A Spectrum of Severe Familial Liver Disorders Associate with Telomerase Mutations
Publication Date
November 20, 2009
Journal
PLOS ONE
Authors
Rodrigo T. Calado, Joshua A. Regal, David E. Kleiner, David S. Schrump, et al
Volume
4
Issue
11
Pages
e7926
DOI
https://dx.plos.org/10.1371/journal.pone.0007926
Publisher URL
http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0007926
PubMed
http://www.ncbi.nlm.nih.gov/pubmed/19936245
PubMed Central
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2775683
Europe PMC
http://europepmc.org/abstract/MED/19936245
Web of Science
000272004800008
Scopus
70949087815
Mendeley
http://www.mendeley.com/research/spectrum-severe-familial-liver-disorders-associate-telomerase-mutations
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Mendeley | Further Information

{"title"=>"A spectrum of severe familial liver disorders associate with telomerase mutations", "type"=>"journal", "authors"=>[{"first_name"=>"Rodrigo T.", "last_name"=>"Calado", "scopus_author_id"=>"6701738527"}, {"first_name"=>"Joshua A.", "last_name"=>"Regal", "scopus_author_id"=>"15766367500"}, {"first_name"=>"David E.", "last_name"=>"Kleiner", "scopus_author_id"=>"7004569556"}, {"first_name"=>"David S.", "last_name"=>"Schrump", "scopus_author_id"=>"7004105061"}, {"first_name"=>"Nathan R.", "last_name"=>"Peterson", "scopus_author_id"=>"35321514600"}, {"first_name"=>"Veronica", "last_name"=>"Pons", "scopus_author_id"=>"23036051300"}, {"first_name"=>"Stephen J.", "last_name"=>"Chanock", "scopus_author_id"=>"7006047196"}, {"first_name"=>"Peter M.", "last_name"=>"Lansdorp", "scopus_author_id"=>"7101658202"}, {"first_name"=>"Neal S.", "last_name"=>"Young", "scopus_author_id"=>"36051587400"}], "year"=>2009, "source"=>"PLoS ONE", "identifiers"=>{"sgr"=>"70949087815", "doi"=>"10.1371/journal.pone.0007926", "pui"=>"355732650", "pmid"=>"19936245", "scopus"=>"2-s2.0-70949087815", "issn"=>"19326203", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)"}, "id"=>"408d8a86-f927-3064-8a78-d3df4e0f2274", "abstract"=>"BACKGROUND: Telomerase is an enzyme specialized in maintaining telomere lengths in highly proliferative cells. Loss-of-function mutations cause critical telomere shortening and are associated with the bone marrow failure syndromes dyskeratosis congenita and aplastic anemia and with idiopathic pulmonary fibrosis. Here, we sought to determine the spectrum of clinical manifestations associated with telomerase loss-of-function mutations. METHODOLOGY/PRINCIPAL FINDINGS: Sixty-nine individuals from five unrelated families with a variety of hematologic, hepatic, and autoimmune disorders were screened for telomerase complex gene mutations; leukocyte telomere length was measured by flow fluorescence in situ hybridization in mutation carriers and some non-carriers; the effects of the identified mutations on telomerase activity were determined; and genetic and clinical data were correlated. In six generations of a large family, a loss-of-function mutation in the telomerase enzyme gene TERT associated with severe telomere shortening and a range of hematologic manifestations, from macrocytosis to acute myeloid leukemia, with severe liver diseases marked by fibrosis and inflammation, and one case of idiopathic pulmonary fibrosis but not with autoimmune disorders. Additionally, we identified four unrelated families in which loss-of-function TERC or TERT gene mutations tracked with marrow failure, pulmonary fibrosis, and a spectrum of liver disorders. CONCLUSIONS/SIGNIFICANCE: These results indicate that heterozygous telomerase loss-of-function mutations associate with but are not determinant of a large spectrum of hematologic and liver abnormalities, with the latter sometimes occurring in the absence of marrow failure. Our findings, along with the link between pulmonary fibrosis and telomerase mutations, also suggest a common pathogenic mechanism for fibrotic diseases in which defective telomere repair plays important role.", "link"=>"http://www.mendeley.com/research/spectrum-severe-familial-liver-disorders-associate-telomerase-mutations", "reader_count"=>63, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Professor > Associate Professor"=>1, "Researcher"=>20, "Student > Ph. D. Student"=>11, "Student > Postgraduate"=>6, "Student > Master"=>8, "Other"=>3, "Student > Bachelor"=>4, "Lecturer"=>2, "Lecturer > Senior Lecturer"=>1, "Professor"=>5}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Professor > Associate Professor"=>1, "Researcher"=>20, "Student > Ph. D. Student"=>11, "Student > Postgraduate"=>6, "Student > Master"=>8, "Other"=>3, "Student > Bachelor"=>4, "Lecturer"=>2, "Lecturer > Senior Lecturer"=>1, "Professor"=>5}, "reader_count_by_subject_area"=>{"Unspecified"=>4, "Biochemistry, Genetics and Molecular Biology"=>10, "Nursing and Health Professions"=>1, "Medicine and Dentistry"=>27, "Agricultural and Biological Sciences"=>18, "Business, Management and Accounting"=>1, "Immunology and Microbiology"=>2}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>27}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>18}, "Nursing and Health Professions"=>{"Nursing and Health Professions"=>1}, "Business, Management and Accounting"=>{"Business, Management and Accounting"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>10}, "Unspecified"=>{"Unspecified"=>4}}, "reader_count_by_country"=>{"Canada"=>1, "United States"=>1, "Japan"=>1, "Brazil"=>2}, "group_count"=>2}

CrossRef

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/875231"], "description"=>"<p>Hepatic profile of patients with telomerase mutations and liver disease.</p>", "links"=>[], "tags"=>["patients", "telomerase", "mutations"], "article_id"=>545683, "categories"=>["Medicine", "Genetics", "Virology", "Cancer"], "users"=>["Rodrigo T. Calado", "Joshua A. Regal", "David E. Kleiner", "David S. Schrump", "Nathan R. Peterson", "Veronica Pons", "Stephen J. Chanock", "Peter M. Lansdorp", "Neal S. Young"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0007926.t001", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Hepatic_profile_of_patients_with_telomerase_mutations_and_liver_disease_/545683", "title"=>"Hepatic profile of patients with telomerase mutations and liver disease.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-02-21 03:47:37"}
  • {"files"=>["https://ndownloader.figshare.com/files/875151"], "description"=>"<p><b>(A)</b> Telomere length in peripheral-blood total white blood cells (ordinate) from patients and their relatives with or without telomerase gene mutations as a function of age (abscissa) compared to healthy controls. Telomere lengths were measured by flow fluorescence <i>in situ</i> hybridization (flow-FISH). Small gray circles represent the telomere lengths for 400 healthy volunteers <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0007926#pone.0007926-Yamaguchi1\" target=\"_blank\">[10]</a>, and the curve marks the 50<sup>th</sup> percentile for healthy controls as a function of age. <b>(B)</b> Telomerase activity - measured by telomeric-repeat amplification assay - of lysates of telomerase-negative WI38-VA13 cells cotransfected with mutated <i>TERC</i> and wild-type <i>TERT</i> expression vectors (2 µg per vector per transfection reaction). Enzymatic activity was normalized to <i>TERC</i> expression as measured by Real Time RT-PCR and to the telomerase activity of wild-type <i>TERC</i>, which was set at 100%. Quadruplicate measurements were performed using one microgram of cell lysate protein per reaction. “Empty vector” refers to protein from VA13 cells transfected with an empty pcDNA3-Flag vector in lieu of <i>TERC</i>.</p>", "links"=>[], "tags"=>["telomerase"], "article_id"=>545603, "categories"=>["Medicine", "Genetics", "Virology", "Cancer"], "users"=>["Rodrigo T. Calado", "Joshua A. Regal", "David E. Kleiner", "David S. Schrump", "Nathan R. Peterson", "Veronica Pons", "Stephen J. Chanock", "Peter M. Lansdorp", "Neal S. Young"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0007926.g003", "stats"=>{"downloads"=>1, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Functional_analysis_of_telomerase_mutations_/545603", "title"=>"Functional analysis of telomerase mutations.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-21 03:47:11"}
  • {"files"=>["https://ndownloader.figshare.com/files/874950"], "description"=>"<p><b>(A)</b> Family A proband's bone marrow was hypocellular with isolated regions of normal cellularity (hematoxylin and eosin [H&E] staining; low power magnification). <b>(B)</b> Proband's father's bone marrow smear (Subject A-IV-29), illustrating dysplastic changes and increased number of blasts (H&E, high power magnification). <b>(C)</b> Subject A-IV-23's liver biopsy revealing islands of liver surrounded by zones of necrosis and parenchymal collapse (H&E, low magnification). The necrosis was far enough in the past that hepatocytes have mostly disappeared. In the inset, in some of the areas where hepatocytes were preserved there was still necrosis near the central veins. Little evidence of inflammation exists. <b>(D)</b> Subject's A-IV-25's liver biopsy showing small portal areas and poorly formed veins (H&E, low power magnification). <b>(E)</b> Same liver biopsy exhibiting widened hepatocyte plates on the reticulin stain (high power magnification), but clear changes of nodular regenerative hyperplasia were not seen. <b>(F)</b> The CD34 stain by was positive in sinusoidal endothelial cells consistent with an abnormal proportion of arterial blood flow to the sinuses (immunohistochemistry, low power magnification). <b>(G)</b> Liver biopsy of Subject A-III-11 in which the hepatic architecture is distorted by bridging fibrosis (low power magnification); the inset gives a close-up of the fibrosis. The biopsy revealed moderate inflammation but not elevated levels of plasma cells relative to other inflammatory cells. Other changes included interface hepatitis and cholatestasis. <b>(H)</b> Subject B-II-3's liver biopsy demonstrating portal inflammation with interface hepatitis (H&E, low power magnification). In the inset, Masson staining shows sclerosis around central vein with perisinusoidal fibrosis. <b>(I)</b> Subject B-III-7's liver biopsy with mild, macrovesicular steatosis in a zone 3 distribution. The inset indicates that there is mild lymphocytic portal inflammation with focal interface hepatitis (H&E). <b>(J)</b> Subject C-III-3's liver biopsy shows mild hepatocellular iron accumulation in a pericanalicular pattern; the sinusoidal-lining cells show mild to moderate iron accumulation. The inset illustrates mild variation in hepatocyte nuclear size. <b>(K)</b> Subject C-III-3's reticulin staining exemplifying several zones in which the hepatocyte plates were abnormally widened, consistent with regeneration. <b>(L)</b> Subject E-II-1's liver biopsy revealing some portal areas with mild inflammation and all with poorly formed, slit-like veins (H&E). <b>(M)</b> The reticulin stain showed evidence of nodular regenerative hyperplasia, with zones of plate widening alternating with areas of compression. <b>(N)</b> CD34 stain was abnormally positive in the sinusoidal endothelial cells by immunohistochemistry, indicating abnormal proportion of arterial blood flow to the sinuses.</p>", "links"=>[], "tags"=>["eosin", "marrow", "sections", "probands", "relatives", "aplastic", "acute", "myeloid"], "article_id"=>545395, "categories"=>["Medicine", "Genetics", "Virology", "Cancer"], "users"=>["Rodrigo T. Calado", "Joshua A. Regal", "David E. Kleiner", "David S. Schrump", "Nathan R. Peterson", "Veronica Pons", "Stephen J. Chanock", "Peter M. Lansdorp", "Neal S. Young"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0007926.g002", "stats"=>{"downloads"=>1, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Hematoxylin_and_Eosin_Bone_Marrow_and_Liver_Sections_from_Probands_and_Relatives_with_Aplastic_Anemia_Acute_Myeloid_Leukemia_and_Severe_Liver_Disease_/545395", "title"=>"Hematoxylin and Eosin Bone Marrow and Liver Sections from Probands and Relatives with Aplastic Anemia, Acute Myeloid Leukemia, and Severe Liver Disease.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-21 03:46:04"}
  • {"files"=>["https://ndownloader.figshare.com/files/874768"], "description"=>"<p><b>(A)</b> The <i>TERT</i> K570N mutation tracked with hematological disorders and severe liver disease (lower pedigree) in Family A. In the extended family (upper pedigree), several disorders are found, including autoimmune diseases, anemia, thyroid diseases, liver diseases, and multiple miscarriages; however, the mutation was only associated with liver disease and multiple miscarriages. Two consanguineous relationships are not show: Subject A-IV-17 is a grand-daughter of Subjects A-II-7 and A-II-8, and Subject A-IV-7 is a grandson of Subjects A-III-14 and A-III-15. The genetic status for the immediate family (lower pedigree) and its association with bone marrow failure have been previously reported by us <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0007926#pone.0007926-Xin1\" target=\"_blank\">[15]</a>. In smaller pedigrees, <b>(B)</b><i>TERC</i> nucleotide 341-360 deletion tracked to liver disease in family B, <b>(C)</b> liver disease occurred in a family with a <i>TERC</i> nucleotide 28–34 deletion, and <b>(D)</b> in a family with <i>TERC</i> nucleotide 109–123 deletion. The following are denoted by their abbreviations: common variable immunodeficiency (CVID), aplastic anemia (AA), myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), insulin-dependent diabetes mellitus (IDDM), systemic lupus erythematosus (SLE), idiopathic thrombocytic purpura (ITP), and non-alcoholic steatohepatitis (NASH).</p>", "links"=>[], "tags"=>["telomerase", "mutations"], "article_id"=>545217, "categories"=>["Medicine", "Genetics", "Virology", "Cancer"], "users"=>["Rodrigo T. Calado", "Joshua A. Regal", "David E. Kleiner", "David S. Schrump", "Nathan R. Peterson", "Veronica Pons", "Stephen J. Chanock", "Peter M. Lansdorp", "Neal S. Young"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0007926.g001", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Pedigrees_showing_Telomerase_Mutations_and_Disease_Phenotypes_/545217", "title"=>"Pedigrees showing Telomerase Mutations and Disease Phenotypes.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-21 03:45:03"}

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  • {"unique-ip"=>"13", "full-text"=>"14", "pdf"=>"2", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"10"}
  • {"unique-ip"=>"12", "full-text"=>"11", "pdf"=>"4", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"11"}
  • {"unique-ip"=>"7", "full-text"=>"5", "pdf"=>"0", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"12"}
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  • {"unique-ip"=>"8", "full-text"=>"10", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"7"}
  • {"unique-ip"=>"11", "full-text"=>"11", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"9"}
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  • {"unique-ip"=>"15", "full-text"=>"15", "pdf"=>"7", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"10"}
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  • {"unique-ip"=>"8", "full-text"=>"11", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"8", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"3"}
  • {"unique-ip"=>"14", "full-text"=>"12", "pdf"=>"4", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"4"}
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  • {"unique-ip"=>"14", "full-text"=>"14", "pdf"=>"4", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"8"}
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  • {"unique-ip"=>"10", "full-text"=>"10", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"10"}
  • {"unique-ip"=>"8", "full-text"=>"12", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"12"}
  • {"unique-ip"=>"15", "full-text"=>"14", "pdf"=>"4", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"2"}
  • {"unique-ip"=>"10", "full-text"=>"12", "pdf"=>"3", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"3"}
  • {"unique-ip"=>"16", "full-text"=>"16", "pdf"=>"3", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"4"}
  • {"unique-ip"=>"18", "full-text"=>"20", "pdf"=>"6", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"5"}
  • {"unique-ip"=>"16", "full-text"=>"18", "pdf"=>"7", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"6"}
  • {"unique-ip"=>"21", "full-text"=>"26", "pdf"=>"6", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"7"}
  • {"unique-ip"=>"13", "full-text"=>"15", "pdf"=>"5", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"8"}
  • {"unique-ip"=>"18", "full-text"=>"20", "pdf"=>"5", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2020", "month"=>"9"}
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Relative Metric

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