Abstract
TRIP4 is one of the subunits of the transcriptional coregulator ASC-1, a ribonucleoprotein complex that participates in transcriptional coactivation and RNA processing events. Recessive variants in the TRIP4 gene have been associated with spinal muscular atrophy with bone fractures as well as a severe form of congenital muscular dystrophy. Here we present the diagnostic journey of a patient with cerebellar hypoplasia and spinal muscular atrophy (PCH1) and congenital bone fractures. Initial exome sequencing analysis revealed no candidate variants. Reanalysis of the exome data by inclusion in the Solve-RD project resulted in the identification of a homozygous stop-gain variant in the TRIP4 gene, previously reported as disease-causing. This highlights the importance of analysis reiteration and improved and updated bioinformatic pipelines. Proteomic profile of the patient’s fibroblasts showed altered RNA-processing and impaired exosome activity supporting the pathogenicity of the detected variant. In addition, we identified a novel genetic form of PCH1, further strengthening the link of this characteristic phenotype with altered RNA metabolism.
Highlights
The thyroid receptor interacting protein 4, encoded by the TRIP4 gene, is one of the four subunits of the transcriptional coregulator ASC-1
TRIP4, together with ASCC1, ASCC2 and ASCC3, form a ribonucleoprotein complex that participates in transcriptional coactivation and RNA
Recessive variants in TRIP4 have been associated with two distinct phenotypes: spinal muscular atrophy with bone fractures (OMIM #616866; ref. [1]) and a severe form of congenital muscular dystrophy (CMD)(OMIM #617066; ref. [4, 5])
Summary
The thyroid receptor interacting protein 4, encoded by the TRIP4 gene, is one of the four subunits of the transcriptional coregulator ASC-1. Recessive variants in TRIP4 have been associated with two distinct phenotypes: spinal muscular atrophy with bone fractures [4, 5]) Changes in another subunit of the transcriptional coregulator ASC-1, ASCC1, result in a prenatal muscle weakness with arthrogryposis and congenital bone fractures [1, 6]. We present the diagnostic journey of a patient with cerebellar hypoplasia, spinal muscular atrophy (PCH1-like) and congenital bone fractures, where we identified a homozygous stop-gain variant in the TRIP4 gene; the ninth case reported world-wide. The mass spectrometry proteomics data was submitted to the ProteomeXchange Consortium via the PRIDE (PXD023584; https://www.ebi.ac. uk/pride)
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