Unraveling the pathogenesis of Hoyeraal-Hreidarsson syndrome, a complex telomere biology disorder

Abstract

Hoyeraal-Hreidarsson (HH) syndrome is a multisystem genetic disorder characterized by very short telomeres and considered a clinically severe variant of dyskeratosis congenita. The main cause of mortality, usually in early childhood, is bone marrow failure. Mutations in several telomere biology genes have been reported to cause HH in about 60% of the HH patients, but the genetic defects in the rest of the patients are still unknown. Understanding the aetiology of HH and its diverse manifestations is challenging because of the complexity of telomere biology and the multiple telomeric and non-telomeric functions played by telomere-associated proteins in processes such as telomere replication, telomere protection, DNA damage response and ribosome and spliceosome assembly. Here we review the known clinical complications, molecular defects and germline mutations associated with HH, and elucidate possible mechanistic explanations and remaining questions in our understanding of the disease.

Keywords: Hoyeraal-Hreidarsson syndrome; cerebellar hypoplasia; dyskeratosis congenita; immunodeficiency; telomere.

Figure 1. Clinical Features of Patients with Hoyeraal-Hreidarsson Syndrome

A) cerebellar hypoplasia (arrow), B) skin pigmentation abnormalities, C) oral leucoplakia, D) nail dystrophy

Figure 2. Factors involved in telomere maintenance and associated with telomere biology disorders

Factors implicated in Hoyeraal-Hreidarsson syndrome (HH) are marked with red. The percentages are based on unpublished National Cancer Institute dyskeratosis congenita (DC) cohort data and review of the literature. They represent the combination of DC, HH, and Revesz syndrome. The shelterin complex binds along the telomeric DNA, protects the telomere end by forming a t-loop, suppressing DDR, and regulating telomerase action. TCAB1 regulates telomerase trafficking to the Cajal body. The telomerase ribonucleoprotein complex elongates the 3′ end of the telomere. The CTC1-STN1-TEN1 (CST) complex contributes to telomere replication and telomerase regulation. RTEL1 is an essential DNA helicase involved in telomere maintenance. Abbreviations: AD, autosomal dominant; AR, autosomal recessive; XLR, X-linked recessive.

Figure 3. Hoyeraal-Hreidarsson syndrome-associated mutations

A) Dyskerin (DKC1). Indicated are nuclear localization (NL) signals (purple), dyskerin-like domain (DKLD; green), TruB pseudouridine synthase catalytic domain (blue) and PUA RNA binding domain (cyan). B) TERT. Indicated are TEN domain (yellow), telomerase RNA binding domain (TRBD; green), T-motif within TRBD (blue), reverse transcriptase (RT) domain (cyan) and C-terminal extension (CTE; magenta). C) TIN2 (TINF2). Indicated are TIN2_N domain (green), exon 6a (cyan), TRF1 binding site (yellow) and HP1γ binding site (blue). D) RTEL1. Indicated are RAD3-related helicase domain (cyan) containing the helicase type 2 ATP binding and C-terminus domains (blue), PIP boxes (red), Harmonin N-like domains (pink) and RING-finger domain (light violet). Amino acid numbering refers to the main, 1,300aa, splice variant of RTEL1 (NM_001283009; left) and to a 1243aa splice variant, which includes an alternative 24aa exon close to the C-terminus (NM_032957; right). E) TPP1 (ADC). Indicated are OB fold (cyan), POT1 binding domain (green) and TIN2 binding domain (magenta). The schemes were illustrated using DOG 1.0 (Ren, et al 2009).