RNA Lariat-Debranching Enzyme (DBR1) Variations in Sabinas Brittle Hair Syndrome Form of Trichothiodystrophy: A Trichothiodystrophy-Causing Gene.

Trichothiodystrophy (TTD), a rare, autosomal recessive, multisystem developmental disorder, is characterized by short, brittle hair with "tiger-tailed banding" on polarized microscopy. TTD is caused by variations in 10 genes: 3 nucleotide excision repair/basal transcription factor IIH genes, 4 amino acid charging transfer RNA genes, basal transcription factor IIE, RNF113A, and an RNA-splicing gene (MPLKIP/TTDN1). We performed whole-exome sequencing to identify a candidate gene in Sabinas brittle hair syndrome, a mild form of TTD. We report 5 nonphotosensitive adult patients from 3 unrelated families with a homozygous missense variation in DBR1 (p.D262Y) encoding the RNA lariat-debranching enzyme DBR1, which is involved in the removal of introns from pre-mRNA in the nucleus. Post-UV DNA cell survival was normal, indicating that DBR1 was not involved in nucleotide excision repair/transcription factor IIH. There were reduced levels of DBR1 mRNA and protein. Interacting TTDN1 protein in cells from patients with DBR1 variations was markedly reduced. Genetic analysis suggests an ancient origin of this variation. Thus, Sabinas syndrome is caused by DBR1 variations, further indicating that TTD is a disorder of RNA metabolism (RNAopathy).