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Short telomere syndromes manifest as familial idiopathic pulmonary fibrosis; they are the most common premature aging disorders. We used genome-wide linkage to identify heterozygous loss of function of  ZCCHC8 , a zinc-knuckle containing protein, as a cause of autosomal dominant pulmonary fibrosis. ZCCHC8 associated with  TR  and was required for telomerase function. In ZCCHC8 knockout cells and in mutation carriers, genomically extended telomerase RNA ( TR ) accumulated at the expense of mature  TR , consistent with a role for ZCCHC8 in mediating  TR  3′ end targeting to the nuclear RNA exosome. We generated  Zcchc8 -null mice and found that heterozygotes, similar to human mutation carriers, had  TR  insufficiency but an otherwise preserved transcriptome. In contrast,  Zcchc8 −/−   mice developed progressive and fatal neurodevelopmental pathology with features of a ciliopathy. The  Zcchc8 −/−   brain transcriptome was highly dysregulated, showing accumulation and 3′ end misprocessing of other low-abundance RNAs, including those encoding cilia components as well as the intronless replication-dependent histones. Our data identify a novel cause of human short telomere syndromes-familial pulmonary fibrosis and uncover nuclear exosome targeting as an essential 3′ end maturation mechanism that vertebrate  TR  shares with replication-dependent histones.

ZCCHC8, the nuclear exosome targeting component, is mutated in familial pulmonary fibrosis and is required for telomerase RNA maturation