Journal article
The Influence of a Genetic Variant in CCDC78 on LMNA -Associated Skeletal Muscle Disease
International journal of molecular sciences, Vol.25(9), 4930
04/30/2024
DOI: 10.3390/ijms25094930
PMCID: PMC11084688
PMID: 38732148
Abstract
Mutations in the
gene-encoding A-type lamins can cause Limb-Girdle muscular dystrophy Type 1B (LGMD1B). This disease presents with weakness and wasting of the proximal skeletal muscles and has a variable age of onset and disease severity. This variability has been attributed to genetic background differences among individuals; however, such variants have not been well characterized. To identify such variants, we investigated a multigeneration family in which affected individuals are diagnosed with LGMD1B. The primary genetic cause of LGMD1B in this family is a dominant mutation that activates a cryptic splice site, leading to a five-nucleotide deletion in the mature mRNA. This results in a frame shift and a premature stop in translation. Skeletal muscle biopsies from the family members showed dystrophic features of variable severity, with the muscle fibers of some family members possessing cores, regions of sarcomeric disruption, and a paucity of mitochondria, not commonly associated with LGMD1B. Using whole genome sequencing (WGS), we identified 21 DNA sequence variants that segregate with the family members possessing more profound dystrophic features and muscle cores. These include a relatively common variant in
(
). This variant was given priority because another mutation in
causes autosomal dominant centronuclear myopathy-4, which causes cores in addition to centrally positioned nuclei. Therefore, we analyzed muscle biopsies from family members and discovered that those with both the
mutation and the
variant contain muscle cores that accumulated both CCDC78 and RyR1. Muscle cores containing mislocalized CCDC78 and RyR1 were absent in the less profoundly affected family members possessing only the
mutation. Taken together, our findings suggest that a relatively common variant in
can impart profound muscle pathology in combination with a
mutation and accounts for variability in skeletal muscle disease phenotypes.
Details
- Title: Subtitle
- The Influence of a Genetic Variant in CCDC78 on LMNA -Associated Skeletal Muscle Disease
- Creators
- Nathaniel P Mohar - University of IowaEfrem M Cox - University of IowaEmily Adelizzi - University of IowaSteven A Moore - University of IowaKatherine D Mathews - University of IowaBenjamin W Darbro - University of IowaLori L Wallrath - University of Iowa
- Resource Type
- Journal article
- Publication Details
- International journal of molecular sciences, Vol.25(9), 4930
- DOI
- 10.3390/ijms25094930
- PMID
- 38732148
- PMCID
- PMC11084688
- ISSN
- 1661-6596
- eISSN
- 1422-0067
- Grant note
- T32GM144636 / NIH HHS 1U54NS053672 / NIH HHS R21AR075193 / NIH HHS
- Language
- English
- Date published
- 04/30/2024
- Academic Unit
- Neurology; Stead Family Department of Pediatrics; Pathology; Iowa Neuroscience Institute; Medical Genetics and Genomics; Biochemistry and Molecular Biology; Neurology (Pediatrics); University College Courses
- Record Identifier
- 9984627000002771
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