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Human Molecular Genetics Advance Access originally published online on May 16, 2007
Human Molecular Genetics 2007 16(13):1619-1629; doi:10.1093/hmg/ddm111
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Genetic heterogeneity in autosomal recessive dyskeratosis congenita with one subtype due to mutations in the telomerase-associated protein NOP10

Amanda J. Walne1,*, Tom Vulliamy1, Anna Marrone1, Richard Beswick1, Michael Kirwan1, Yuka Masunari1, Fat-hia Al-Qurashi2, Mahmoud Aljurf2 and Inderjeet Dokal1

1 Academic Unit of Paediatrics, Institute of Cell and Molecular Science, Barts and The London, Queen Mary's School of Medicine and Dentistry, The Blizard Building, 4 Newark Street, London E1 2AT, UK and 2 King Faisal Specialist Hospital and Research Center, PO Box 3354, Riyadh, Saudi Arabia

* To whom correspondence should be addressed. Tel: +44 2078822458; Fax: +44 2078822185; Email: a.walne{at}qmul.ac.uk

Received December 20, 2006; Revised April 17, 2007; Accepted April 25, 2007

Dyskeratosis congenita (DC) is characterized by multiple features including mucocutaneous abnormalities, bone marrow failure and an increased predisposition to cancer. It exhibits marked clinical and genetic heterogeneity. DKC1 encoding dyskerin, a component of H/ACA small nucleolar ribonucleoprotein (snoRNP) particles is mutated in X-linked recessive DC. Telomerase RNA component (TERC), the RNA component and TERT the enzymatic component of telomerase, are mutated in autosomal dominant DC, suggesting that DC is primarily a disease of defective telomere maintenance. The gene(s) involved in autosomal recessive DC remains elusive. This paper describes studies aimed at defining the genetic basis of AR-DC. Homozygosity mapping in 16 consanguineous families with 25 affected individuals demonstrates that there is no single genetic locus for AR-DC. However, we show that NOP10, a component of H/ACA snoRNP complexes including telomerase is mutated in a large consanguineous family with classical DC. Affected homozygous individuals have significant telomere shortening and reduced TERC levels. While a reduction of TERC levels is not a universal feature of DC, it can be brought about through a reduction of NOP10 transcripts, as demonstrated by siRNA interference studies. A similar reduction in TERC levels is also seen when the mutant NOP10 is expressed in HeLa cells. These findings identify the genetic basis of one subtype of AR-DC being due to the first documented mutations in NOP10. This further strengthens the model that defective telomere maintenance is the primary pathology in DC and substantiates the evidence in humans for the involvement of NOP10 in the telomerase complex and telomere maintenance.


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