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1.  GLUT4 Defects in Adipose Tissue Are Early Signs of Metabolic Alterations in Alms1GT/GT, a Mouse Model for Obesity and Insulin Resistance 
PLoS ONE  2014;9(10):e109540.
Dysregulation of signaling pathways in adipose tissue leading to insulin resistance can contribute to the development of obesity-related metabolic disorders. Alström 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 Alström 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 Alström 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. Alström 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.
PMCID: PMC4192353  PMID: 25299671
2.  Alström Syndrome: Cardiac Magnetic Resonance findings 
International journal of cardiology  2012;167(4):1257-1263.
Alström 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).
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 15 min after gadolinium by comparing inversion time values (TI) at null time in ALMS and control group.
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 (5 min:152±12 vs 186±16, p 0,0002; 10 min: 175±8 vs 204±18, p 0,0012; 15 min: 193± 9 vs 224±16, p 0,0002).
Cardiac involvement in ALMS is characterized by progressive DCM, associated with systolic dysfunction, myocardial fibrosis and reduced myocardial mass.
PMCID: PMC3422598  PMID: 22498418
Alström Syndrome; ALMS1; Dilated cardiomyopathy; Cardiac Magnetic Resonance; fibrosis
3.  Syndromic obesity: clinical implications of a correct diagnosis 
Although individual occurrence is rare, syndromic obesity with mental retardation has been reported in conjunction with 140 different diseases.
Case presentation
The patient was born at term after a pregnancy complicated by threatened miscarriage. A diagnosis of Bardet-Biedl syndrome (BBS; OMIM #209900) was made in another hospital when she was 8 years old, but other clinical problems emerged subsequently. She came to our attention for the first time when she was 14 years old. The clinical picture, characterized by the presence of ophtalmological, renal, endocrinological, and liver disorders associated with a peculiar weight growth pattern, was more suggestive for Alström syndrome (ALMS; OMIM #203800); consequently, a genetic study was performed. Genetic analysis revealed a novel compound heterozygous frameshift mutation on exon 8 of ALMS1 (c. [3251_3258delCTGACCAG] and c. [6731delA]), which has not previously been described.
Early onset of retinal degeneration associated with obesity represents a diagnostic challenge in paediatric and genetic practice, although the absence of skeletal abnormalities and developmental delay could help in addressing the clinical diagnosis. Confirmation of clinical suspicion by genetic analysis has been diriment in this case, since only a single gene is known to cause ALMS.
PMCID: PMC4230022  PMID: 24690487
Alström syndrome; Bardet-Biedl syndrome; Cone-rod dystrophy; Obesity; Syndromic obesity
4.  Brain involvement in Alström syndrome 
Alström Syndrome (AS) is a rare ciliopathy characterized by cone–rod retinal dystrophy, sensorineural hearing loss, obesity, type 2 diabetes mellitus and cardiomyopathy. Most patients do not present with neurological issues and demonstrate normal intelligence, although delayed psychomotor development and psychiatric disorders have been reported. To date, brain Magnetic Resonance Imaging (MRI) abnormalities in AS have not been explored.
We investigated structural brain changes in 12 genetically proven AS patients (mean-age 22 years; range: 6–45, 6 females) and 19 matched healthy and positive controls (mean-age 23 years; range: 6–43; 12 females) using conventional MRI, Voxel-Based Morphometry (VBM) and Diffusion Tensor Imaging (DTI).
6/12 AS patients presented with brain abnormalities such as ventricular enlargement (4/12), periventricular white matter abnormalities (3/12) and lacune-like lesions (1/12); all patients older than 30 years had vascular-like lesions. VBM detected grey and white matter volume reduction in AS patients, especially in the posterior regions. DTI revealed significant fractional anisotropy decrease and radial diffusivity increase in the supratentorial white matter, also diffusely involving those regions that appeared normal on conventional imaging. On the contrary, axial and mean diffusivity did not differ from controls except in the fornix.
Brain involvement in Alström syndrome is not uncommon. Early vascular-like lesions, gray and white matter atrophy, mostly involving the posterior regions, and diffuse supratentorial white matter derangement suggest a role of cilia in endothelial cell and oligodendrocyte function.
PMCID: PMC3584911  PMID: 23406482
Alström syndrome; MRI; DTI; VBM
5.  The progression from obesity to type 2 diabetes in Alström syndrome 
Pediatric Diabetes  2011;13(1):59-67.
Alström syndrome (ALMS) is a rare autosomal recessive monogenic disease associated with obesity, hyperinsulinemia and alterations of glucose metabolism that often lead to the development of type 2 diabetes in a young age.
Relationship between weight and metabolism has been studied in a group of ALMS patients and matched controls.
Research design and methods
Fifteen ALMS patients (8 M, 7 F, aged 3-51 yrs) were compared in a cross-sectional study with an age- and weight-matched control population. Anthropometric parameters, fat mass, glucose and insulin secretion in basal and dynamic (OGTT) conditions were measured. Further anthropometric and body composition data were obtained from an International group of 27 ALMS patients (13 M, 14 F, age range: 4-29 yrs).
In ALMS we observed an inverse correlation between age and SDS for height, weight and BMI. The OGTT glycemic curves of ALMS subjects were similar to those of age-matched controls, while insulin response was clearly greater. In ALMS individuals the insulin response showed a reduction with age. We documented pathologic values of the derived indices HOMA-IR, ISI, HOMA%β cell and Insulinogenic Index in ALMS, but unlike the insulin-resistance indices, the beta-cell function indices showed a significant reduction with age.
In ALMS the progression from the early onset obesity towards the impaired fasting glucose or IGT and overt diabetes is mostly due to a progressive failure of β-cell insulin secretion without any further worsening of insulin resistance with age, even in the presence of weight reduction.
PMCID: PMC3345208  PMID: 21722283
Alström syndrome; ALMS1; obesity; diabetes; insulin resistance
6.  The Alström Syndrome Protein, ALMS1, Interacts with α-Actinin and Components of the Endosome Recycling Pathway 
PLoS ONE  2012;7(5):e37925.
Alström syndrome (ALMS) is a progressive multi-systemic disorder characterized by cone-rod dystrophy, sensorineural hearing loss, childhood obesity, insulin resistance and cardiac, renal, and hepatic dysfunction. The gene responsible for Alström syndrome, ALMS1, is ubiquitously expressed and has multiple splice variants. The protein encoded by this gene has been implicated in ciliary function, cell cycle control, and intracellular transport. To gain better insight into the pathways through which ALMS1 functions, we carried out a yeast two hybrid (Y2H) screen in several mouse tissue libraries to identify ALMS1 interacting partners. The majority of proteins found to interact with the murine carboxy-terminal end (19/32) of ALMS1 were α-actinin isoforms. Interestingly, several of the identified ALMS1 interacting partners (α-actinin 1, α-actinin 4, myosin Vb, rad50 interacting 1 and huntingtin associated protein1A) have been previously associated with endosome recycling and/or centrosome function. We examined dermal fibroblasts from human subjects bearing a disruption in ALMS1 for defects in the endocytic pathway. Fibroblasts from these patients had a lower uptake of transferrin and reduced clearance of transferrin compared to controls. Antibodies directed against ALMS1 N- and C-terminal epitopes label centrosomes and endosomal structures at the cleavage furrow of dividing MDCK cells, respectively, suggesting isoform-specific cellular functions. Our results suggest a role for ALMS1 variants in the recycling endosome pathway and give us new insights into the pathogenesis of a subset of clinical phenotypes associated with ALMS.
PMCID: PMC3365098  PMID: 22693585
8.  ALMS1-Deficient Fibroblasts Over-Express Extra-Cellular Matrix Components, Display Cell Cycle Delay and Are Resistant to Apoptosis 
PLoS ONE  2011;6(4):e19081.
Alström Syndrome (ALMS) is a rare genetic disorder (483 living cases), characterized by many clinical manifestations, including blindness, obesity, type 2 diabetes and cardiomyopathy. ALMS is caused by mutations in the ALMS1 gene, encoding for a large protein with implicated roles in ciliary function, cellular quiescence and intracellular transport. Patients with ALMS have extensive fibrosis in nearly all tissues resulting in a progressive organ failure which is often the ultimate cause of death. To focus on the role of ALMS1 mutations in the generation and maintenance of this pathological fibrosis, we performed gene expression analysis, ultrastructural characterization and functional assays in 4 dermal fibroblast cultures from ALMS patients. Using a genome-wide gene expression analysis we found alterations in genes belonging to specific categories (cell cycle, extracellular matrix (ECM) and fibrosis, cellular architecture/motility and apoptosis). ALMS fibroblasts display cytoskeleton abnormalities and migration impairment, up-regulate the expression and production of collagens and despite the increase in the cell cycle length are more resistant to apoptosis. Therefore ALMS1-deficient fibroblasts showed a constitutively activated myofibroblast phenotype even if they do not derive from a fibrotic lesion. Our results support a genetic basis for the fibrosis observed in ALMS and show that both an excessive ECM production and a failure to eliminate myofibroblasts are key mechanisms. Furthermore, our findings suggest new roles for ALMS1 in both intra- and extra-cellular events which are essential not only for the normal cellular function but also for cell-cell and ECM-cell interactions.
PMCID: PMC3082548  PMID: 21541333
9.  Clonal Characterization of Rat Muscle Satellite Cells: Proliferation, Metabolism and Differentiation Define an Intrinsic Heterogeneity 
PLoS ONE  2010;5(1):e8523.
Satellite cells (SCs) represent a distinct lineage of myogenic progenitors responsible for the postnatal growth, repair and maintenance of skeletal muscle. Distinguished on the basis of their unique position in mature skeletal muscle, SCs were considered unipotent stem cells with the ability of generating a unique specialized phenotype. Subsequently, it was demonstrated in mice that opposite differentiation towards osteogenic and adipogenic pathways was also possible. Even though the pool of SCs is accepted as the major, and possibly the only, source of myonuclei in postnatal muscle, it is likely that SCs are not all multipotent stem cells and evidences for diversities within the myogenic compartment have been described both in vitro and in vivo. Here, by isolating single fibers from rat flexor digitorum brevis (FDB) muscle we were able to identify and clonally characterize two main subpopulations of SCs: the low proliferative clones (LPC) present in major proportion (∼75%) and the high proliferative clones (HPC), present instead in minor amount (∼25%). LPC spontaneously generate myotubes whilst HPC differentiate into adipocytes even though they may skip the adipogenic program if co-cultured with LPC. LPC and HPC differ also for mitochondrial membrane potential (ΔΨm), ATP balance and Reactive Oxygen Species (ROS) generation underlying diversities in metabolism that precede differentiation. Notably, SCs heterogeneity is retained in vivo. SCs may therefore be comprised of two distinct, though not irreversibly committed, populations of cells distinguishable for prominent differences in basal biological features such as proliferation, metabolism and differentiation. By these means, novel insights on SCs heterogeneity are provided and evidences for biological readouts potentially relevant for diagnostic purposes described.
PMCID: PMC2796166  PMID: 20049087
10.  Dissecting the Immune Response to Moloney Murine Sarcoma/Leukemia Virus-Induced Tumors by Means of a DNA Vaccination Approach 
Journal of Virology  1999;73(3):2280-2287.
The intramuscular inoculation of Moloney murine sarcoma/leukemia (M-MSV/M-MuLV) retroviral complex gives rise to sarcomas that undergo spontaneous regression due to the induction of a strong immune reaction mediated primarily by cytotoxic T lymphocytes (CTL). We used a DNA-based vaccination approach to dissect the CTL response against the Gag and Env proteins of M-MSV/M-MuLV in C57BL/6 (B6) mice and to evaluate whether plasmid DNA-immunized mice would be protected against a subsequent challenge with syngeneic tumor cells expressing the viral antigens. Intramuscular DNA vaccination induced CTL against both Gag and Env proteins. A detailed analysis of epitopes recognized by CTL generated in mice inoculated with the whole virus and with the Gag-expressing plasmid confirmed the presence of an immunodominant peptide in the leader sequence of Gag protein (Gag85–93, CCLCLTVFL) that is identical to that described in B6 mice immunized with Friend MuLV-induced leukemia cells. Moreover, CTL generated by immunization with the Env-encoding plasmid recognized a subdominant Env peptide (Env189–196, SSWDFITV), originally described in the B6.CH-2bm13 mutant strain. B6 mice immunized with the Gag-expressing plasmid were fully protected against a lethal tumor challenge with M-MuLV-transformed MBL-2 leukemia cells, while vaccination with the Env-expressing plasmid resulted in rejection of the tumor in 44% of the mice and in increased survival of an additional 17% of the animals. Taken together, these results indicate the existence of a hierarchy in the capacity of different structural viral proteins to induce a protective immune response against retrovirus-induced tumors.
PMCID: PMC104473  PMID: 9971811

Results 1-10 (10)