An intronic mutation in <i>DKC1</i> in an infant with Høyeraal–Hreidarsson syndrome

Pearson, Toni S.; Curtis, Fiona K.; Al‐Eyadhy, Ayman; Al‐Tamemi, Salem; Mazer, Bruce; Dror, Yigal; Abish, Sharon; Bale, Sherri J.; Compton, John G.; Ray, Reena; Scott, Patrick; Kaloustian, Vazken M. Der

doi:10.1002/ajmg.a.32412

Cited by 21 publications

(16 citation statements)

References 13 publications

(20 reference statements)

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“…Profound decreases in B‐cell numbers and NK‐cell numbers as well as hypogammaglobulinemia were the most common findings. A total of four patients (three infants and one teenager) had a T+B‐NK‐ phenotype, which has been previously described in patients with Hoyeraal‐Hreidarsson syndrome, a severe variant of DKC (5–7, 10, 11). More severe immunologic abnormalities and opportunistic infections were found in the infant‐onset form of disease, mirroring the severe somatic findings in this age group.…”

Section: Discussionmentioning

confidence: 77%

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Dyskeratosis congenita: a combined immunodeficiency with broad clinical spectrum – a single‐center pediatric experience

Jyonouchi

Forbes

Ruchelli

et al. 2011

Pediatric Allergy Immunology

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Section: Discussionmentioning

confidence: 77%

“…The immunologic features of previously reported DKC cases with cell‐mediated and humoral immune evaluations are summarized in Table 5 (5–11). The most comprehensive evaluation of immunologic features in DKC to date was reported by Knudson et al.…”

Section: Discussionmentioning

confidence: 99%

Dyskeratosis congenita: a combined immunodeficiency with broad clinical spectrum – a single‐center pediatric experience

Jyonouchi

Forbes

Ruchelli

et al. 2011

Pediatric Allergy Immunology

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“…Individuals may be diagnosed with Hoyeraal-Hreidarsson syndrome if four or more of these findings are present or if they have cerebellar hypoplasia and additional features of DC [12, 13]. Like Revesz syndrome, the mucocutaneous features of DC and cerebral calcifications may be present [18, 19]. …”

Section: Clinical Features Of Dyskeratosis Congenita and Its Variantsmentioning

confidence: 99%

Dyskeratosis congenita as a disorder of telomere maintenance

Nelson

Bertuch

2012

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

122

116

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Since 1998, there have been great advances in our understanding of the pathogenesis of dyskeratosis congenita (DC), a rare inherited bone marrow failure and cancer predisposition syndrome with prominent mucocutaneous abnormalities and features of premature aging. DC is now characterized molecularly by the presence of short age-adjusted telomeres. Mutations in seven genes have been unequivocally associated with DC, each with a role in telomere length maintenance. These observations, combined with knowledge that progressive telomere shortening can impose a proliferative barrier on dividing cells and contribute to chromosome instability, have led to the understanding that extreme telomere shortening drives the clinical features of DC. However, some of the genes implicated in DC encode proteins that are also components of H/ACA-ribonucleoprotein enzymes, which are responsible for the posttranslational modification of ribosomal and spliceosomal RNAs, raising the question whether alterations in these activities play a role in the pathogenesis of DC. In addition, recent reports suggest that some cases of DC may not be characterized by short age-adjusted telomeres. This review will highlight our current knowledge of the telomere length defects in DC and the factors involved in its development.

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“…Observations that HHS is more frequent in boys and presents with progressive bone marrow failure, led to the speculation that HHS may be a variant of DC. Subsequent molecular analyses confirmed that individuals diagnosed with HHS showed mutations in DKC1 and TERT [181][182][183][184]. Patients were also found to have shortened 3′ telomeric overhangs [185].…”

Section: Hoyeraal-hreidarsson Syndromementioning

confidence: 83%

Genetic Variations in Telomere Maintenance, with Implications on Tissue Renewal Capacity and Chronic Disease Pathologies

Trudeau¹,

Wong²

2010

CPPM

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Premature loss of telomere repeats underlies the pathologies of inherited bone marrow failure syndromes. Over the past decade, researchers have mapped genetic lesions responsible for the accelerated loss of telomere repeats. Haploinsufficiencies in the catalytic core components of the telomere maintenance enzyme telomerase, as well as genetic defects in telomerase holoenzyme components responsible for enzyme stability, have been linked to hematopoietic failure pathologies. Frequencies of these disease-associated alleles in human populations are low. Accordingly, the diseases themselves are rare. On the other hand, single nucleotide polymorphisms of telomerase enzyme components are found with much higher frequencies, with several non-synonymous SNP alleles observed in 2-4% of the general population. Importantly, recent advents of molecular diagnostic techniques have uncovered links between telomere length maintenance deficiencies and an increasing number of pathologies unrelated to the hematopoietic system. In these cases, short telomere length correlates to tissue renewal capacities and predicts clinical progression and disease severity. To the authors of this review, these new discoveries imply that even minor genetic defects in telomere maintenance can culminate in the premature failure of tissue compartments with high renewal rates. In this review, we discuss the biology and molecules of telomere maintenance, and the pathologies associated with an accelerated loss of telomeres, along with their etiologies. We also discuss single nucleotide polymorphisms of key telomerase components and their association with tissue renewal deficiency syndromes and other pathologies. We suggest that inter-individual variability in telomere maintenance capacity could play a significant role in chronic inflammatory diseases, and that this is not yet fully appreciated in the translational research of pharmacogenomics and personalized medicine.

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An intronic mutation in DKC1 in an infant with Høyeraal–Hreidarsson syndrome

Cited by 21 publications

References 13 publications

Dyskeratosis congenita: a combined immunodeficiency with broad clinical spectrum – a single‐center pediatric experience

Dyskeratosis congenita: a combined immunodeficiency with broad clinical spectrum – a single‐center pediatric experience

Dyskeratosis congenita as a disorder of telomere maintenance

Genetic Variations in Telomere Maintenance, with Implications on Tissue Renewal Capacity and Chronic Disease Pathologies

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