Expansion of 5’ UTR CGG repeat in RILPL1 is associated with oculopharyngodistal myopathy

Abstract

Oculopharyngodistal myopathy is an adult-onset degenerative muscle disorder characterized by ptosis, ophthalmoplegia and weakness of the facial, pharyngeal and limb muscles. Trinucleotide repeat expansions in non-coding regions of LRP12, G1PC1and NOTCH2NLC were recently reported to be the etiologies for OPDM. However, a significant portion of OPDM patients still have unknown genetic causes. In this study, we performed long-read whole-genome sequencing in a large five-generation family of 156 individuals, including 22 patients diagnosed with typical OPDM and identified CGG repeat expansions in RILPL1 gene in all patients we tested while not in unaffected family members. Methylation analysis indicated that methylation levels of the RILPL1 gene were unaltered in OPDM patients, which was in consistent with previous reports. Our findings first provided evidences that RILPL1 were associated OPDM which we suggested as OPDM type 4.

Trinucleotide CGG Repeat Diseases: An Expanding Field of Polyglycine Proteins?

“…Importantly, the mutations causing OPDM were recently identified as similar expansions of ~70 to 200-300 CGG repeats located within the 5′UTR of two different genes, LRP12 and GIPC1 (Ishiura et al, 2019;Deng et al, 2020;Kumutpongpanich et al, 2021;Xi et al, 2021). Furthermore, an expansion of CGG repeats in the 5′UTR of the NOTCH2NLC gene was identified in OPDM cases with variable neurological manifestations (Ogasawara et al, 2020;Yu et al, 2021), and an expansion of CGG repeats within the 5′UTR of the RILPL1 gene was recently reported in medRxiv in affected individuals of a large Chinese family with OPDM (Yang et al, 2021). Consequently, OPDM is now distinguished by its genetic cause with oculopharyngodistal myopathy type 1 (OPDM1) caused by a CGG repeat expansion in LRP12, OPDM type 2 is caused by a CGG expansion in GIPC1, OPDM3/NIID1 is caused by a CGG expansion in NOTCH2NLC and OPDM4 is potentially associated with a CGG expansion in RILPL1.…”

Dissecting the cis-regulatory syntax of transcription initiation with deep learning

“…S2B). Some of these resembled CGG repeats, which have been characterized as structural features in the 5'-UTRs of some genes [90][91][92][93] . No single motif emerged as a definitive marker for this region's role in initiation, suggesting that the transcription machinery's preference for the DPR might be nonspecific or challenging to represent as a single motif.…”