title: Hoyeraal-Hreidarsson syndrome caused by a germline mutation in the TEL patch of the telomere protein TPP1.
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.
authors.affiliation: Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA;
authors.forename: Hande
authors.initials: H
authors.lastname: Kocak
authors.affiliation: Division of Cancer Epidemiology and Genetics (DCEG), National Cancer Institute (NCI), Rockville, Maryland 20850, USA;
authors.forename: Bari J
authors.initials: BJ
authors.lastname: Ballew
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109, USA;
authors.forename: Kamlesh
authors.initials: K
authors.lastname: Bisht
authors.affiliation: Cancer Genomics Research Laboratory, Leidos Biomedical Research, NCI-Frederick, Rockville, Maryland 20850, USA;
authors.forename: Rebecca
authors.initials: R
authors.lastname: Eggebeen
authors.affiliation: Cancer Genomics Research Laboratory, Leidos Biomedical Research, NCI-Frederick, Rockville, Maryland 20850, USA;
authors.forename: Belynda D
authors.initials: BD
authors.lastname: Hicks
authors.affiliation: Cancer Genomics Research Laboratory, Leidos Biomedical Research, NCI-Frederick, Rockville, Maryland 20850, USA;
authors.forename: Shalabh
authors.initials: S
authors.lastname: Suman
authors.affiliation: Cancer Genomics Research Laboratory, Leidos Biomedical Research, NCI-Frederick, Rockville, Maryland 20850, USA;
authors.forename: Adri
authors.initials: A
authors.lastname: O'Neil
authors.affiliation: Division of Cancer Epidemiology and Genetics (DCEG), National Cancer Institute (NCI), Rockville, Maryland 20850, USA;
authors.forename: Neelam
authors.initials: N
authors.lastname: Giri
authors.affiliation: 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;
authors.forename: Ivan
authors.initials: I
authors.lastname: Maillard
authors.affiliation: Division of Cancer Epidemiology and Genetics (DCEG), National Cancer Institute (NCI), Rockville, Maryland 20850, USA;
authors.forename: Blanche P
authors.initials: BP
authors.lastname: Alter
authors.affiliation: Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA; Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Keegan
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109, USA;
authors.forename: Jayakrishnan
authors.initials: J
authors.lastname: Nandakumar
authors.affiliation: Division of Cancer Epidemiology and Genetics (DCEG), National Cancer Institute (NCI), Rockville, Maryland 20850, USA; savagesh@mail.nih.gov jknanda@umich.edu.
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Savage
mesh_terms: D000328:Adult; D002648:Child; D002675:Child, Preschool; D019871:Dyskeratosis Congenita / Q000235:genetics* / Q000473:pathology; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics* / Q000473:pathology; D018095:Germ-Line Mutation / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics* / Q000473:pathology; D008297:Male; D008831:Microcephaly / Q000235:genetics* / Q000473:pathology; D008958:Models, Molecular; D020125:Mutation, Missense / Q000235:genetics; D010375:Pedigree; D017434:Protein Structure, Tertiary; D017384:Sequence Deletion / Q000235:genetics; D057057:Serine Proteases / Q000737:chemistry / Q000235:genetics*; D000089804:Shelterin Complex; D019098:Telomerase / Q000378:metabolism; D034501:Telomere-Binding Proteins / Q000378:metabolism
chemical_list: C495876:ACD protein, human; D000089804:Shelterin Complex; C440868:TINF2 protein, human; D034501:Telomere-Binding Proteins; D019098:Telomerase; D057057:Serine Proteases
keywords: ACD; Hoyeraal-Hreidarsson syndrome; TPP1; dyskeratosis congenita; telomerase; telomere