Investigation of chromosome X inactivation and clinical phenotypes in female carriers of DKC1 mutations

Jialin Xu, Payal P. Khincha, Neelam Giri, Blanche P. Alter, Sharon A. Savage, Judy M Y Wong

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


Dyskeratosis congenita (DC) is an inherited bone marrow failure and cancer susceptibility syndrome caused by germline mutations in telomere biology genes. Germline mutations in DKC1, which encodes the protein dyskerin, cause X-linked recessive DC. Because of skewed X-chromosome inactivation, female DKC1 mutation carriers do not typically develop clinical features of DC. This study evaluated female DKC1 mutation carriers with DC-associated phenotypes to elucidate the molecular features of their mutations, in comparison with unaffected carriers and mutation-negative female controls. All female DKC1 mutation carriers had normal leukocyte subset telomere lengths and similarly skewed X-inactivation in multiple tissue types, regardless of phenotype. We observed dyskerin expression, telomerase RNA accumulation, and pseudouridylation present in all mutation carriers at levels comparable to healthy wild-type controls. Our study suggests that mechanisms in addition to X chromosome inactivation, such as germline mosaicism or epigenetics, may contribute to DC-like phenotypes present in female DKC1 mutation carriers. Future studies are warranted to understand the molecular mechanisms associated with the phenotypic variability in female DKC1 mutation carriers, and to identify those at risk of disease. Am. J. Hematol. 91:1215–1220, 2016.

Original languageEnglish (US)
Pages (from-to)1215-1220
Number of pages6
JournalAmerican Journal of Hematology
Issue number12
StatePublished - Dec 1 2016
Externally publishedYes

ASJC Scopus subject areas

  • Hematology


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