Unraveling the pathogenesis of Hoyeraal-Hreidarsson syndrome, a complex telomere biology disorder.
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.
Department of Genetics, The Silberman Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem, Israel.
Galina
G
Glousker
INSERM UMR 1163, Laboratory of Genome Dynamics in the Immune System, Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, Paris, France.
Fabien
F
Touzot
INSERM UMR 1163, Laboratory of Genome Dynamics in the Immune System, Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, Paris, France.
Patrick
P
Revy
Department of Genetics, The Silberman Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem, Israel.
Yehuda
Y
Tzfati
Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
Sharon A
SA
Savage
D019871:Dyskeratosis Congenita / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D005317:Fetal Growth Retardation / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D008831:Microcephaly / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D016615:Telomere / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D059505:Telomere Homeostasis / Q000235:genetics*
Hoyeraal-Hreidarsson syndrome; cerebellar hypoplasia; dyskeratosis congenita; immunodeficiency; telomere