A novel splice site variant in TIMM8A induced abnormal mRNA splicing resulting in Mohr-Tranebjaerg syndrome

Mohr-Tranebjaerg syndrome (MTS) is an X-linked recessive neurodegenerative disorder caused by pathogenic variants in TIMM8A. Of the 39 previously reported disease-causing variants in the TIMM8A, five are splice site variants; however, none of these variants have been evaluated by transcript analysis.

We performed panel-based targeted exome analysis in a Japanese boy with sensorineural hearing loss and rapidly progressive dystonia. To assess the effect of the identified splice donor site variant, transcript analysis was performed using RNA derived from peripheral blood.

A novel hemizygous splice donor site variant in TIMM8A (NM_004085.4:c.132+5G>A) was identified. Transcript analysis revealed three aberrant transcripts: two transcripts with partial intron 1 inclusion of 606 bp or 492 bp (INS606bp and INS492bp) and one transcript with a 60 bp partial deletion of exon 1 (Δ60bp), with no detectable normal transcript. Both INS606bp and INS492bp transcripts contain premature stop codons due to the inserted intronic sequences, leading to the loss of 53 amino acids, whereas the Δ60bp transcript leads to the loss of 20 amino acids. All aberrant transcripts lacked part of the Tim10/DDP family zinc finger domain, which is essential for TIM8A function.

This study provides the first transcript analysis elucidating the pathogenic mechanism of a splice donor site variant in TIMM8A. The findings suggest that splice donor site variants may share a common disease mechanism involving the production of functionally defective TIM8A protein.