TERT – Dyskeratosis congenita

Dyskeratosis congenita (DC) is a telomere biology disorder characterized by nail dystrophy, reticular pigmentation, mucosal leukoplakia, bone marrow failure, and pulmonary fibrosis. Germline pathogenic variants in the reverse transcriptase component of telomerase, TERT, impair telomere maintenance and underlie both autosomal dominant and recessive forms of DC (PMID:20658629).

Autosomal dominant inheritance predominates for heterozygous loss-of-function variants, while homozygous or compound heterozygous variants cause severe early-onset Hoyeraal-Hreidarsson syndrome (PMID:17785587, PMID:23538340). Across studies, >150 unrelated probands with DC- or aplastic anemia-like presentations harbor pathogenic TERT variants in both coding and splice regions (PMID:15885610, PMID:19936245). Case series report recurrent missense and loss-of-function alleles, including the founder splice donor mutation c.2286+1G>A (p.?) in pulmonary fibrosis phenotypes and the novel coding variant c.286G>T (p.Val96Leu) segregating with classical DC signs (PMID:20658629).

Segregation analysis in multigenerational families demonstrates cosegregation of TERT variants with disease: affected sibships in consanguineous pedigrees and anticipation in autosomal dominant lineages converge on short telomere phenotypes (PMID:23538340, PMID:17785587). Compound heterozygotes and homozygotes exhibit bone marrow failure, cerebellar hypoplasia, immunodeficiency, and intrauterine growth retardation, confirming allelic dosage effects. Overall, at least 8 additional affected relatives across families have been reported with segregating TERT variants.

Functional assays consistently show that DC-associated TERT variants disrupt reverse transcriptase activity and telomere elongation. In vitro reconstitution and telomerase repeat amplification protocols reveal marked loss of enzymatic function for multiple missense alleles, including p.Thr567Met and p.Arg811Cys (PMID:17785587, PMID:23538340). Patient fibroblasts and hematopoietic stem cells demonstrate critically short telomeres, reduced colony formation, and failure of mTOR-inhibition rescue in HSCs (PMID:26546739). Homozygous mutations yield higher-than-expected telomerase RNA levels yet abrogate repeat processivity, linking structure–function defects to severe early-onset DC spectrum disorders.

No conflicting studies dispute the role of TERT in DC. Variants of uncertain significance have emerged, but disease-causing alleles consistently demonstrate loss-of-function without dominant-negative interference in primary cell assays (PMID:18710936). These findings cement telomerase insufficiency as the mechanistic basis of DC and related telomere biology disorders.

Key Take-home: Germline TERT variants cause definitive telomere maintenance defects in dyskeratosis congenita, informing genetic diagnosis, family counselling, and potential telomerase-targeted therapeutic strategies.

References

• Blood cells, molecules & diseases • 2005 • Mutations in the reverse transcriptase component of telomerase (TERT) in patients with bone marrow failure. PMID:15885610
• PLoS one • 2009 • A spectrum of severe familial liver disorders associate with telomerase mutations. PMID:19936245
• Pediatric blood & cancer • 2010 • Compound heterozygosity for two new TERT mutations in a patient with aplastic anemia. PMID:20658629
• Blood • 2007 • Telomerase reverse-transcriptase homozygous mutations in autosomal recessive dyskeratosis congenita and Hoyeraal-Hreidarsson syndrome. PMID:17785587
• Blood • 2013 • A homozygous telomerase T-motif variant resulting in markedly reduced repeat addition processivity in siblings with Hoyeraal Hreidarsson syndrome. PMID:23538340
• Molecular and cellular biology • 2008 • Disease-associated human telomerase RNA variants show loss of function for telomere synthesis without dominant-negative interference. PMID:18710936
• Aging • 2015 • A novel autosomal recessive TERT T1129P mutation in a dyskeratosis congenita family leads to cellular senescence and loss of CD34+ hematopoietic stem cells not reversible by mTOR-inhibition. PMID:26546739

Evidence Based Scoring (AI generated)