A New Syndrome of Familial Aplastic Anemia and Chronic Liver Disease

Qazilbash, Muzaffar H.; Liu, Johnson M.; Vlachos, Adrianna; Fruchtman, S.; Messner, Hans A.; Zipursky, Alvin; Alter, Blanche P.; Young, Neal S.

doi:10.1159/000203674

Cited by 12 publications

(11 citation statements)

References 5 publications

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“…His father (Subject E-II-1) was forty-four years old when first seen, and at the time, he had a 10-year history of thrombocytopenia and leukopenia along with a mildly hypocellular bone marrow. This unusual association between aplastic anemia and liver cirrhotic disease observed in this pedigree and in an additional family led us to describe a “new familial syndrome” in 1997, which appeared to have an autosomal dominant inheritance, but genetic analysis was not available at that time (family E in the present series corresponds to family A in our previous report) [16]. Six years post-presentation, the father developed a nonproductive cough and dyspnea on exertion.…”

Section: Resultsmentioning

confidence: 61%

A Spectrum of Severe Familial Liver Disorders Associate with Telomerase Mutations

Calado¹,

Regal²,

Kleiner³

et al. 2009

PLoS ONE

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218

203

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BackgroundTelomerase 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 FindingsSixty-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/SignificanceThese 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.

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Section: Resultsmentioning

confidence: 61%

A Spectrum of Severe Familial Liver Disorders Associate with Telomerase Mutations

Calado¹,

Regal²,

Kleiner³

et al. 2009

PLoS ONE

Self Cite

218

203

View full text Add to dashboard Cite

show abstract

“…Once the number of telomeric repeated sequence (TMR) is reduced to 13, chromosomal instability is observed [48]. Several diseases are linked to telomere dysfunctions and/or telomerase mutations such as hematopoietic dysfunction, pulmonary fibrosis, liver disease, degenerative diseases and cancer [49][50][51][52][53][54][55][56][57][58][59]. Alterations within telomeric regions are therefore a likely cause for cellular dysfunctions linked to diseases.…”

Section: Introductionmentioning

confidence: 99%

Chromosomally integrated HHV-6: impact on virus, cell and organismal biology

Kaufer

Flamand

2014

Current Opinion in Virology

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“…In fact, Huang et al recently reported that the chromosome harboring integrated HHV-6 is often the shortest, suggesting that integration affects telomeric integrity (20). Several diseases are linked with telomere dysfunctions and/or telomerase mutations such as cardiovascular diseases, hematopoietic dysfunction, pulmonary fibrosis, liver disease, degenerative diseases, and cancer (21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31). Alterations within telomeric regions are therefore a likely cause for cellular dysfunctions linked to diseases, but many of the factors affecting telomere integrity remain to be identified.…”

mentioning

confidence: 99%

Inherited chromosomally integrated human herpesvirus 6 as a predisposing risk factor for the development of angina pectoris

Gravel

Dubuc

Morissette

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Inherited chromosomally integrated human herpesvirus-6 (iciHHV-6) results in the germ-line transmission of the HHV-6 genome. Every somatic cell of iciHHV-6+ individuals contains the HHV-6 genome integrated in the telomere of chromosomes. Whether having iciHHV-6 predisposes humans to diseases remains undefined. DNA from 19,597 participants between 40 and 69 years of age were analyzed by quantitative PCR (qPCR) for the presence of iciHHV-6. Telomere lengths were determined by qPCR. Medical records, hematological, biochemical, and anthropometric measurements and telomere lengths were compared between iciHHV-6+ and iciHHV-6− subjects. The prevalence of iciHHV-6 was 0.58%. Two-way ANOVA with a Holm-Bonferroni correction was used to determine the effects of iciHHV6, sex, and their interaction on continuous outcomes. Two-way logistic regression with a Holm-Bonferroni correction was used to determine the effects of iciHHV6, sex, and their interaction on disease prevalence. Of 50 diseases monitored, a single one, angina pectoris, is significantly elevated (3.3×) in iciHHV-6+ individuals relative to iciHHV-6− subjects (P = 0.017; 95% CI, 1.73-6.35). When adjusted for potential confounding factors (age, body mass index, percent body fat, and systolic blood pressure), the prevalence of angina remained three times greater in iciHHV-6+ subjects (P = 0.015; 95%CI, 1.23-7.15). Analyses of telomere lengths between iciHHV-6− without angina, iciHHV-6− with angina, and iciHHV-6+ with angina indicate that iciHHV-6+ with angina have shorter telomeres than age-matched iciHHV-6− subjects (P = 0.006). Our study represents, to our knowledge, the first largescale analysis of disease association with iciHHV-6. Our results are consistent with iciHHV-6 representing a risk factor for the development of angina.HHV-6 | telomere | angina | chromosomal integration | ciHHV-6

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A New Syndrome of Familial Aplastic Anemia and Chronic Liver Disease

Cited by 12 publications

References 5 publications

A Spectrum of Severe Familial Liver Disorders Associate with Telomerase Mutations

A Spectrum of Severe Familial Liver Disorders Associate with Telomerase Mutations

Chromosomally integrated HHV-6: impact on virus, cell and organismal biology

Inherited chromosomally integrated human herpesvirus 6 as a predisposing risk factor for the development of angina pectoris

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