Background Oculopharyngodistal myopathy (OPDM) is a rare adult-onset neuromuscular disease, associated with CGG repeat expansions in the 5′ untranslated region of LRP12, GIPC1, NOTCH2NLC and RILPL1. However, the genetic cause of a proportion of pathoclinically confirmed cases remains unknown.
Methods A total of 26 OPDM patients with unknown genetic cause(s) from 4 tertiary referral hospitals were included in this study. Clinical data and laboratory findings were collected. Muscle samples were observed by histological and immunofluorescent staining. Long-read sequencing was initially conducted in six patients with OPDM. Repeat-primed PCR was used to screen the CGG repeat expansions in LOC642361/NUTM2B-AS1 in all 26 patients.
Results We identified CGG repeat expansion in the non-coding transcripts of LOC642361/NUTM2B-AS1 in another two unrelated Chinese cases with typical pathoclinical features of OPDM. The repeat expansion was more than 70 times in the patients but less than 40 times in the normal controls. Both patients showed no leucoencephalopathy but one showed mild cognitive impairment detected by Montreal Cognitive Assessment. Rimmed vacuoles and p62-positive intranuclear inclusions (INIs) were identified in muscle pathology, and colocalisation of CGG RNA foci with p62 was also found in the INIs of patient-derived fibroblasts.
Conclusions We identified another two unrelated cases with CGG repeat expansion in the long non-coding RNA of the LOC642361/NUTM2B-AS1 gene, presenting with a phenotype of OPDM. Our cases broadened the recognised phenotypic spectrum and pathogenesis in the disease associated with CGG repeat expansion in LOC642361/NUTM2B-AS1.
- neuromuscular diseases
- nervous system diseases
Data availability statement
Data are available upon reasonable request. All data that support the findings of this study are available from the corresponding authors upon reasonable request.
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XG, JY and KJ contributed equally.
Contributors XG drafted the manuscript and analysed the data. JY designed and carried out LRS and RP-PCR, and analysed data. KJ designed and carried out primary fibroblast culture, RNA fluorescence in situ hybridisation and immunofluorescence. JDeng supervised the molecular analysis and created the figures. XX contributed to primary fibroblast culture and RNA fluorescence in situ hybridisation. KQ provided technical support for electrophysiological diagnosis. DY analysed muscle imaging and provided technical assistance for muscle pathology. MG provided technical assistance for muscle pathology. CZ verified and interpreted the clinical, pathological and molecular results. JDong, GH, JS, CY, LD and YD contributed to case diagnosis and acquisition of clinical data. WZ revised the manuscript and supervised the project. JX drafted and revised the manuscript, designed and supervised the project. ZW designed and conceptualised the study, revised the manuscript and supervised the project. All authors have participated sufficiently in the work and approved the final version of the manuscript for submission. Authors acting as guarantors: ZW and JX.
Funding The study was supported by research grant from the National Natural Science Foundation of China (82071409, 82171398, 82271437, 82171846 and U20A20356) and Beijing Nova Program (2022018).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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