Collapse of Telomere Homeostasis in Hematopoietic Cells Caused by Heterozygous Mutations in Telomerase Genes
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{"title"=>"Collapse of Telomere homeostasis in hematopoietic cells caused by heterozygous mutations in Telomerase genes", "type"=>"journal", "authors"=>[{"first_name"=>"Geraldine", "last_name"=>"Aubert", "scopus_author_id"=>"7102890492"}, {"first_name"=>"Gabriela M.", "last_name"=>"Baerlocher", "scopus_author_id"=>"6701778921"}, {"first_name"=>"Irma", "last_name"=>"Vulto", "scopus_author_id"=>"6506774248"}, {"first_name"=>"Steven S.", "last_name"=>"Poon", "scopus_author_id"=>"7102884266"}, {"first_name"=>"Peter M.", "last_name"=>"Lansdorp", "scopus_author_id"=>"7101658202"}], "year"=>2012, "source"=>"PLoS Genetics", "identifiers"=>{"issn"=>"15537390", "scopus"=>"2-s2.0-84863641682", "sgr"=>"84863641682", "pui"=>"365220718", "isbn"=>"1553-7404 (Electronic)\\r1553-7390 (Linking)", "pmid"=>"22661914", "doi"=>"10.1371/journal.pgen.1002696"}, "id"=>"3c4377be-b1e2-3db0-be09-2ae9ad32048f", "abstract"=>"Telomerase activity is readily detectable in extracts from human hematopoietic stem and progenitor cells, but appears unable to maintain telomere length with proliferation in vitro and with age in vivo. We performed a detailed study of the telomere length by flow FISH analysis in leukocytes from 835 healthy individuals and 60 individuals with reduced telomerase activity. Healthy individuals showed a broad range in average telomere length in granulocytes and lymphocytes at any given age. The average telomere length declined with age at a rate that differed between age-specific breakpoints and between cell types. Gender differences between leukocyte telomere lengths were observed for all cell subsets studied; interestingly, this trend could already be detected at birth. Heterozygous carriers for mutations in either the telomerase reverse transcriptase (hTERT) or the telomerase RNA template (hTERC) gene displayed striking and comparable telomere length deficits. Further, non-carrier relatives of such heterozygous individuals had somewhat shorter leukocyte telomere lengths than expected; this difference was most profound for granulocytes. Failure to maintain telomere homeostasis as a result of partial telomerase deficiency is thought to trigger cell senescence or cell death, eventually causing tissue failure syndromes. Our data are consistent with these statements and suggest that the likelihood of similar processes occurring in normal individuals increases with age. Our work highlights the essential role of telomerase in the hematopoietic system and supports the notion that telomerase levels in hematopoietic cells, while limiting and unable to prevent overall telomere shortening, are nevertheless crucial to maintain telomere homeostasis with age.", "link"=>"http://www.mendeley.com/research/collapse-telomere-homeostasis-hematopoietic-cells-caused-heterozygous-mutations-telomerase-genes", "reader_count"=>66, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Student > Doctoral Student"=>3, "Researcher"=>17, "Student > Ph. D. Student"=>12, "Student > Postgraduate"=>8, "Student > Master"=>9, "Other"=>2, "Student > Bachelor"=>7, "Lecturer"=>2, "Lecturer > Senior Lecturer"=>1, "Professor"=>3}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Student > Doctoral Student"=>3, "Researcher"=>17, "Student > Ph. D. Student"=>12, "Student > Postgraduate"=>8, "Student > Master"=>9, "Other"=>2, "Student > Bachelor"=>7, "Lecturer"=>2, "Lecturer > Senior Lecturer"=>1, "Professor"=>3}, "reader_count_by_subject_area"=>{"Unspecified"=>4, "Environmental Science"=>2, "Biochemistry, Genetics and Molecular Biology"=>15, "Nursing and Health Professions"=>1, "Agricultural and Biological Sciences"=>22, "Medicine and Dentistry"=>14, "Neuroscience"=>1, "Physics and Astronomy"=>1, "Chemistry"=>2, "Psychology"=>1, "Social Sciences"=>1, "Immunology and Microbiology"=>2}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>14}, "Neuroscience"=>{"Neuroscience"=>1}, "Chemistry"=>{"Chemistry"=>2}, "Social Sciences"=>{"Social Sciences"=>1}, "Physics and Astronomy"=>{"Physics and Astronomy"=>1}, "Psychology"=>{"Psychology"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>22}, "Nursing and Health Professions"=>{"Nursing and Health Professions"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>15}, "Unspecified"=>{"Unspecified"=>4}, "Environmental Science"=>{"Environmental Science"=>2}}, "reader_count_by_country"=>{"United States"=>4, "Japan"=>1, "Brazil"=>1, "Denmark"=>1}, "group_count"=>5}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/636840"], "description"=>"<p>Summary of telomere loss adjusted for age (Δtel) in telomerase heterozygous individuals considered as a group (<i>Tel</i>), considered as <i>TERT</i> or <i>TERC</i> heterozygous individuals separately, and unaffected relatives of telomerase heterozygous individuals considered as a group (<i>Tel</i>), or separating parents or siblings.</p>§<p>Difference between the median telomere length and the regression estimate of the telomere length distribution in healthy individuals of the same age (Δtel).</p><p><i>Tel</i>: <i>hTERC</i> or <i>hTERT</i> gene.</p>", "links"=>[], "tags"=>["corrected", "telomerase", "heterozygous", "individuals", "unaffected"], "article_id"=>307328, "categories"=>["Genetics", "Hematology"], "users"=>["Geraldine Aubert", "Gabriela M. Baerlocher", "Irma Vulto", "Steven S. Poon", "Peter M. Lansdorp"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002696.t002", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Telomere_loss_corrected_for_age_916_tel_in_telomerase_heterozygous_individuals_and_unaffected_relatives_/307328", "title"=>"Telomere loss corrected for age (Δtel) in telomerase heterozygous individuals and unaffected relatives.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-05-17 02:02:08"}
  • {"files"=>["https://ndownloader.figshare.com/files/636628"], "description"=>"<p>A. Telomere length measurements in leukocyte subsets from female (pink) versus male (blue) healthy newborns (n = 58; females n = 29, males n = 29). The following white blood cell subsets were tested lymphocytes, granulocytes, “naïve” T lymphocytes (CD45RA+CD20−), memory T lymphocytes (CD45RA−CD20−) and B lymphocytes (CD20+). Each dot represents an individual sample, mean (horizontal bar) and standard deviation (vertical bar) for each cell type are shown. All subsets display a trend for longer average telomere lengths in females; however this trend does not reach statistical significance (Student's t test, data not shown). B. Piece-wise linear regression analysis representing the calculated telomere length per age for females (pink) versus males (blue) “naïve” T lymphocytes (CD45RA+CD20−). Breakpoints were at 1 year of age and at 18 years. Analysis of variance for females versus males (statistical model in R) showed significance (F(4,825) = 9.05; P = 3.7×10<sup>−7</sup>, ANOVA test result comparing regression fits). For data on other subsets and details of statistical analysis, see <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002696#pgen.1002696.s003\" target=\"_blank\">Figure S3</a> and <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002696#pgen.1002696.s009\" target=\"_blank\">Table S5</a>.</p>", "links"=>[], "tags"=>["differences", "leukocyte", "telomere"], "article_id"=>307124, "categories"=>["Genetics", "Hematology"], "users"=>["Geraldine Aubert", "Gabriela M. Baerlocher", "Irma Vulto", "Steven S. Poon", "Peter M. Lansdorp"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002696.g003", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Gender_differences_in_leukocyte_telomere_length_/307124", "title"=>"Gender differences in leukocyte telomere length.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-17 01:58:44"}
  • {"files"=>["https://ndownloader.figshare.com/files/329984", "https://ndownloader.figshare.com/files/330039", "https://ndownloader.figshare.com/files/330082", "https://ndownloader.figshare.com/files/330129", "https://ndownloader.figshare.com/files/330182", "https://ndownloader.figshare.com/files/330201", "https://ndownloader.figshare.com/files/330238", "https://ndownloader.figshare.com/files/330287", "https://ndownloader.figshare.com/files/330326"], "description"=>"<div><p>Telomerase activity is readily detectable in extracts from human hematopoietic stem and progenitor cells, but appears unable to maintain telomere length with proliferation <em>in vitro</em> and with age <em>in vivo</em>. We performed a detailed study of the telomere length by flow FISH analysis in leukocytes from 835 healthy individuals and 60 individuals with reduced telomerase activity. Healthy individuals showed a broad range in average telomere length in granulocytes and lymphocytes at any given age. The average telomere length declined with age at a rate that differed between age-specific breakpoints and between cell types. Gender differences between leukocyte telomere lengths were observed for all cell subsets studied; interestingly, this trend could already be detected at birth. Heterozygous carriers for mutations in either the telomerase reverse transcriptase (<em>hTERT</em>) or the telomerase RNA template (<em>hTERC</em>) gene displayed striking and comparable telomere length deficits. Further, non-carrier relatives of such heterozygous individuals had somewhat shorter leukocyte telomere lengths than expected; this difference was most profound for granulocytes. Failure to maintain telomere homeostasis as a result of partial telomerase deficiency is thought to trigger cell senescence or cell death, eventually causing tissue failure syndromes. Our data are consistent with these statements and suggest that the likelihood of similar processes occurring in normal individuals increases with age. Our work highlights the essential role of telomerase in the hematopoietic system and supports the notion that telomerase levels in hematopoietic cells, while limiting and unable to prevent overall telomere shortening, are nevertheless crucial to maintain telomere homeostasis with age.</p> </div>", "links"=>[], "tags"=>["telomere", "homeostasis", "hematopoietic", "cells", "caused", "heterozygous", "mutations", "telomerase", "genes"], "article_id"=>125154, "categories"=>["Genetics", "Hematology"], "users"=>["Geraldine Aubert", "Gabriela M. Baerlocher", "Irma Vulto", "Steven S. Poon", "Peter M. Lansdorp"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1002696.s001", "https://dx.doi.org/10.1371/journal.pgen.1002696.s002", "https://dx.doi.org/10.1371/journal.pgen.1002696.s003", "https://dx.doi.org/10.1371/journal.pgen.1002696.s004", "https://dx.doi.org/10.1371/journal.pgen.1002696.s005", "https://dx.doi.org/10.1371/journal.pgen.1002696.s006", "https://dx.doi.org/10.1371/journal.pgen.1002696.s007", "https://dx.doi.org/10.1371/journal.pgen.1002696.s008", "https://dx.doi.org/10.1371/journal.pgen.1002696.s009"], "stats"=>{"downloads"=>29, "page_views"=>22, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Collapse_of_Telomere_Homeostasis_in_Hematopoietic_Cells_Caused_by_Heterozygous_Mutations_in_Telomerase_Genes/125154", "title"=>"Collapse of Telomere Homeostasis in Hematopoietic Cells Caused by Heterozygous Mutations in Telomerase Genes", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2012-05-17 01:25:54"}
  • {"files"=>["https://ndownloader.figshare.com/files/636459"], "description"=>"<p>The median telomere length in nucleated blood cells from 835 healthy individuals ranging from birth (umbilical cord blood) to 102 years of age were measured by flow FISH. The results were used to calculate the telomere attrition over time using linear regression in three age segments. A. Median telomere length in lymphocytes (black dots). B. Median telomere length in granulocytes (grey dots). Breakpoints in the piece-wise linear regression lines are marked by rectangles and the three age groups are marked by dotted vertical grey lines at 1 and 18 years. On average 8 individuals were tested per age-year. C. At any given age, a wide range of telomere length was observed and the decline in telomere length with age in lymphocytes was more pronounced than in granulocytes. The shaded area represents the estimated length of subtelomeric DNA. Note that in older individuals, on average only 1–2 kb of telomere repeats were present in lymphocytes.</p>", "links"=>[], "tags"=>["telomere", "differs", "lymphocytes"], "article_id"=>306954, "categories"=>["Genetics", "Hematology"], "users"=>["Geraldine Aubert", "Gabriela M. Baerlocher", "Irma Vulto", "Steven S. Poon", "Peter M. Lansdorp"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002696.g001", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Decline_in_telomere_length_with_age_differs_between_lymphocytes_and_granulocytes_/306954", "title"=>"Decline in telomere length with age differs between lymphocytes and granulocytes.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-17 01:55:54"}
  • {"files"=>["https://ndownloader.figshare.com/files/636698"], "description"=>"<p>The telomere length distribution in healthy individuals (<a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002696#pgen-1002696-g002\" target=\"_blank\">Figure 2</a>) was used to plot the median telomere length values of leukocyte subsets obtained with: A. leukocytes from 60 telomerase deficient patients (red) and 37 non-carrier relatives (black). B. leukocytes from 37 <i>hTERT</i> mutation heterozygous individuals (red) and 23 <i>hTERC</i> mutation heterozygous carriers (black).</p>", "links"=>[], "tags"=>["telomere"], "article_id"=>307191, "categories"=>["Genetics", "Hematology"], "users"=>["Geraldine Aubert", "Gabriela M. Baerlocher", "Irma Vulto", "Steven S. Poon", "Peter M. Lansdorp"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002696.g004", "stats"=>{"downloads"=>0, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Telomerase_is_essential_to_maintain_telomere_length_in_leukocytes_/307191", "title"=>"Telomerase is essential to maintain telomere length in leukocytes.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-17 01:59:51"}
  • {"files"=>["https://ndownloader.figshare.com/files/636545"], "description"=>"<p>A. Cross-sectional median telomere length in nucleated cell types determined by flow FISH in 835 healthy individuals over the age range from birth to 102 years of age. The following nucleated blood cell subtypes were analyzed : lymphocytes, granulocytes, CD45RA positive CD20 positive B lymphocytes (CD20+), CD45RA positive CD20 negative lymphocytes (CD45RA+pos CD20−) “naïve” T cells, CD45RA negative CD20 negative lymphocytes (CD45RA−) memory T cells and CD45RA positive CD57 positive mature NK/T cells (CD57+). Data were analyzed using a piece-wise linear regression model in the age categories 0, 1 yr; 18 yrs and 102 years and for calculation and representation of the telomere length distribution range at any given age (expressed as a percentile): 99<sup>th</sup> (red), 90<sup>th</sup> (dashed green top), 50<sup>th</sup> (green), 10<sup>th</sup> (dashed green bottom) and 1<sup>st</sup> (blue). Some of the healthy subjects (n = 835) did not have sufficient cells for analysis of one or more of the cell subsets. B. Piece-wise linear regression analysis overlay representing the modeled estimate of telomere length per age for: B lymphocytes (grey), granulocytes (black dashed), “naïve” T lymphocytes (black), memory T lymphocytes (black interrupted dashed) and mature NK/T lymphocytes (grey dashed). Regression breakpoints were set at age 1 and age 18 years. C. Paired comparison of telomere length in granulocytes and memory T lymphocytes from the same individuals. Age groups were as follows: cord blood samples and below age 1 (n = 60, red), age 1 to 18 (n = 171, black), 19 and above 19 (n = 604, green).</p>", "links"=>[], "tags"=>["differences", "attrition", "leukocyte", "telomere"], "article_id"=>307032, "categories"=>["Genetics", "Hematology"], "users"=>["Geraldine Aubert", "Gabriela M. Baerlocher", "Irma Vulto", "Steven S. Poon", "Peter M. Lansdorp"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002696.g002", "stats"=>{"downloads"=>0, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Cell_type_8211_specific_differences_in_the_range_and_attrition_rate_of_leukocyte_telomere_length_/307032", "title"=>"Cell type–specific differences in the range and attrition rate of leukocyte telomere length.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-17 01:57:12"}
  • {"files"=>["https://ndownloader.figshare.com/files/636872"], "description"=>"<p>Telomere length loss between the three selected age segments, results of the piece wise linear regression analysis for each age as depicted in <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002696#pgen-1002696-g001\" target=\"_blank\">Figure 1</a>, <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002696#pgen-1002696-g002\" target=\"_blank\">Figure 2</a>, and <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1002696#pgen-1002696-g004\" target=\"_blank\">Figure 4</a> as well as telomere length ranges are summarized for each leukocyte subsets.</p><p>MTL median telomere length.</p>", "links"=>[], "tags"=>["age-related", "telomere"], "article_id"=>307364, "categories"=>["Genetics", "Hematology"], "users"=>["Geraldine Aubert", "Gabriela M. Baerlocher", "Irma Vulto", "Steven S. Poon", "Peter M. Lansdorp"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1002696.t001", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Telomere_length_distribution_and_age_related_telomere_length_decline_in_healthy_individuals_/307364", "title"=>"Telomere length distribution and age-related telomere length decline in healthy individuals.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-05-17 02:02:44"}

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Relative Metric

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