Divergent Metabolic Phenotype between Two Sisters with Congenital Generalized Lipodystrophy Due to Double AGPAT2 Homozygous Mutations. A Clinical, Genetic and In Silico Study
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{"title"=>"Divergent metabolic phenotype between two sisters with congenital generalized lipodystrophy due to double AGPAT2 homozygous mutations. A clinical, genetic and in silico study", "type"=>"journal", "authors"=>[{"first_name"=>"Víctor A.", "last_name"=>"Cortés", "scopus_author_id"=>"15834275900"}, {"first_name"=>"Susan V.", "last_name"=>"Smalley", "scopus_author_id"=>"23091916900"}, {"first_name"=>"Denisse", "last_name"=>"Goldenberg", "scopus_author_id"=>"56073518100"}, {"first_name"=>"Carlos F.", "last_name"=>"Lagos", "scopus_author_id"=>"23019461900"}, {"first_name"=>"María I.", "last_name"=>"Hodgson", "scopus_author_id"=>"7102531156"}, {"first_name"=>"José L.", "last_name"=>"Santos", "scopus_author_id"=>"35390966900"}], "year"=>2014, "source"=>"PLoS ONE", "identifiers"=>{"scopus"=>"2-s2.0-84900314697", "doi"=>"10.1371/journal.pone.0087173", "sgr"=>"84900314697", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "pmid"=>"24498038", "issn"=>"19326203", "pui"=>"373059496"}, "id"=>"39985e11-874a-38c9-8611-1c73f0b49daa", "abstract"=>"Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by extreme reduction of white adipose tissue (WAT) mass. CGL type 1 is the most frequent form and is caused by mutations in AGPAT2. Genetic and clinical studies were performed in two affected sisters of a Chilean family. These patients have notoriously dissimilar metabolic abnormalities that correlate with differential levels of circulating leptin and soluble leptin receptor fraction. Sequencing of AGPAT2 exons and exon-intron boundaries revealed two homozygous mutations in both sisters. Missense mutation c.299G>A changes a conserved serine in the acyltransferase NHX4D motif of AGPAT2 (p.Ser100Asn). Intronic c.493-1G>C mutation destroy a conserved splicing site that likely leads to exon 4 skipping and deletion of whole AGPAT2 substrate binding domain. In silico protein modeling provided insights of the mechanisms of lack of catalytic activity owing to both mutations.", "link"=>"http://www.mendeley.com/research/divergent-metabolic-phenotype-between-two-sisters-congenital-generalized-lipodystrophy-due-double-ag", "reader_count"=>21, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>3, "Librarian"=>1, "Student > Doctoral Student"=>1, "Researcher"=>3, "Student > Ph. D. Student"=>4, "Student > Postgraduate"=>1, "Student > Master"=>4, "Student > Bachelor"=>1, "Lecturer > Senior Lecturer"=>1, "Professor"=>1}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>3, "Librarian"=>1, "Student > Doctoral Student"=>1, "Researcher"=>3, "Student > Ph. D. Student"=>4, "Student > Postgraduate"=>1, "Student > Master"=>4, "Student > Bachelor"=>1, "Lecturer > Senior Lecturer"=>1, "Professor"=>1}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>6, "Nursing and Health Professions"=>2, "Agricultural and Biological Sciences"=>5, "Medicine and Dentistry"=>6, "Pharmacology, Toxicology and Pharmaceutical Science"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>6}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>5}, "Nursing and Health Professions"=>{"Nursing and Health Professions"=>2}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>6}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "reader_count_by_country"=>{"Chile"=>2}, "group_count"=>2}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1372016"], "description"=>"<p><b>A)</b> Patient 1 (P1) and patient 2 (P2) harbor the single nucleotide substitution c.299G>A in exon 2 of <i>AGPAT2</i> gene (black arrows). This changes wild type codon AGC (not shown), that encodes for serine, to AAC (underlined), that encodes for Asparagine. <b>B)</b> Patient 1 (P1) and patient 2 (P2) also harbor the single nucleotide substitution c.493-1G>C (black arrows) in intron 3– exon 4 boundary. *denotes the first nucleotide of exon 4.</p>", "links"=>[], "tags"=>["Biochemistry", "lipids", "Fatty acids", "metabolism", "Lipid metabolism", "Bioenergetics", "genetics", "Human genetics", "Autosomal recessive", "Genetic mutation", "Anatomy and physiology", "Endocrine system", "Endocrine physiology", "insulin", "Integrative physiology", "Physiological processes", "Clinical genetics", "Congenital hereditary myopathies", "Endocrinology", "Diabetic endocrinology", "Diabetes mellitus type 2", "Metabolic disorders", "nutrition", "obesity", "mutated", "sisters"], "article_id"=>922662, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Víctor A. Cortés", "Susan V. Smalley", "Denisse Goldenberg", "Carlos F. Lagos", "María I. Hodgson", "José L. Santos"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0087173.g001", "stats"=>{"downloads"=>0, "page_views"=>19, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_AGPAT2_is_double_mutated_in_two_sisters_with_CGL_/922662", "title"=>"<i>AGPAT2</i> is double mutated in two sisters with CGL.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-01-31 04:04:43"}
  • {"files"=>["https://ndownloader.figshare.com/files/1372023"], "description"=>"_", "links"=>[], "tags"=>["Biochemistry", "lipids", "Fatty acids", "metabolism", "Lipid metabolism", "Bioenergetics", "genetics", "Human genetics", "Autosomal recessive", "Genetic mutation", "Anatomy and physiology", "Endocrine system", "Endocrine physiology", "insulin", "Integrative physiology", "Physiological processes", "Clinical genetics", "Congenital hereditary myopathies", "Endocrinology", "Diabetic endocrinology", "Diabetes mellitus type 2", "Metabolic disorders", "nutrition", "obesity", "primers", "exon", "intron", "boundaries"], "article_id"=>922667, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Víctor A. Cortés", "Susan V. Smalley", "Denisse Goldenberg", "Carlos F. Lagos", "María I. Hodgson", "José L. Santos"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0087173.t001", "stats"=>{"downloads"=>5, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_PCR_primers_used_for_AGPAT2_exon_intron_boundaries_sequencing_/922667", "title"=>"PCR primers used for <i>AGPAT2</i> exon - intron boundaries sequencing.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-01-31 04:04:43"}
  • {"files"=>["https://ndownloader.figshare.com/files/1372021"], "description"=>"<p><b>A</b>) Representation of the secondary structure of the modeled human AGPAT2 protein. Green color denotes the segment between Leu165 and Ala195 that contains the acyl-glycerol-3-phosphate substrate binding motif (PEGTR) and that is encoed by exon 4. This segment is possibly deleted in c.493-1G>C mutants and converge with the catalytic site, that is colored in magenta. <b>B)</b> Snapshot of the proposed molecular interactions between LPA (C18∶1) and human AGPAT2. The polar part of the substrate make contacts with a cluster of basic residues, while its alkyl chain is accommodated inside a tunnel made of a cluster of hydrophobic aminoacid side chains.</p>", "links"=>[], "tags"=>["Biochemistry", "lipids", "Fatty acids", "metabolism", "Lipid metabolism", "Bioenergetics", "genetics", "Human genetics", "Autosomal recessive", "Genetic mutation", "Anatomy and physiology", "Endocrine system", "Endocrine physiology", "insulin", "Integrative physiology", "Physiological processes", "Clinical genetics", "Congenital hereditary myopathies", "Endocrinology", "Diabetic endocrinology", "Diabetes mellitus type 2", "Metabolic disorders", "nutrition", "obesity", "modeling"], "article_id"=>922665, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Víctor A. Cortés", "Susan V. Smalley", "Denisse Goldenberg", "Carlos F. Lagos", "María I. Hodgson", "José L. Santos"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0087173.g002", "stats"=>{"downloads"=>1, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Molecular_modeling_of_hAGPAT2_/922665", "title"=>"Molecular modeling of hAGPAT2.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-01-31 04:04:43"}
  • {"files"=>["https://ndownloader.figshare.com/files/1372022"], "description"=>"1<p>Reference values of normal Chilean female population (Pontificia Universidad Católica de Chile).</p>2<p>Reference values obtained from 13 healthy subjects matched by age and sex.</p>3<p>Reference resting energy expenditure was individually determined by instrument’s internal algorithm on the basis of anthropometry, age and sex individual’s data.</p><p>Abbreviations: A1C, glycated hemoglobin; HOMA-IR, HOMA-insulin resistance; HDL, high density lipoprotein, SGOT, serum glutamic oxalacetic transaminase; SGPT, Serum glutamic pyruvic transaminase; Free T4, free thyroxine; TSH, thyroid stimulating hormone; SHBG, sex hormone binding globulin; LepRs, leptin receptor soluble fraction; N.D., not-detected.</p>", "links"=>[], "tags"=>["Biochemistry", "lipids", "Fatty acids", "metabolism", "Lipid metabolism", "Bioenergetics", "genetics", "Human genetics", "Autosomal recessive", "Genetic mutation", "Anatomy and physiology", "Endocrine system", "Endocrine physiology", "insulin", "Integrative physiology", "Physiological processes", "Clinical genetics", "Congenital hereditary myopathies", "Endocrinology", "Diabetic endocrinology", "Diabetes mellitus type 2", "Metabolic disorders", "nutrition", "obesity", "expenditure", "characterization", "sisters"], "article_id"=>922666, "categories"=>["Biological Sciences", "Medicine"], "users"=>["Víctor A. Cortés", "Susan V. Smalley", "Denisse Goldenberg", "Carlos F. Lagos", "María I. Hodgson", "José L. Santos"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0087173.t002", "stats"=>{"downloads"=>6, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Biochemical_hormone_body_composition_and_energy_expenditure_characterization_of_two_sisters_with_CGL1_/922666", "title"=>"Biochemical, hormone, body composition and energy expenditure characterization of two sisters with CGL1.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-01-31 04:04:43"}

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