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Cytogenetics and molecular genetics

Characterization of an X-chromosome-linked telomere biology disorder in females with DKC1 mutation

Leukemia volume 33, pages 275–278 (2019)Cite this article

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Dyskeratosis congenita (DC) caused by mutations in genes implicated in telomere biology is an inherited syndrome affecting multiple tissues. Clinical severity and the spectrum of symptoms are variable but classically patients present with significant hemato-immunological, odontological, mucosal, and dermatological disturbances [1]. This is due to defective telomere maintenance in rapidly renewing tissues, causing shortened telomeres and DC-like manifestations in the respective organ. Other common clinical features are hepatic, pulmonal, ophthalmologic, and neuropsychiatric health problems. DC also predisposes patients to cancer, especially hematological malignancies and squamous cell carcinomas of the head and neck [2]. Remarkably, the risk of myelodysplastic syndrome (MDS) is over 500-fold in comparison to healthy individuals [2]. Hence, early recognition of all patients with DC or other telomere biology disorder (TBD) is crucial.

One of the genes linked to DC is DKC1, located on chromosome X and encoding a highly conserved protein dyskerin. Dyskerin is an essential nucleolar protein, which maintains stability of the human telomerase RNA (TERC) by interacting with H/ACA consensus sequence in TERC. Pathogenic mutations in DKC1 result in a dysfunctional protein, leading to reduced levels of TERC, decreased telomerase activity, and premature telomere shortening in males [3]. Dyskerin has a role also in controlling ribosome biogenesis [3]. X-chromosome inactivation (XCI) silences transcription from one of the two X chromosomes in female cells to balance expression dosage between males and females. The inactivation process is sometimes incomplete in human tissues, thus up to one-third of X-chromosomal genes may be expressed from both the active and silenced X chromosomes [3]. There are few reports on females with DKC1 mutation [4,5,6]. Here, we report results of detailed molecular and clinical investigation of three symptomatic sisters aiming at enlightening X-linked TBD in females.

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Acknowledgements

This study was funded by grants from Academy of Finland (#274474, #312492, and #284538), Helsinki University Hospital Comprehensive Cancer Center Research Funding, Cancer Society of Finland, Signe and Ane Gyllenberg Foundation, and Väre Foundation for Pediatric Cancer Research. We are grateful to patients who participated and thus made this study possible. We thank Lotta Honkala, Pihla Siipola, and Annukka Ruokolainen for excellent technical assistance, and FIMM Technology Center for Sanger sequencing services.

Author contributions

EAMH and SP conducted the molecular laboratory experiments and analyzed the results (except the telomere analysis). AN and SD conducted the telomere length analysis and analyzed the results. KH-J and HV are responsible for the dermatological and odontological and oral mucosal examination and interpretation, respectively. OK and UW-K designed the study, participated in the analyses, and finalized the manuscript. All authors participated in drafting the manuscript and have read and approved the final manuscript.

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Author notes

  1. These authors contributed equally: Outi Kilpivaara, Ulla Wartiovaara-Kautto.

Authors and Affiliations

  1. Genome-Scale Biology/Research Programs Unit, and Department of Medical and Clinical Genetics/Medicum, University of Helsinki, Helsinki, Finland

    Elina A. M. Hirvonen, Saara Peuhkuri & Outi Kilpivaara

  2. Department of Medical Biosciences, Medical and Clinical Genetics, Umeå University, Umeå, Sweden

    Anna Norberg & Sofie Degerman

  3. Department of Dermatology and Allergology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland

    Katariina Hannula-Jouppi

  4. Folkhälsan Institute of Genetics, Helsinki, and Molecular Neurology/Research Programs Unit, University of Helsinki, Helsinki, Finland

    Katariina Hannula-Jouppi

  5. Department of Virology, University of Helsinki and Department of Oral and Maxillofacial Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland

    Hannamari Välimaa

  6. Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center and University of Helsinki, Helsinki, Finland

    Ulla Wartiovaara-Kautto

Authors
  1. Elina A. M. Hirvonen
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Correspondence to Outi Kilpivaara or Ulla Wartiovaara-Kautto.

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Hirvonen, E.A.M., Peuhkuri, S., Norberg, A. et al. Characterization of an X-chromosome-linked telomere biology disorder in females with DKC1 mutation. Leukemia 33, 275–278 (2019). https://doi.org/10.1038/s41375-018-0243-5

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