A Homozygous Telomerase Reverse Transcriptase T Motif Variant Resulting in Markedly Reduced Telomerase Repeat Addition Processivity in Siblings with Hoyeraal Hreidarsson Syndrome

Abstract 1272

Hoyeraal Hreidarsson syndrome (HHS) is a severe form of dyskeratosis congenita (DC) characterized by bone marrow failure, intrauterine growth retardation, developmental delay, microcephaly, cerebellar hypoplasia, immunodeficiency, and extremely short telomeres. As with DC, mutations in genes that encode factors required for telomere maintenance, such as the telomerase reverse transcriptase (TERT), have been found in patients with HHS. We describe two sibling cases of HHS caused by a homozygous mutation (p.T567M) within the TERT T motif, which is a highly conserved motif specific to the telomerase-class of reverse transcriptases. This mutation resulted in a marked reduction in the capacity of telomerase to processively synthesize telomeric repeats, indicating for the first time a role for the T motif in this unique aspect of telomerase function. The consanguineous parents, heterozygous for this mutation, exhibited telomere lengths around the first percentile and no evidence of a DC phenotype. Although heterozygous processivity defects have been associated with familial adult-onset pulmonary fibrosis, these cases demonstrate the severe clinical and functional impact of biallelic processivity mutations. Thus, despite retaining the capacity to catalyze the addition of short stretches of telomeric repeats onto the shortest telomeres, the sole expression of telomerase repeat addition processivity mutants leads to a profound failure of telomere maintenance and early onset disease. In the course of our investigation of this mutant, several commonly used algorithms predicted no effect of TERT p.567M upon protein function. To examine this further, we compiled missense changes that are associated with a clinical phenotype and correlated each with its reported telomerase activity and presence of the phenotype in more than one family member. We then summarized the predicted functional impact for each of these mutations based upon four commonly used algorithms. Our results demonstrate these algorithms to be limited in their capacity for predicting the effect of missense changes upon telomerase function, emphasizing the importance of in vitro functional analyses including processivity assays for TERT variants of unknown significance.