2. Academic Validation
  3. Hoyeraal-Hreidarsson syndrome caused by a germline mutation in the TEL patch of the telomere protein TPP1

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

  • Genes Dev. 2014 Oct 1;28(19):2090-102. doi: 10.1101/gad.248567.114.
Hande Kocak 1,  Bari J Ballew 2,  Kamlesh Bisht 3,  Rebecca Eggebeen 4,  Belynda D Hicks 4,  Shalabh Suman 4,  Adri O'Neil 4,  Neelam Giri 2,  NCI DCEG Cancer Genomics Research Laboratory,  NCI DCEG Cancer Sequencing Working Group,  Ivan Maillard 5,  Blanche P Alter 2,  Catherine E Keegan 6,  Jayakrishnan Nandakumar 3,  Sharon A Savage 7
Affiliations

Affiliations

  • 1 Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA;
  • 2 Division of Cancer Epidemiology and Genetics (DCEG), National Cancer Institute (NCI), Rockville, Maryland 20850, USA;
  • 3 Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109, USA;
  • 4 Cancer Genomics Research Laboratory, Leidos Biomedical Research, NCI-Frederick, Rockville, Maryland 20850, USA;
  • 5 Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA; Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA; Department of Cell and Developmental Biology, Ann Arbor, Michigan 48109, USA;
  • 6 Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA; Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109, USA.
  • 7 Division of Cancer Epidemiology and Genetics (DCEG), National Cancer Institute (NCI), Rockville, Maryland 20850, USA; savagesh@mail.nih.gov jknanda@umich.edu.
PMID: 25233904 DOI: 10.1101/gad.248567.114
Abstract

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.

Keywords

ACD; Hoyeraal-Hreidarsson syndrome; TPP1; dyskeratosis congenita; telomerase; telomere.

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