A homozygous telomerase T-motif variant resulting in markedly reduced repeat addition processivity in siblings with Hoyeraal Hreidarsson syndrome.

摘要

Hoyeraal Hreidarsson syndrome (HHS) is a 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 encoding factors required for telomere maintenance, such as telomerase reverse transcriptase (TERT), have been found in patients with HHS. We describe 2 sibling HHS cases caused by a homozygous mutation (p.T567M) within the TERT T motif. This mutation resulted in a marked reduction in the capacity of telomerase to processively synthesize telomeric repeats, indicating a role for the T motif in this unique aspect of telomerase function. We support this finding by demonstrating defective processivity in the previously reported p.K570N T-motif mutation. The consanguineous, heterozygous p.T567M parents 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 add short stretches of telomeric repeats onto the shortest telomeres, sole expression of telomerase processivity mutants can lead to a profound failure of telomere maintenance and early-onset multisystem disease.