Variants in the X-linked gene RNF113A are exceedingly rare and to date, only six cases that have been reported. Clinical features associated with pathogenic variants in RNF113A have been considered consistent with a trichothiodystrophy that is characterized sparse and brittle hair with a ‘tiger-tail’ pattern of banding and reduced sulfur content.
Other findings include developmental delays and intellectual disability (ID), microcephaly that can be progressive, seizures, brain anomalies with thin or absent corpus callosum and cerebellar hypoplasia, facial anomalies, and renal dysplasia. There may be frequent infections with immunodeficiency and low IgG levels. Delayed growth that can be of prenatal onset has also been described. Hypogonadism with cryptorchidism, small or absent testes and microphallus are typical in affected males and abnormal hormonal testing with increased thyroid stimulating hormone (TSH), luteinizing hormone (LH) and follicle stimulating hormone (FSH), low testosterone and thyroxine (T4) levels have also been reported.
The gene was first studied as ZNF183 and comprises a single exon that encodes two zinc finger domains - a C3H1-type zinc finger domain present in RNA-binding proteins involved in splicing and a C3HC4 RING-type zinc finger domain found in E3 ubiquitin ligases. Pathogenic variants have been predicted to act by loss of function. The gene is expressed in all tissues and conserved from yeast to human. The RNF113A protein interacts with the E2 protein, UBE2U, and is hypothed to act as an E3 ligase that is involved in spliceosome function. RNF113A is also involved in the cellular response to alkylating agents. Cellular photosensitivity and ichthyosis that are characteristic findings of trichothiodystrophies have not been present.
RNF113A