A variant in CCDC78 collaborates with a mutation in LMNA to cause LGMD and core myopathy in a large family


Pre-Clinical Research

Poster Number: T361


Lori Wallrath, PhD, University of Iowa, Nathan Mohar, BS, University of Iowa, Steven Moore, MD, PhD, Department of Pathology/University of Iowa, Katherine Mathews, MD, FAAN, University of Iowa, Benjamin Darbro, MD, PhD, Department of Pediatrics/University of Iowa

Background: Limb-Girdle muscular dystrophy (LGMD) refers to a collection of diseases that cause progressive weakness and wasting, starting in the proximal muscles. One of the more common autosomal dominant types of LGMD (LGMD1B) is caused by mutations in the LMNA gene, encoding nuclear lamins. The age of onset and disease severity of LGMD1B is highly variable among individuals, even within families. Here, we describe a multi-generation family with a splice site mutation in LMNA causing LGMD1B in which family members exhibit clinical phenotypic variability.
Objective: Our goal was to identify genetic variants that act in combination with LMNA to drive the variable phenotypes in this family.
Results: Muscle biopsy tissue collected for clinical analyses from individuals within this family was reviewed. Surprisingly, a subset of the affected individuals possessed muscle core pathology, a phenotype not typically associated with LGMD or caused by LMNA mutations. Whole genome sequencing revealed a relatively common variant of uncertain significance in the gene coiled-coil domain containing protein 78 (CCDC78) that is present only in those family members with core pathology. In a prior study, a mutation in CCDC78 was found to cause autosomal dominant centronuclear myopathy-4 that affects distal muscles and is characterized by internal nuclei and cores. Immunostaining of muscle tissue from family members in our study showed CCDC78 aggregation in muscle cores only in individuals with the CCDC78 variant. Additionally, the CCDC78 aggregates co-localized with abnormal aggregates of RYR1 in the muscle cores, consistent with the published report of CCDC78-associated myopathy.
Conclusions: Taken together, our findings support that a relatively common variant in CCDC78, together with a pathological LMNA mutation, accounts for the core myopathy and the variability of the skeletal muscle disease in this family.