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Blood, 1 February 2008, Vol. 111, No. 3, pp. 1128-1130.
Prepublished online as a Blood First Edition Paper on November 27, 2007; DOI 10.1182/blood-2007-10-120907.
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Submitted October 30, 2007
Accepted November 20, 2007
Complex inheritance pattern of dyskeratosis congenita in two families with two different mutations in the telomerase reverse transcriptase gene
Hong-Yan Du, Elena Pumbo, Peter Manley, Joshua J Field, Susan J Bayliss, David B Wilson, Philip J Mason, and Monica Bessler*
Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, United States
Department of Pediatric Hematology/Oncology, Brown University School of Medicine, Providence, RI, United States
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
* Corresponding author; email: mbessler{at}im.wustl.edu.
Heterozygous mutations in the telomerase components TERT the reverse transcriptase and TERC the RNA template cause autosomal dominant dyskeratosis congenita due to telomere shortening. Anticipation, whereby the disease severity increases in succeeding generations due to inheritance of shorter telomeres is a feature of this condition. Here we describe two families in which two TERT mutations are segregating. Both families contain compound heterozygotes. In one case the proband is homozygous for a novel mutation causing a P704S substitution while his fathers second allele encodes a H412Y mutation. The proband in the second family has mutant alleles Y846C and H876Q. Transfection studies show co-dominant expression of the mutated alleles with no evidence of a dominant negative effect or of intragenic complementation. Thus in these families the expression of both TERT alleles and the inherited telomere length contribute to the clinical phenotype.
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