Curation OPML1 NUTM2B AS1

Gene NUTM2B-AS1

Disease OPML1

Inheritance AD

Score

7.5 + 2 = 9.5 / 18

Genetic + experimental = total

Classification

Moderate

Refuted

Moderate

Definitive

Last Updated 08/18/2025

Pubs Reviewed 4

Publication Span 5 years

Publication Interval 5 years

Curator(s) Macayla Weiner, Laurel Hiatt

Description

A heterozygous CGG/CCG repeat expansion in overlapping noncoding exons of bidirectionally transcribed LOC642361/NUTM2B-AS1 is associated with autosomal dominant OPML1/LOC642361-NUTM2B-AS1-related oculopharyngeal myopathy spectrum. The original report identified the expansion in one Japanese OPML family with leukoencephalopathy, with segregation in affected relatives and absence in unaffected relatives and 1,000 controls. Subsequent independent reports identified OPDM-predominant cases from Chinese and Thai families, expanding the phenotype and showing variable or absent leukoencephalopathy. Patient-muscle studies showed rimmed vacuoles, p62-positive intranuclear inclusions, aggrephagy/RNA-binding protein accumulation, and mitochondrial abnormalities, supporting a repeat-mediated pathogenic mechanism.

All criTRia Curations Locus Page

Genetic evidence

Total: 7.5

Per page

Category	Type	Citation	Score	Details
Singular Evidence	Probands	PMID:31332380 PMID:37923380 PMID:39308795	6	PMID 31332380: one OPML family (F5305) with CGG/CCG expansion in LOC642361/NUTM2B-AS1; PMID 37923380: two unrelated Chinese OPDM cases with expansions >70 repeats among 26 unsolved OPDM cases; PMID 39308795: four Thai OPDM patients from three unrelated families with expansions >100 repeats/strong somatic instability.
Collective Evidence	Segregation	PMID:31332380	1.5	PMID 31332380: In family F5305, RP-PCR confirmed the expansion in four affected individuals and absence in seven unaffected relatives, including three married-in controls; the expansion was absent in 1,000 controls.

Experimental evidence

Total: 2

Per page

Category	Type	Citation	Score	Details
Function	Biochemical function	PMID:38159879	0.5	PMID 38159879: Patient muscle immunofluorescence showed aggrephagy pathway proteins p62, NBR1, and LC3B accumulated in intranuclear inclusions, suggesting the LOC642361/NUTM2B-AS1 CGG expansion may impair aggrephagic capacity.
Function	Protein interaction	PMID:38159879	0.5	PMID 38159879: Patient muscle immunofluorescence showed RNA-binding proteins hnRNPA1, hnRNPA2B1, and MBNL1 accumulated in intranuclear inclusions, consistent with repeat-associated RNA-binding protein sequestration.
Function	Regulatory impact	PMID:38159879	0	Study reports minimal methylation near the LOC642361/NUTM2B-AS1 CGG repeat region, no significant methylation difference between patients and healthy controls, and no significant LOC642361/NUTM2B-AS1 expression difference by RT-qPCR between patients, asymptomatic carriers, and controls. This evidence was not scored, however noted here for completeness.
Functional Alteration	Patient cells	PMID:38159879	1	PMID 38159879: Patient muscle biopsies showed myopathic changes with rimmed vacuoles, p62-positive intranuclear inclusions, filamentous aggregates by electron microscopy, autophagic vacuoles, and swollen/disordered mitochondria.

Maximum score caps apply at evidence type, category, and supercategory levels, so section totals may be lower than the raw sum of row scores.