Hoyeraal-Hreidarsson syndrome caused by a germline mutation in the TEL patch of the telomere protein TPP1

Hande Kocak, Bari J. Ballew, Kamlesh Bisht, Rebecca Eggebeen, Belynda D. Hicks, Shalabh Suman, Adri O'Neil, Neelam Giri, Sara Bass, Joseph Boland, Laurie Burdett, Salma Chowdhury, Michael Cullen, Casey Dagnall, Herbert Higson, Amy A. Hutchinson, Kristine Jones, Sally Larson, Kerrie Lashley, Hyo Jung LeeWen Luo, Michael Malasky, Michelle Manning, Jason Mitchell, David Roberson, Aurelie Vogt, Mingyi Wang, Meredith Yeager, Xijun Zhang, Neil E. Caporaso, Stephen J. Chanock, Mark H. Greene, Lynn R. Goldin, Alisa M. Goldstein, Allan Hildesheim, Nan Hu, Maria Teresa Landi, Jennifer Loud, Phuong L. Mai, Mary L. McMaster, Lisa Mirabello, Lindsay Morton, Dilys Parry, Anand Pathak, Melissa Rotunno, Douglas R. Stewart, Phil Taylor, Geoffrey S. Tobias, Margaret A. Tucker, Jeannette Wong, Xiaohong R. Yang, Guoqin Yu, Ivan Maillard, Blanche P. Alter, Catherine E. Keegan, Jayakrishnan Nandakumar, Sharon A. Savage

Research output: Contribution to journalArticlepeer-review

75 Scopus citations


Germline mutations in telomere biology genes cause dyskeratosis congenita (DC), an inherited bone marrow failure and cancer predisposition syndrome. DC is a clinically heterogeneous disorder diagnosed by the triad of dysplastic nails, abnormal skin pigmentation, and oral leukoplakia; Hoyeraal-Hreidarsson syndrome (HH), a clinically severe variant of DC, also includes cerebellar hypoplasia, immunodeficiency, and intrauterine growth retardation. Approximately 70% of DC cases are associated with a germline mutation in one of nine genes, the products of which are all involved in telomere biology. Using exome sequencing, we identified mutations in Adrenocortical Dysplasia Homolog (ACD) (encoding TPP1), a component of the telomeric shelterin complex, in one family affected by HH. The proband inherited a deletion from his father and a missense mutation from his mother, resulting in extremely short telomeres and a severe clinical phenotype. Characterization of the mutations revealed that the single-amino-acid deletion affecting the TEL patch surface of the TPP1 protein significantly compromises both telomerase recruitment and processivity, while the missense mutation in the TIN2-binding region of TPP1 is not as clearly deleterious to TPP1 function. Our results emphasize the critical roles of the TEL patch in proper stem cell function and demonstrate that TPP1 is the second shelterin component (in addition to TIN2) to be implicated in DC.

Original languageEnglish (US)
Pages (from-to)2090-2102
Number of pages13
JournalGenes and Development
Issue number19
StatePublished - Oct 1 2014


  • ACD
  • Dyskeratosis congenita
  • Hoyeraal-Hreidarsson syndrome
  • TPP1
  • Telomerase
  • Telomere

ASJC Scopus subject areas

  • Medicine(all)


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