RNF113A – Trichothiodystrophy

RNF113A encodes a RING finger protein involved in DNA alkylation repair and pre-messenger RNA splicing. X-linked truncating variants in RNF113A cause a form of non-photosensitive trichothiodystrophy (TTD) with neuroectodermal involvement, sparse brittle hair, intellectual disability, seizures, and growth impairment. The disease locus maps to Xq23–q25 and segregates in an X-linked recessive pattern in affected families.

Two male cousins presenting with microcephaly, profound intellectual disability, sparse brittle hair, seizures, cerebellar hypoplasia, short stature, facial dysmorphism, and partial corpus callosum absence harbored a hemizygous nonsense variant c.901C>T (p.Gln301Ter) in RNF113A, which fully segregated with disease and was absent from over 100 000 control X chromosomes ([PMID:25612912]). This variant was subsequently identified in two additional affected fetuses with overlapping features, supporting replication across two independent families ([PMID:31793730]). Obligate carrier females exhibited 100 % skewed X-chromosome inactivation.

Inheritance is X-linked recessive, with four affected individuals from two families and two segregations in males. Only a single recurrent LoF variant has been reported, consistent with a loss-of-function mechanism and absence of other variant classes.

Functional studies demonstrate that p.Gln301Ter markedly reduces RNF113A protein levels in patient lymphoblastoid cells and impairs DNA alkylation repair ([PMID:31793730]). In vitro splicing assays show RNF113A associates with U2, U4, and U6 snRNAs and spliceosomal proteins; RNF113A depletion by CRISPR reduces splicing efficiency and is rescued by recombinant protein ([PMID:30506991]). RNF113A knockout in HeLa cells activates the NRF2 oxidative stress response, elevates ROS, sensitizes to H₂O₂-induced death, alters glutathione homeostasis, and promotes stress granule formation ([PMID:38741949]).

The collective genetic and experimental evidence supports a loss-of-function mechanism for RNF113A truncating variants in X-linked TTD, linking defective DNA repair and splicing to neuroectodermal pathology. No conflicting reports have been described.

Key take-home: RNF113A LoF variants cause X-linked non-photosensitive trichothiodystrophy by disrupting spliceosomal assembly and DNA repair, guiding diagnosis and genetic counseling in affected families.

References

• Journal of Medical Genetics | 2015 | A novel X-linked trichothiodystrophy associated with a nonsense mutation in RNF113A. PMID:25612912
• American Journal of Medical Genetics Part A | 2020 | Second report of RING finger protein 113A (RNF113A) involvement in a Mendelian disorder. PMID:31793730
• Journal of Cellular Biochemistry | 2019 | Human RNF113A participates of pre-mRNA splicing in vitro. PMID:30506991
• Animal Cells and Systems | 2024 | Effect of RNF113A deficiency on oxidative stress-induced NRF2 pathway. PMID:38741949

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