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.
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Authors | Hande Kocak, Bari J Ballew, Kamlesh Bisht, Rebecca Eggebeen, Belynda D Hicks, Shalabh Suman, Adri O'Neil, Neelam Giri, NCI DCEG Cancer Genomics Research Laboratory, NCI DCEG Cancer Sequencing Working Group, Ivan Maillard, Blanche P Alter, Catherine E Keegan, Jayakrishnan Nandakumar, Sharon A Savage |
Journal | Genes & development
(Genes Dev)
Vol. 28
Issue 19
Pg. 2090-102
(Oct 01 2014)
ISSN: 1549-5477 [Electronic] United States |
PMID | 25233904
(Publication Type: Case Reports, Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
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Copyright | © 2014 Kocak et al.; Published by Cold Spring Harbor Laboratory Press. |
Chemical References |
- ACD protein, human
- Shelterin Complex
- TINF2 protein, human
- Telomere-Binding Proteins
- Telomerase
- Serine Proteases
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Topics |
- Adult
- Child
- Child, Preschool
- Dyskeratosis Congenita
(genetics, pathology)
- Female
- Fetal Growth Retardation
(genetics, pathology)
- Germ-Line Mutation
(genetics)
- HeLa Cells
- Humans
- Infant
- Intellectual Disability
(genetics, pathology)
- Male
- Microcephaly
(genetics, pathology)
- Models, Molecular
- Mutation, Missense
(genetics)
- Pedigree
- Protein Structure, Tertiary
- Sequence Deletion
(genetics)
- Serine Proteases
(chemistry, genetics)
- Shelterin Complex
- Telomerase
(metabolism)
- Telomere-Binding Proteins
(metabolism)
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