Differential inclusion of NEB exons 143 and 144 provides insight into NEB-related myopathy variant interpretation and disease manifestation
Biallelic pathogenic variants in the gene encoding nebulin (NEB) are a known cause of congenital myopathy. We present two brothers with congenital myopathy and compound heterozygous variants (NC_000002.12:g.151692086G>T; NM_001271208.2: c.2079C>A; p.(Cys693Ter) and NC_000002.12:g.151533439T>C; NM_001271208.2:c.21522+3A>G) in NEB. Transcriptomic sequencing on affected individual muscles revealed that the extended splice variant c.21522+3A>G causes exon 144 skipping. Nebulin isoforms containing exon 144 are known to be mutually exclusive with isoforms containing exon 143, and these isoforms are differentially expressed during development and in adult skeletal muscles. Affected individuals' MRI patterns of muscle involvement were compared with the known pattern of relative abundance of these two isoforms in muscle. We propose that the pattern of muscle involvement in these affected individuals better fits the distribution of exon 144-containing isoforms in muscle than with previously published MRI findings in NEB-related disease due to other variants. Our report introduces disease pathogenesis and manifestation as a result of alteration of isoform distributions in muscle.
Authors
- Katherine R. Chao (ORCID: https://orcid.org/0000-0003-2897-2410)
- Safoora Syeda (ORCID: https://orcid.org/0009-0009-3250-6755)
- Rotem Orbach (ORCID: https://orcid.org/0000-0002-1015-1529)
- M. Leach (ORCID: https://orcid.org/0009-0007-5599-3512)
- Katherine G. Meilleur (ORCID: https://orcid.org/0000-0001-5686-5423)
- Svetlana Gorokhova (ORCID: https://orcid.org/0000-0001-6870-4061)
- A. Reghan Foley (ORCID: https://orcid.org/0000-0003-2168-1119)
- Prech Uapinyoying
- C. Bönnemann
- Sandra Donkervoort
- Sarah Silverstein (ORCID: https://orcid.org/0000-0003-3428-3734)
Institutions
- Broad Institute (US)
- National Institutes of Health (US)
- Children's National (US)
- Inserm (FR)
- Aix-Marseille Université (FR)
- Assistance Publique Hôpitaux de Marseille (FR)
- National Institute of Neurological Disorders and Stroke (US)
- Génétique Médicale & Génomique Fonctionelle (FR)
- Centre de Génétique Médicale de Marseille (FR)
Publication Details
- Journal
- Human Genetics and Genomics Advances
- Published
- 2024-09-23
- DOI
- https://doi.org/10.1016/j.xhgg.2024.100354
- Primary Topic
- Genetic Neurodegenerative Diseases
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Colgate-Palmolive Company
- American Association for Dental, Oral, and Craniofacial Research
- Broad Institute
- National Institutes of Health
- Genentech
- National Heart, Lung, and Blood Institute
- National Institute of Mental Health
- National Institute on Drug Abuse
- National Human Genome Research Institute
- NIH Office of the Director
- National Cancer Institute
- National Institute of Neurological Disorders and Stroke
- Common Fund