title: Genetic heterogeneity in autosomal recessive dyskeratosis congenita with one subtype due to mutations in the telomerase-associated protein NOP10.
abstract: 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.
authors.affiliation: 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. a.walne@qmul.ac.uk
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Walne
authors.forename: Tom
authors.initials: T
authors.lastname: Vulliamy
authors.forename: Anna
authors.initials: A
authors.lastname: Marrone
authors.forename: Richard
authors.initials: R
authors.lastname: Beswick
authors.forename: Michael
authors.initials: M
authors.lastname: Kirwan
authors.forename: Yuka
authors.initials: Y
authors.lastname: Masunari
authors.forename: Fat-Hia
authors.initials: FH
authors.lastname: Al-Qurashi
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Aljurf
authors.forename: Inderjeet
authors.initials: I
authors.lastname: Dokal
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D003241:Consanguinity; D019871:Dyskeratosis Congenita / Q000235:genetics*; D008040:Genetic Linkage; D005819:Genetic Markers; D006367:HeLa Cells; D006720:Homozygote; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D034741:RNA, Small Interfering / Q000378:metabolism; D020718:Ribonucleoproteins, Small Nucleolar / Q000235:genetics*; D019098:Telomerase / Q000235:genetics*; D016615:Telomere / Q000648:ultrastructure
chemical_list: D005819:Genetic Markers; C416930:NOP10 protein, human; D034741:RNA, Small Interfering; D020718:Ribonucleoproteins, Small Nucleolar; D019098:Telomerase