to render susceptibility for renal dysfunction, hypertension, and chronic kidney disease (CKD). Mutations in the ALMS1 gene in humans causes Alstrom syndrome, characterized by progressive metabolic alterations including hypertension and CKD. Despite compelling genetic evidence, the underlying biological mechanism by which mutations in the ALMS1 gene lead to the above-mentioned pathophysiology is not understood. We modeled this effect in a KO rat model and showed that ALMS1 genetic deletion leads to hypertension. We demonstrate that the link between ALMS1 and hypertension involves the activation of the renal Na+/K+/2Cl- cotransporter NKCC2, mediated by regulation of its endocytosis. Our findings establish a link between the genetic susceptibility to hypertension, CKD, and the expression of ALMS1 through its role in a salt-reabsorbing tubular segment of the kidney. These data point to ALMS1 as a potentially novel gene involved in BP and renal function regulation.
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abstract 004 caloric restriction prevents the increase in body weight but not hypertension in ALMS1 alstrom syndrome 1 knockout rat
Hypertension, 2018Co-Authors: Keyona N Kingmedina, Pablo A. OrtizAbstract:In humans, mutations in the ALMS1 gene cause obesity, diabetes and kidney disease. The mechanisms causing these alterations are unclear. We generated ALMS1 knockout (KO) rats in the Dahl salt-sensi...
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Abstract 065: Enhanced Glomerular Capillary Pressure and Tubuloglomerular Feedback (tgf) in Obese ALMS1 (alstrom Syndrome 1) Knock Out Rats
Hypertension, 2018Co-Authors: Sumit R. Monu, Keyona King-medina, Pablo A. OrtizAbstract:The ALMS1 gene has been associated to decreased renal function (lower GFR) and hypertension in genome-wide studies humans. The role of ALMS1 in renal dysfunction is unclear. Our lab has identified ...
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Abstract 103: Decreased Ability to Excrete a Na Load and Hypertension in the ALMS1 (Alstrom Syndrome 1) Knockout Rat
Hypertension, 2017Co-Authors: Keyona N King-medina, Ankita Bachhawat Jaykumar, Pablo A. OrtizAbstract:Few genes involved in obesity are known to be involved in hypertension. The Alstrom Syndrome 1 protein (ALMS1) is involved in obesity in humans. We found it is expressed in the thick ascending limb...
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abstract 104 targeting the ALMS1 gene in rats causes hypertension obesity and enhanced nkcc2 trafficking
Hypertension, 2015Co-Authors: Ankita Bachhawat Jaykumar, Paulo Caceres, Emily Henson, Gustavo R Ares, Pablo A. OrtizAbstract:Enhanced NaCl reabsorption by the thick ascending limb (TAL) is associated with salt sensitive hypertension in rodents and humans. NaCl absorption by the TAL depends on the apical Na/K/2Cl cotransporter - NKCC2. NKCC2 activity is regulated in part by protein-protein interactions with its carboxyl terminus that controls its trafficking to the apical membrane. We hypothesized that the proteins binding to this region of NKCC2 may be involved in NKCC2 regulation and trafficking. To identify new TAL proteins that bind NKCC2, we performed a proteomics screen between the NKCC2 carboxyl terminus and TAL proteins. We identified ALMS1 (Alstrom syndrome 1) as a specific interacting partner for this NKCC2 region and confirmed that ALMS1 is expressed in TALs. Little is known about ALMS1 in renal function. Mutation of this gene causes severe metabolic syndrome in humans and is associated with hypertension. To study ALMS1 function we obtained ALMS1 knockout (KO) rats in collaboration with the rat genome editing consortium. We found that ALMS1 KO rats fed a normal salt diet have higher systolic blood pressure (151± 5 mmHg) compared to wild type littermates (125± 4 mmHg, p< 0.02). We also observed an increase in body weight in ALMS1 KO at all ages (WT: 344± 4 g vs KO: 429±11 g, at 11 weeks, p<0.05). ALMS1 KO rats showed large intra-abdominal and sub-cutaneous fat deposits. We then obtained TALs and measured surface and total NKCC2 expression. In TALs from ALMS1 KO, the percentage of total NKCC2 at the surface was higher compared to WT (27±4 vs 14±2 %, p<0.05, n=6). Total NKCC2 expression was not significantly different between ALMS1 KO and WT rats. We conclude that ALMS1 is important for blood pressure regulation. The mechanism for hypertension in ALMS1 KO is unclear but may involve an increase in NKCC2 trafficking to the apical membrane and activity. ALMS1 has been associated with poor kidney function, hypertension, and type 2 diabetes in humans. Understanding the function of ALMS1 could develop new avenues for research into these diseases.
Pietro Maffei - One of the best experts on this subject based on the ideXlab platform.
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Alström syndrome: an ultra-rare monogenic disorder as a model for insulin resistance, type 2 diabetes mellitus and obesity
Endocrine, 2021Co-Authors: Francesca Dassie, Gabriella Milan, Francesca Favaretto, Silvia Bettini, Matteo Parolin, Marina Valenti, Felix Reschke, Thomas Danne, Roberto Vettor, Pietro MaffeiAbstract:Background Alström syndrome (ALMS) is a monogenic ultra-rare disorder with a prevalence of one per million inhabitants caused by pathogenic variants of ALMS1 gene. ALMS1 is located on chromosome 2p13, spans 23 exons and encodes a predicted 461.2-kDa protein of 4169 amino acids. The infantile cone-rod dystrophy with nystagmus and severe visual impairment is the earliest and most consistent clinical manifestation of ALMS. In addition, infantile transient cardiomyopathy, early childhood obesity with hyperphagia, deafness, insulin resistance (IR), type 2 diabetes mellitus (T2DM), systemic fibrosis and progressive renal or liver dysfunction are common findings. ALMS1 encodes a large ubiquitously expressed protein that is associated with the centrosome and the basal body of primary cilium. Current research The localisation of ALMS1 to the ciliary basal body suggests its contribution to ciliogenesis and/or normal ciliary function, or centriolar stability. ALMS1 regulate glucose transport through the actin cytoskeleton, which plays an important role in insulin-stimulated GLUT4 transport. Both extreme IR and β-cell failure are the two determinant factors responsible for the development of glucose metabolism alterations in ALMS. Treatment Currently, there is no known cure for ALMS other than managing the underlying systemic diseases. When possible, individuals with ALMS and families should be referred to a centre of expertise and followed by a multidisciplinary team. Lifestyle modification, aerobic exercise and dietary induced weight loss are highly recommended as primary treatment for ALMS patients with T2DM and obesity. Conclusion Managing a rare disease requires not only medical care but also a support network including patient associations.
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Consensus clinical management guidelines for Alström syndrome
Orphanet Journal of Rare Diseases, 2020Co-Authors: Natascia Tahani, Pietro Maffei, Gabriella Milan, R B Paisey, Helene Dollfus, Francesca Favaretto, Diana Valverde, Joan C. Han, Shyam C. Madathil, Charlotte DawsonAbstract:Alström Syndrome (ALMS) is an ultra-rare multisystem genetic disorder caused by autosomal recessive variants in the ALMS1 gene, which is located on chromosome 2p13. ALMS is a multisystem, progressive disease characterised by visual disturbance, hearing impairment, cardiomyopathy, childhood obesity, extreme insulin resistance, accelerated non-alcoholic fatty liver disease (NAFLD), renal dysfunction, respiratory disease, endocrine and urologic disorders. Clinical symptoms first appear in infancy with great variability in age of onset and severity. ALMS has an estimated incidence of 1 case per 1,000,000 live births and ethnically or geographically isolated populations have a higher-than-average frequency. The rarity and complexity of the syndrome and the lack of expertise can lead to delayed diagnosis, misdiagnosis and inadequate care. Multidisciplinary and multiprofessional teams of experts are essential for the management of patients with ALMS, as early diagnosis and intervention can slow the progression of multi-organ dysfunctions and improve patient quality of life. These guidelines are intended to define standard of care for patients suspected or diagnosed with ALMS of any age. All information contained in this document has originated from a systematic review of the literature and the experiences of the authors in their care of patients with ALMS. The Appraisal of Guidelines for Research & Evaluation (AGREE II) system was adopted for the development of the guidelines and for defining the related levels of evidence and strengths of recommendations. These guidelines are addressed to: a) specialist centres, other hospital-based medical teams and staffs involved with the care of ALMS patients, b) family physicians and other primary caregivers and c) patients and their families.
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Ophthalmic features of cone-rod dystrophy caused by pathogenic variants in the ALMS1 gene.
Acta ophthalmologica, 2017Co-Authors: Fadi Nasser, Pietro Maffei, Gabriella Milan, Nicole Weisschuh, Corina Heller, Eberhart Zrenner, Susanne Kohl, Laura KuehleweinAbstract:PURPOSE We aim to describe ophthalmic characteristics and systemic findings in a cohort of seven patients with cone-rod retinal dystrophy (CORD) caused by pathogenic variants in the ALMS1 gene. METHODS Seven patients with Alstrom syndrome (ALMS) were included in the study. A comprehensive ophthalmological examination was performed, including best-corrected visual acuity (BCVA), a semiautomated kinetic visual field exam, colour vision testing, full-field electroretinography testing according to International Society for Clinical Electrophysiology of Vision (ISCEV) standards, spectral domain optical coherence tomography (SD-OCT) and fundus autofluorescence (FAF) imaging, and slit lamp and dilated fundus examination. DNA samples were analysed using Sanger sequencing or exome sequencing. RESULTS In our cohort, the ocular phenotype presented with a wide variability in retinal function and disease severity. However, age of symptom onset (i.e. nystagmus and photophobia) was at 6-9 months in all patients. These symptoms mostly mislead to the diagnosis of congenital achromatopsia (ACHM), Leber congenital amaurosis (LCA), isolated CORD or Bardet-Biedl syndrome. The systemic manifestations in our cohort were highly variable. CONCLUSION In summary, we can report that most of our ALMS patients primarily presented with nystagmus and severe photophobia since early childhood interestingly without night blindness in the absence of systemic symptoms. Only genetic testing analysing both nonsyndromic retinal disease (RD) genes and syndromic ciliopathy genes by comprehensive panel sequencing can result in the correct diagnosis, genetically and clinically, with important implication for the physical health of the individual.
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Alström Syndrome: Mutation Spectrum of ALMS1.
Human mutation, 2015Co-Authors: Jan D. Marshall, Gayle B. Collin, Gabriella Milan, Francesca Favaretto, Jean Muller, Stephen F. Kingsmore, Darrell L. Dinwiddie, Emily G. Farrow, Neil A. Miller, Pietro MaffeiAbstract:Alstrom Syndrome (ALMS), a recessive, monogenic ciliopathy caused by mutations in ALMS1, is typically characterized by multisystem involvement including early cone-rod retinal dystrophy and blindness, hearing loss, childhood obesity, type 2 diabetes mellitus, cardiomyopathy, fibrosis, and multiple organ failure. The precise function of ALMS1 remains elusive, but roles in endosomal and ciliary transport and cell cycle regulation have been shown. The aim of our study was to further define the spectrum of ALMS1 mutations in patients with clinical features of ALMS. Mutational analysis in a world-wide cohort of 204 families identified 109 novel mutations, extending the number of known ALMS1 mutations to 239 and highlighting the allelic heterogeneity of this disorder. This study represents the most comprehensive mutation analysis in patients with ALMS, identifying the largest number of novel mutations in a single study worldwide. Here, we also provide an overview of all ALMS1 mutations identified to date.
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GLUT4 defects in adipose tissue are early signs of metabolic alterations in ALMS1GT/GT, a mouse model for obesity and insulin resistance.
PloS one, 2014Co-Authors: Francesca Favaretto, Gayle B. Collin, Jan D. Marshall, Pietro Maffei, Gabriella Milan, Roberto Vettor, Fabio Stasi, Juergen K NaggertAbstract:Dysregulation of signaling pathways in adipose tissue leading to insulin resistance can contribute to the development of obesity-related metabolic disorders. Alstrom Syndrome, a recessive ciliopathy, caused by mutations in ALMS1, is characterized by progressive metabolic alterations such as childhood obesity, hyperinsulinemia, and type 2 diabetes. Here we investigated the role of ALMS1 disruption in AT expansion and insulin responsiveness in a murine model for Alstrom Syndrome. A gene trap insertion in ALMS1 on the insulin sensitive C57BL6/Ei genetic background leads to early hyperinsulinemia and a progressive increase in body weight. At 6 weeks of age, before the onset of the metabolic disease, the mutant mice had enlarged fat depots with hypertrophic adipocytes, but without signs of inflammation. Expression of lipogenic enzymes was increased. Pre-adipocytes isolated from mutant animals demonstrated normal adipogenic differentiation but gave rise to mature adipocytes with reduced insulin-stimulated glucose uptake. Assessment of whole body glucose homeostasis revealed glucose intolerance. Insulin stimulation resulted in proper AKT phosphorylation in adipose tissue. However, the total amount of glucose transporter 4 (SLC4A2) and its translocation to the plasma membrane were reduced in mutant adipose depots compared to wildtype littermates. Alterations in insulin stimulated trafficking of glucose transporter 4 are an early sign of metabolic dysfunction in Alstrom mutant mice, providing a possible explanation for the reduced glucose uptake and the compensatory hyperinsulinemia. The metabolic signaling deficits either reside downstream or are independent of AKT activation and suggest a role for ALMS1 in GLUT4 trafficking. Alstrom mutant mice represent an interesting model for the development of metabolic disease in which adipose tissue with a reduced glucose uptake can expand by de novo lipogenesis to an obese state.
Juergen K Naggert - One of the best experts on this subject based on the ideXlab platform.
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Role of Alström syndrome 1 in the regulation of blood pressure and renal function.
JCI insight, 2018Co-Authors: Ankita Bachhawat Jaykumar, Juergen K Naggert, Keyona N King-medina, Paulo S. Caceres, Tang-dong Liao, Indrani Datta, Dipak Maskey, Mariela Mendez, William H. Beierwaltes, Pablo A. OrtizAbstract:Elevated blood pressure (BP) and renal dysfunction are complex traits representing major global health problems. Single nucleotide polymorphisms identified by genome-wide association studies have identified the Alstrom syndrome 1 (ALMS1) gene locus to render susceptibility for renal dysfunction, hypertension, and chronic kidney disease (CKD). Mutations in the ALMS1 gene in humans causes Alstrom syndrome, characterized by progressive metabolic alterations including hypertension and CKD. Despite compelling genetic evidence, the underlying biological mechanism by which mutations in the ALMS1 gene lead to the above-mentioned pathophysiology is not understood. We modeled this effect in a KO rat model and showed that ALMS1 genetic deletion leads to hypertension. We demonstrate that the link between ALMS1 and hypertension involves the activation of the renal Na+/K+/2Cl- cotransporter NKCC2, mediated by regulation of its endocytosis. Our findings establish a link between the genetic susceptibility to hypertension, CKD, and the expression of ALMS1 through its role in a salt-reabsorbing tubular segment of the kidney. These data point to ALMS1 as a potentially novel gene involved in BP and renal function regulation.
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Triple Vectors Expand AAV Transfer Capacity in the Retina
Molecular therapy : the journal of the American Society of Gene Therapy, 2017Co-Authors: Andrea Maddalena, Juergen K Naggert, P. Tornabene, Paola Tiberi, Renato Minopoli, Anna Manfredi, Margherita Mutarelli, Settimio Rossi, Francesca Simonelli, Davide CacchiarelliAbstract:Retinal gene transfer with adeno-associated viral (AAV) vectors holds great promise for the treatment of inherited retinal degenerations (IRDs). One limit of AAV is its transfer capacity of about 5 kb, which can be expanded to about 9 kb, using dual AAV vectors. This strategy would still not suffice for treatment of IRDs such as Usher syndrome type 1D or Alstrom syndrome type I (ALMS) due to mutations in CDH23 or ALMS1, respectively. To overcome this limitation, we generated triple AAV vectors, with a maximal transfer capacity of about 14 kb. Transcriptomic analysis following triple AAV transduction showed the expected full-length products along a number of aberrant transcripts. However, only the full-length transcripts are efficiently translated in vivo. We additionally showed that approximately 4% of mouse photoreceptors are transduced by triple AAV vectors and showed correct localization of recombinant ALMS1. The low-photoreceptor transduction levels might justify the modest and transient improvement we observe in the retina of a mouse model of ALMS. However, the levels of transduction mediated by triple AAV vectors in pig retina reached 40% of those observed with single vectors, and this bodes well for further improving the efficiency of triple AAV vectors in the retina.
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Spectral-domain optical coherence tomography findings in Alström Syndrome
Ophthalmic genetics, 2017Co-Authors: Gad Dotan, Gayle B. Collin, Juergen K Naggert, Jan D. Marshall, Vikas Khetan, Elizabeth Affel, Denise Armiger-george, Alex V. LevinAbstract:Background: Alstrom syndrome is a multi-system recessive disorder caused by mutations in ALMS1 gene. The aim of this study was to characterize morphological retinal changes in Alstrom patients usin...
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GLUT4 defects in adipose tissue are early signs of metabolic alterations in ALMS1GT/GT, a mouse model for obesity and insulin resistance.
PloS one, 2014Co-Authors: Francesca Favaretto, Gayle B. Collin, Jan D. Marshall, Pietro Maffei, Gabriella Milan, Roberto Vettor, Fabio Stasi, Juergen K NaggertAbstract:Dysregulation of signaling pathways in adipose tissue leading to insulin resistance can contribute to the development of obesity-related metabolic disorders. Alstrom Syndrome, a recessive ciliopathy, caused by mutations in ALMS1, is characterized by progressive metabolic alterations such as childhood obesity, hyperinsulinemia, and type 2 diabetes. Here we investigated the role of ALMS1 disruption in AT expansion and insulin responsiveness in a murine model for Alstrom Syndrome. A gene trap insertion in ALMS1 on the insulin sensitive C57BL6/Ei genetic background leads to early hyperinsulinemia and a progressive increase in body weight. At 6 weeks of age, before the onset of the metabolic disease, the mutant mice had enlarged fat depots with hypertrophic adipocytes, but without signs of inflammation. Expression of lipogenic enzymes was increased. Pre-adipocytes isolated from mutant animals demonstrated normal adipogenic differentiation but gave rise to mature adipocytes with reduced insulin-stimulated glucose uptake. Assessment of whole body glucose homeostasis revealed glucose intolerance. Insulin stimulation resulted in proper AKT phosphorylation in adipose tissue. However, the total amount of glucose transporter 4 (SLC4A2) and its translocation to the plasma membrane were reduced in mutant adipose depots compared to wildtype littermates. Alterations in insulin stimulated trafficking of glucose transporter 4 are an early sign of metabolic dysfunction in Alstrom mutant mice, providing a possible explanation for the reduced glucose uptake and the compensatory hyperinsulinemia. The metabolic signaling deficits either reside downstream or are independent of AKT activation and suggest a role for ALMS1 in GLUT4 trafficking. Alstrom mutant mice represent an interesting model for the development of metabolic disease in which adipose tissue with a reduced glucose uptake can expand by de novo lipogenesis to an obese state.
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alstrom syndrome cardiac magnetic resonance findings
International Journal of Cardiology, 2013Co-Authors: Francesco Corbetti, Juergen K Naggert, Jan D. Marshall, Gabriella Milan, Renato Razzolini, Vera Bettini, Francesco Tona, Pietro MaffeiAbstract:Abstract Background Alstrom Syndrome (ALMS) is an extremely rare multiorgan disease caused by mutations in ALMS1 . Dilated cardiomyopathy (DCM) is a common finding but only one series has been investigated by Cardiac Magnetic Resonance (CMR). Methods Eight genetically proven ALMS patients (ages 11–41) underwent CMR performed by standard cine steady state, T1, T2 and late gadolinium enhancement (LGE) sequences. Ejection fraction (EF), Diastolic Volume (EDV) and Systolic Volume normalized for body surface area (ESV), and mass indices were determined, as well as EDV/Mass ratio, an index expressing the adequacy of cardiac mass to heart volume. Regional fibrosis was assessed by LGE; diffuse fibrosis was measured by a TI scout sequence acquired at 5, 10 and 15min after gadolinium by comparing inversion time values (TI) at null time in ALMS and control group. Results In one patient severe DCM was present with diffuse LGE. There were seven cases without clinical DCM. In these patients, EF was at lower normal limits or slightly reduced and ESV index increased; six patients had decreased mass index and EDV/Mass ratio. Mild regional non ischemic fibrosis was detected by LGE in three cases; diffuse fibrosis was observed in all cases, as demonstrated by shorter TI values in ALMS in comparison with controls (5min: 152±12 vs 186±16, p 0.0002; 10min: 175±8 vs 204±18, p 0.0012; 15min: 193±9 vs 224±16, p 0.0002). Conclusions Cardiac involvement in ALMS is characterized by progressive DCM, associated with systolic dysfunction, myocardial fibrosis and reduced myocardial mass.