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1.
EMBO J ; 39(17): e105696, 2020 09 01.
Article in English | MEDLINE | ID: mdl-32716134

ABSTRACT

Lysosomal degradation of the endoplasmic reticulum (ER) via autophagy (ER-phagy) is emerging as a critical regulator of cell homeostasis and function. The recent identification of ER-phagy receptors has shed light on the molecular mechanisms underlining this process. However, the signaling pathways regulating ER-phagy in response to cellular needs are still largely unknown. We found that the nutrient responsive transcription factors TFEB and TFE3-master regulators of lysosomal biogenesis and autophagy-control ER-phagy by inducing the expression of the ER-phagy receptor FAM134B. The TFEB/TFE3-FAM134B axis promotes ER-phagy activation upon prolonged starvation. In addition, this pathway is activated in chondrocytes by FGF signaling, a critical regulator of skeletal growth. FGF signaling induces JNK-dependent proteasomal degradation of the insulin receptor substrate 1 (IRS1), which in turn inhibits the PI3K-PKB/Akt-mTORC1 pathway and promotes TFEB/TFE3 nuclear translocation and enhances FAM134B transcription. Notably, FAM134B is required for protein secretion in chondrocytes, and cartilage growth and bone mineralization in medaka fish. This study identifies a new signaling pathway that allows ER-phagy to respond to both metabolic and developmental cues.


Subject(s)
Autophagy , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism , Cell Nucleus/metabolism , Endoplasmic Reticulum/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Membrane Proteins/metabolism , Signal Transduction , Active Transport, Cell Nucleus , Animals , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics , Cell Nucleus/genetics , Endoplasmic Reticulum/genetics , HeLa Cells , Humans , Intracellular Signaling Peptides and Proteins/genetics , Mechanistic Target of Rapamycin Complex 1/genetics , Mechanistic Target of Rapamycin Complex 1/metabolism , Membrane Proteins/genetics , Mice , Oryzias
2.
J Clin Invest ; 127(10): 3717-3729, 2017 Oct 02.
Article in English | MEDLINE | ID: mdl-28872463

ABSTRACT

The mammalian target of rapamycin complex 1 (mTORC1) kinase promotes cell growth by activating biosynthetic pathways and suppressing catabolic pathways, particularly that of macroautophagy. A prerequisite for mTORC1 activation is its translocation to the lysosomal surface. Deregulation of mTORC1 has been associated with the pathogenesis of several diseases, but its role in skeletal disorders is largely unknown. Here, we show that enhanced mTORC1 signaling arrests bone growth in lysosomal storage disorders (LSDs). We found that lysosomal dysfunction induces a constitutive lysosomal association and consequent activation of mTORC1 in chondrocytes, the cells devoted to bone elongation. mTORC1 hyperphosphorylates the protein UV radiation resistance-associated gene (UVRAG), reducing the activity of the associated Beclin 1-Vps34 complex and thereby inhibiting phosphoinositide production. Limiting phosphoinositide production leads to a blockage of the autophagy flux in LSD chondrocytes. As a consequence, LSD chondrocytes fail to properly secrete collagens, the main components of the cartilage extracellular matrix. In mouse models of LSD, normalization of mTORC1 signaling or stimulation of the Beclin 1-Vps34-UVRAG complex rescued the autophagy flux, restored collagen levels in cartilage, and ameliorated the bone phenotype. Taken together, these data unveil a role for mTORC1 and autophagy in the pathogenesis of skeletal disorders and suggest potential therapeutic approaches for the treatment of LSDs.


Subject(s)
Autophagy , Bone Development , Lysosomal Storage Diseases/metabolism , Multiprotein Complexes/metabolism , TOR Serine-Threonine Kinases/metabolism , Animals , Beclin-1/genetics , Beclin-1/metabolism , Chondrocytes/metabolism , Chondrocytes/pathology , Lysosomal Storage Diseases/genetics , Lysosomal Storage Diseases/pathology , Mechanistic Target of Rapamycin Complex 1 , Mice , Mice, Knockout , Multiprotein Complexes/genetics , Phosphatidylinositols/genetics , Phosphatidylinositols/metabolism , Phosphorylation/genetics , Phosphorylation/radiation effects , TOR Serine-Threonine Kinases/genetics , Ultraviolet Rays
3.
J Food Sci ; 77(12): S413-8, 2012 Dec.
Article in English | MEDLINE | ID: mdl-22888812

ABSTRACT

Food preferences are the main factor driving food intake and choice. There are good reasons to suspect some genetic influence on food acceptance, not least because genetic factors are implicated in a number of factors that are likely to be related to food choice. In addition, some food dislikes show themselves early in life, before there is any evidence for aversive experiences. Although taste has been widely studied in regards of pure tastes such as bitter or sweet perception, the relationship between taste-related genes and food preferences has seldom been explored. In this work we investigated relationship of 37 taste-related genes with food preferences. The study was carried out during a scientific expedition through Caucasus and Central Asia (Silk Road) analyzing more than 400 samples from 5 different countries. A food preference questionnaire was administered to each participant and a DNA sample was obtained. Other information, such as age, sex, life style and anthropometrical measures, were also collected. We found significant associations with variants of: (1) TAS1R2 [Correction added after initial online publication on 27 Aug 2012. TAS1R3 was changed to TAS1R2.] gene and liking of Vodka (P= 1.6 × 10(-3)), white wine (P= 4.0 × 10(-4)) and lamb meat (P= 1.6 × 10(-3)); (2) PCLB2 gene and preference for Hot Tea (P= 8.0 × 10(-4)); (3) TPRV1 gene and beet liking (P= 3.8 × 10(-5)); and (4) ITPR3 gene and liking of both lamb meat (5.8 × 10(-4)) and sheep cheese (8.9×10(-4)). These findings give a new insight on a better understanding, of genetic factors influencing food preferences which is critical to the development of effective dietary interventions, especially for people that may be genetically not predisposed for liking specific nutrients.


Subject(s)
Choice Behavior , Feeding Behavior , Food Preferences , Taste/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Azerbaijan , Child , Cohort Studies , Female , Gene Frequency , Genotype , Georgia (Republic) , Humans , Kazakhstan , Linear Models , Male , Middle Aged , Polymorphism, Single Nucleotide , Quantitative Trait Loci , Surveys and Questionnaires , Tajikistan , Uzbekistan , Young Adult
4.
Eur J Hum Genet ; 19(5): 593-6, 2011 May.
Article in English | MEDLINE | ID: mdl-21248747

ABSTRACT

Large-scale population studies have established that genetic factors contribute to individual differences in smoking behavior. Linkage and genome-wide association studies have shown many chromosomal regions and genes associated with different smoking behaviors. One study was the association of single-nucleotide polymorphisms (SNPs) in the CHRNA5-A3-B4 gene cluster to nicotine addiction. Here, we report a replication of this association in the Italian population represented by three genetically isolated populations. One, the Val Borbera, is a genetic isolate from North-Western Italy; the Cilento population, is located in South-Western Italy; and the Carlantino village is located in South-Eastern Italy. Owing to their position and their isolation, the three populations have a different environment, different history and genetic structure. The variant A of the rs1051730 SNP was significantly associated with smoking quantity in two populations, Val Borbera and Cilento, no association was found in Carlantino population probably because difference in LD pattern in the variant region.


Subject(s)
Genome-Wide Association Study , Nerve Tissue Proteins/genetics , Polymorphism, Single Nucleotide , Receptors, Nicotinic/genetics , Smoking/genetics , Tobacco Use Disorder/genetics , Genetic Predisposition to Disease , Humans , Italy , Multigene Family
5.
PLoS One ; 5(8): e12394, 2010 Aug 25.
Article in English | MEDLINE | ID: mdl-20811630

ABSTRACT

Humans' bitter taste perception is mediated by the hTAS2R subfamily of the G protein-coupled membrane receptors (GPCRs). Structural information on these receptors is currently limited. Here we identify residues involved in the binding of phenylthiocarbamide (PTC) and in receptor activation in one of the most widely studied hTAS2Rs (hTAS2R38) by means of structural bioinformatics and molecular docking. The predictions are validated by site-directed mutagenesis experiments that involve specific residues located in the putative binding site and trans-membrane (TM) helices 6 and 7 putatively involved in receptor activation. Based on our measurements, we suggest that (i) residue N103 participates actively in PTC binding, in line with previous computational studies. (ii) W99, M100 and S259 contribute to define the size and shape of the binding cavity. (iii) W99 and M100, along with F255 and V296, play a key role for receptor activation, providing insights on bitter taste receptor activation not emerging from the previously reported computational models.


Subject(s)
Phenylthiourea/metabolism , Phenylthiourea/pharmacology , Receptors, G-Protein-Coupled/agonists , Receptors, G-Protein-Coupled/metabolism , Amino Acid Sequence , Calcium/metabolism , Cell Line , Computational Biology , Dose-Response Relationship, Drug , Humans , Intracellular Space/drug effects , Intracellular Space/metabolism , Ligands , Models, Molecular , Molecular Sequence Data , Mutagenesis, Site-Directed , Protein Binding , Protein Structure, Secondary , Receptors, G-Protein-Coupled/chemistry , Receptors, G-Protein-Coupled/genetics
6.
Chem Senses ; 35(9): 801-12, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20801896

ABSTRACT

Although bitter taste has a crucial role in nutrition by preventing the ingestion of toxic foods, there are few studies on bitter taste neuroimaging. To identify cortical areas involved in bitter taste perception and to determine if individual differences in taste sensitivity to 6-n-propylthiouracil (PROP) are represented in the brain by different cortical activation patterns, we examined 48 healthy volunteers using functional near-infrared spectroscopy. Participants rated the perceived intensity of filter paper disks impregnated with PROP and NaCl during the imaging procedure and were then classified as PROP tasters and nontasters. We monitored cortical activity in both the anterior and posterior regions of the dorsolateral prefrontal cortex (DLPFC) and in the ventrolateral prefrontal cortex (VLPFC). No activity was detected in the anterior DLPFC in any of the participants. However, during the administration of PROP, significant cortical activation was detected in the more posterior regions of the left DLPFC and in the left and right VLPFC but only in PROP tasters. PROP nontasters showed no cortical activity in these areas. These data suggest that the prefrontal cortex is involved in the conscious perception of the bitter taste of PROP and that the pattern of activity is consistent with individual differences in the ability to taste this compound. Thus, the PROP phenotype is associated with fundamental differences in cortical taste processing.


Subject(s)
Individuality , Perception/drug effects , Prefrontal Cortex/drug effects , Propylthiouracil/pharmacology , Sodium Chloride/pharmacology , Spectroscopy, Near-Infrared/methods , Taste Threshold/drug effects , Taste/drug effects , Adult , Eating , Female , Food Preferences , Humans , Male , Perception/physiology , Phenotype , Prefrontal Cortex/physiology , Taste/physiology , Taste Threshold/physiology , Young Adult
7.
Amino Acids ; 38(1): 65-73, 2010 Jan.
Article in English | MEDLINE | ID: mdl-19067108

ABSTRACT

The study of two different Italian isolated populations was combined with a metabonomic approach to better understand tubular handling of amino acids. Levels of amino acids and metabolites have been analyzed by Nucleic Magnetic Resonance and expressed as ratio vs urinary creatinine concentration (mmol/mol). For most of the amino acids there is an age-related U shape pattern of excretion, with the peaks during childhood and old age, and a significant reduction in the adult age. Hierarchical cluster analysis has clearly identified three groups clustering the same amino acids: His, Thr and Ala (group one); Gly and Phe (group two) and a third larger one. Results have been further confirmed by factor and regression analysis, and used to confirm and, in some cases, infer new amino acids networks. As a matter of facts, the identification of strong evidences for clustering of urine excretion of several neutral amino acids suggests the predominant impact of relevant and common transporters.


Subject(s)
Amino Acids/urine , Metabolomics , Population Groups , Adolescent , Adult , Age Factors , Aged , Amino Acids/chemistry , Child , Child, Preschool , Female , Humans , Italy , Male , Middle Aged , Rural Population , Young Adult
8.
Ann N Y Acad Sci ; 1170: 126-39, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19686122

ABSTRACT

The ability to taste bitter thiourea compounds and related chemicals is a well-known human trait. The majority of individuals perceive these compounds, typified by the bitterness of 6-n-propylthiouracil (PROP) and phenylthiocarbamide (PTC), as moderately-to-extremely bitter. Approximately 30% of the population is taste blind to these substances. It has been hypothesized that PROP/PTC tasters are more sensitive to other bitter tastes, sweet taste, the pungency of chili peppers, the astringency of alcohol, and the texture of fats. Tasters may also show lower preferences for foods with these taste qualities than nontasters who show the opposite set of responses (i.e., lower taste sensitivities and higher preferences for these sensory qualities). This pathway is illustrated in the following model: PROP Sensitivity --> Food Perception -->Preference --> Selection. Robust associations between PROP status and taste perceptions have been well documented. However, subsequent links to food preferences and diet selection have been more difficult to demonstrate. This is not surprising given the complexity of human ingestive behavior that is influenced by numerous factors including health attitudes, personality traits, and cultural norms. Our laboratory has been using PROP screening to investigate individual differences in the selection of bitter foods, especially bitter tasting vegetables and fruits that may have long-term health implications. This chapter will discuss new and recent findings addressing the following issues: 1) whether PROP-related differences in perception of bitter compounds predict the perception and liking of bitter foods; 2) the role of bitter taste modifiers; and 3) the influence of personal characteristics such as food attitudes and cultural background on PROP-related food preferences.


Subject(s)
Food Preferences , Genetic Variation , Propylthiouracil/pharmacology , Taste Perception/drug effects , Humans , Taste Perception/genetics
9.
Obesity (Silver Spring) ; 16(10): 2289-95, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18719631

ABSTRACT

OBJECTIVE: Variation in the bitter-taste receptor gene, TAS2R38 confers the ability to taste 6-n-propylthiouracil (PROP). The objective of this study was to relate TAS2R38 haplotypes and PROP-tasting phenotypes to adiposity in a genetically isolated population. We hypothesized that the nontaster phenotype would be associated with higher BMI and waist circumference (WC) in females, and that dietary restraint would mediate this relationship. METHODS AND PROCEDURES: Participants were 540 healthy inhabitants of the genetically isolated village of Carlantino in southern Italy who were 15-89 years of age at the time of the study. Haplotype analyses were performed and PROP tasting was assessed using a filter paper method. Height, weight, and WC were measured and restrained eating was assessed using a brief questionnaire. RESULTS: Nontaster females had higher BMI and WC than females who were phenotypic tasters, and this relationship was specific to females with low dietary restraint. Regression analysis showed that BMI declined by 1.7 units across taster groups in females when the model included the PROP by restraint interaction. PROP phenotype was not significantly associated with WC in the regression models. Polymorphisms in TAS2R38 were not associated with BMI or WC in females. Neither TAS2R38 haplotype nor PROP phenotype was strongly related to BMI or WC in males. DISCUSSION: These data support previous findings of a relation between the nontaster phenotype and higher BMI in females that is modified by dietary restraint. Assessment of PROP phenotypes might provide unique information about adiposity that is not captured by haplotype analysis alone.


Subject(s)
Adiposity/genetics , Polymorphism, Genetic , Receptors, G-Protein-Coupled/genetics , Taste/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Body Height , Body Mass Index , Body Weight , Caloric Restriction , Female , Haplotypes , Humans , Italy , Male , Middle Aged , Phenotype , Propylthiouracil/administration & dosage , Regression Analysis , Sex Factors , Surveys and Questionnaires
10.
Haematologica ; 93(9): 1372-5, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18603552

ABSTRACT

Normal hemoglobin levels vary greatly according to genetic and acquired factors. As a consequence there is no general agreement on the definition of anemia in terms of hemoglobin levels. Here we compare the hemoglobin levels of subjects recruited from normal genetically isolated Italian populations whose medical history, life style habits and results of laboratory tests are available. After the exclusion of pathological samples we analyzed the hemoglobin levels of 3,849 subjects (1,661 males and 2,188 females) and evaluated the hemoglobin heritability. Normal subjects of different age groups from a northern Italian isolate have significantly higher hemoglobin levels when compared to matched subjects of southern Italian isolates. The estimated heritability of hemoglobin levels ranges from 0.34 to 0.42 in the different isolates. Our study provides a dataset of hemoglobin levels for normal subjects of different geographical origin and indicate that hemoglobin levels are substantially influenced by heritable components.


Subject(s)
Hemoglobins/genetics , Hemoglobins/metabolism , Phylogeny , Adolescent , Adult , Aged , Aged, 80 and over , Female , Humans , Italy , Male , Middle Aged
11.
Blood ; 103(11): 4317-21, 2004 Jun 01.
Article in English | MEDLINE | ID: mdl-14982873

ABSTRACT

Juvenile or type 2 hemochromatosis (JH) is transmitted as a recessive trait that leads to severe iron overload and organ damage typically before age 30 years. Linkage to a locus on chromosome 1q has been found in most patients with JH. The recently identified causal gene encodes hemojuvelin, a protein with a proposed crucial role in iron metabolism. A second, rare type of JH, with clinical expression identical to the 1q-linked form, is due to inactivation of hepcidin, the key regulator of iron homeostasis. Here we report the spectrum of mutations of the hemojuvelin gene (HJV) in 34 patients who did not show hepcidin mutations. This represents the largest cohort of patients with JH collected worldwide. We identified 17 different (16 novel) mutations of HJV, both at the homozygous and at the compound heterozygous state. Mutations either generate premature termination codons or were missense substitutions, affecting highly conserved residues, relevant to the protein structure and/or function.


Subject(s)
Hemochromatosis/genetics , Membrane Proteins/genetics , Point Mutation , Adolescent , Adult , Cohort Studies , Family Health , Female , GPI-Linked Proteins , Genetic Testing , Genotype , Hemochromatosis Protein , Humans , Male , Phenotype
12.
Eur J Hum Genet ; 11(8): 585-9, 2003 Aug.
Article in English | MEDLINE | ID: mdl-12891378

ABSTRACT

Juvenile hemochromatosis (JH) is a rare autosomal recessive disorder that causes iron overload. In the French Canadian region of Saguenay Lac-Saint-Jean the worldwide largest cohort of JH cases has been identified. Here, we report the mapping of this large cohort of cases to the HFE2 locus on chromosome 1q. A maximum multipoint location score of 7.02 was observed with marker D1S2344. A common ancestral haplotype, showing the presence of a founder effect, was identified. The analysis of recombinants allowed us to confirm the JH candidate region.


Subject(s)
Chromosome Mapping/methods , Chromosomes, Human, Pair 1 , Hemochromatosis/genetics , Adult , Canada/ethnology , Female , Genetic Linkage , Genetic Markers , Haplotypes/genetics , Humans , Lod Score , Male , Pedigree
14.
Blood Cells Mol Dis ; 30(1): 22-9, 2003.
Article in English | MEDLINE | ID: mdl-12667984

ABSTRACT

Congenital dyserythropoietic anemias (CDA) are genetic disorders characterized by anemia and ineffective erythropoiesis. Three main types of CDA have been distinguished: CDA I, CDAII and CDA III, whose loci have been already mapped. After the identification of the locus for CDA II, also known as HEMPAS (hereditary erythroblast multinuclearity with positive acidified serum test), on the long arm of chromosome 20 (20q11.2) we have analyzed by a mutational search seven candidate genes in a large series of CDA II patients. In particular, the following genes have been investigated: integrin beta 4 binding protein, ribophorin II, ubiquitin protein ligase ITCH, mannosil-oligosaccharide alpha-1,2-mannosidase like protein, erythrocyte protein band 4.1 like protein, zinc finger protein PLAGL2, and finally novel zinc finger protein. None of them resulted as the causative gene but several protein variants and DNA polymorphisms have been identified. These data exclude the role of the above mentioned genes in causing CDA II and add further information in the process of cloning the CDA II gene.


Subject(s)
Anemia, Dyserythropoietic, Congenital/genetics , Genetic Predisposition to Disease/genetics , Anemia, Dyserythropoietic, Congenital/classification , Anemia, Dyserythropoietic, Congenital/pathology , Chromatography, High Pressure Liquid , Chromosome Mapping , Chromosomes, Human, Pair 20/genetics , Erythrocytes/pathology , Erythropoiesis/genetics , Genetic Linkage/genetics , Humans , Mutation , Polymerase Chain Reaction , Polymorphism, Genetic
15.
Am J Med Genet A ; 118A(3): 217-22, 2003 Apr 30.
Article in English | MEDLINE | ID: mdl-12673650

ABSTRACT

X-linked nonspecific mental retardation (MRX) accounts for approximately 25% of mental retardation in males. A number of MRX loci have been mapped on the X chromosome, reflecting the complexity of gene action in central nervous system (CNS) specification and function. Eleven MRX genes have been identified, but many other causative loci remain to be refined to the single gene level. In 21 MRX families, the causative gene is located in the pericentromeric region; and we report here the identification by linkage analysis of a further such locus, MRX81. The new MRX locus was identified by two- and multi-point parametric analysis carried out on a large Italian family. Tight linkage of MRX81 to DNA markers ALAS2, DXS991, and DXS7132 was observed with a maximum LOD score of 3.43. Haplotype construction delineates an MRX81 critical region of 8 cM, the smallest MRX pericentromeric interval so far described, between DXS1039 and DXS1216, and placing it in Xp11.2-Xq12. So far, automated sequencing of two candidates in the region, the MRX gene oligophrenin (OPHN1) and the brain-specific ephrinB1 (EFNB1) gene, in DNA from affected males excluded their candidacy for MRX81, suggesting a novel disease gene.


Subject(s)
Chromosomes, Human, X , Cytoskeletal Proteins , GTPase-Activating Proteins , Genetic Linkage , Lod Score , Mental Retardation, X-Linked/genetics , 5-Aminolevulinate Synthetase/genetics , Alleles , Centrosome/ultrastructure , Chromosome Mapping , DNA Mutational Analysis , Databases as Topic , Ephrin-B1/genetics , Exons , Family Health , Female , Genotype , Haplotypes , Humans , Male , Models, Genetic , Nuclear Proteins/genetics , Pedigree , Phosphoproteins/genetics , Recombination, Genetic
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