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Unraveling the pathogenesis of Hoyeraal–Hreidarsson syndrome, a complex telomere biology disorder
Author(s) -
Glousker Galina,
Touzot Fabien,
Revy Patrick,
Tzfati Yehuda,
Savage Sharon A.
Publication year - 2015
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.13442
Subject(s) - telomere , dyskeratosis congenita , telomerase , spliceosome , biology , germline , bone marrow failure , genetics , germline mutation , mutation , gene , stem cell , haematopoiesis , rna , rna splicing
Summary 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.