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Mutations in a broad variety of genes can provoke the severe childhood disorder trichothiodystrophy (TTD) which is classified as a DNA repair disease or a transcription syndrome of RNA polymerase II. In an attempt to identify the common underlying pathomechanism of TTD, a knockdown of RNF113A was performed, and the consequences on ribosomal biogenesis and performance were investigated. Interestingly, interference with RNF113A created a nearly uniform impact on RNA polymerase I transcription with downregulation of UBF, disturbed rRNA processing, and reduction of the backbone of the small ribosomal subunit rRNA 18S. This was accompanied by reduced quality of decoding in protein translation and the accumulation of misfolded and carbonylated proteins indicating a loss of protein homeostasis (proteostasis). As loss of proteostasis by the ribosome has been identified in the other forms of TTD, we here postulate that ribosomal dysfunction is a common underlying pathomechanism of TTD.

We describe an 11-year old boy with severe global developmental delays, failure to thrive and growth retardation, refractory seizures with recurrent status epilepticus, hypogammaglobulinemia, hypergonadotropic hypogonadism, and duodenal strictures. He had facial and skin findings compatible with trichothiodystrophy, including sparse and brittle hair, thin eyebrows, and dry skin. Exome sequencing showed a hemizygous, truncating variant in RNF113A, c.903_910delGCAGACCA, predicting p.(Gln302fs*12), that was inherited from his mother. Although his clinical features overlap closely with features described in the two previously reported male first cousins with RNF113A loss of function mutations, the duodenal strictures seen in this patient have not been reported. Interestingly, the patient's mother had short stature and 100% skewed X-inactivation as seen in other obligate female carriers. A second male with developmental delays, microcephaly, seizures, ambiguous genitalia, and facial anomalies that included sparse and brittle hair, thin eyebrows and dry skin was recently reported to have c.897_898delTG, predicting p.(Cys299*) in RNF113A and we provide additional clinical details for this patient. This report further supports deleterious variants in RNF113A as a cause of a novel trichothiodystrophy syndrome.

RING Finger Protein 113 A (RNF113A, MIM 300951) is a highly conserved gene located on chromosome Xq24-q25, encoding a protein containing two conserved zinc finger domains involved in DNA alkylation repair and premessenger RNA splicing. To date, only one pathogenic variant of RNF113A, namely c.901C>T; p.Gln301Ter, has been reported in humans by Tarpey et al. in 2009. Thereafter, Corbett et al. stated that this variant was responsible for an X-linked form of nonphotosensitive trichothiodystrophy associated with profound intellectual disability, microcephaly, partial corpus callosum agenesis, microphallus, and absent or rudimentary testes. This variant was then shown to alter DNA alkylation repair, providing an additional argument supporting its pathogenicity and important clues about the underlying pathophysiology of nonphotosensitive trichothiodystrophy. Using exome sequencing, we identified exactly the same RNF113A variant in two fetuses affected with abnormalities similar to those previously reported by Corbett et al. To our knowledge, this is the second report of a RNF113A pathogenic variant in humans.

Trichothiodystrophy is a rare condition associated with autosomal recessive or X-linked dominant variants in the ERCC2, ERCC3, GTF2H5, MPLKIP, RNF113A or GTF2E2 genes. The genes associated to photosensitive trichothiodystrophy encode subunits of transcription factor IIH, involved in the nucleotide excision repair pathway. The disease is characterised by cysteine-deficient brittle hair along with other neuroectodermal abnormalities. It has a variable clinical expression and some cases might be associated with photosensitivity, resulting in the acronym PIBIDS (photosensitivity, ichthyosis, brittle hair, intellectual impairment, decreased fertility and short stature). We report clinical findings of two siblings diagnosed with trichothiodystrophy associated with marked photosensitivity.