Telomerase reverse-transcriptase homozygous mutations in autosomal recessive dyskeratosis congenita and Hoyeraal-Hreidarsson syndrome

Abstract

Dyskeratosis congenita (DC) is a multisystem bone marrow failure syndrome characterized by a triad of mucocutaneous abnormalities and an increased predisposition to malignancy. X-linked DC is due to mutations in DKC1, while heterozygous mutations in TERC (telomerase RNA component) and TERT (telomerase reverse transcriptase) have been found in autosomal dominant DC. Many patients with DC remain uncharacterized, particularly families displaying autosomal recessive (AR) inheritance. We have now identified novel homozygous TERT mutations in 2 unrelated consanguineous families, where the index cases presented with classical DC or the more severe variant, Hoyeraal-Hreidarsson (HH) syndrome. These TERT mutations resulted in reduced telomerase activity and extremely short telomeres. As these mutations are homozygous, these patients are predicted to have significantly reduced telomerase activity in vivo. Interestingly, in contrast to patients with heterozygous TERT mutations or hemizygous DKC1 mutations, these 2 homozygous TERT patients were observed to have higherthan-expected TERC levels compared with controls. Collectively, the findings from this study demonstrate that homozygous TERT mutations, resulting in a pure but severe telomerase deficiency, produce a phenotype of classical AR-DC and its severe variant, the HH syndrome. IntroductionDyskeratosis congenita (DC) is a genetically and clinically heterogeneous inherited bone marrow (BM) failure syndrome that is classically characterized by a mucocutaneous triad of abnormal skin pigmentation, nail dystrophy, and leukoplakia, as well as a wide range of other cutaneous abnormalities. 1 The X-linked recessive form of DC was linked to mutations in DKC1, which encodes the highly conserved multifunctional protein dyskerin. [2][3][4][5][6][7] Dyskerin associates with a subclass of small nucleolar RNAs (snoRNAs) through the RNAs H/ACA domain. [8][9][10] These 2 molecules ultimately form a ribonucleoprotein (RNP) complex with the additional proteins GAR1, NHP2, and NOP10. [11][12][13] This complex has at least 2 significant biologic functions. First, it is responsible for the pseudouridylation of ribosomal RNA at residues specified by the snoRNA contained within the RNP. 14 Second, in addition to these pseudouridylation functions, the vertebrate version of this RNP complex associates with a reverse transcriptase (RT) to form the telomerase complex. [15][16][17] Telomeres are unique tandem repeat structures located at the ends of linear eukaryotic chromosomes. 18 Their presence serves many functions including prevention of chromosome end-to-end fusion, maintenance of chromosomal stability, and prevention of chromosomal degradation. 19 Telomerase is a specialized RNP complex that elongates the G-rich telomeric repeats. 20,21 It is proposed that telomerase acts after DNA replication where this specialized enzyme extends the leading DNA strand, reestablishing the 3Ј overhang that is lost during normal cell division due to end processing and the "end replication problem." 22,23 Th...

Ribosomopathies: human disorders of ribosome dysfunction

“…54 Also of note, mutations in the TERT gene have been identified in some patients with aplastic anemia and short telomeres. 55 Further confusing the picture is a hypomorphic Dkc1 mutant mouse, which demonstrated impaired ribosomal RNA pseudo-uridylation before the onset of clinical features of DKC, whereas reductions in telomere length became evident only in later generations.…”

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

“…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].…”

“…Only selective intronic and regulatory region SNPs are listed due to space limitation, but the full list can be found at the dbSNP website. As well, rare disease-associating mutations are not listed here, but are summarized in several review articles [166,183]. At the time of writing this review, TIN2 is the only member of the shelterin complex identified with disease-associating genetic variations.…”

Genetic Basis of Inherited Bone Marrow Failure Syndromes

“…(Heiss, Knight et al 1998;Vulliamy, Marrone et al 2001;Vulliamy, Walne et al 2005;Marrone, Walne et al 2007;Walne, Vulliamy et al 2007;Savage, Giri et al 2008;Vulliamy, Beswick et al 2008) All are components of the telomerase complex or shelterin (Fig 4). The X-linked recessive disease is a common form of DC.…”