POPDC3 (Popeye Domain-Containing Protein 3) was first reported in relation to autosomal recessive limb-girdle muscular dystrophy in 2019 (Vissing et al., PMID: 31610034). POPDC3 is a Popeye domain-containing protein that is abundantly expressed in heart and/or skeletal muscle. Autosomal recessive LGMD (MONDO:0015152) is characterized by adult-onset weakness primarily affecting the proximal muscles of the lower limbs. Summary of Genetic Evidence (6.8 points): Three unique missense variants from this initial publication have been reported in humans and segregate with the disease in two additional family members (PMID:31610034). One unique missense variant (PMID:35075722), and two unique variants considered LOF (PMID:35842834, PMID:37104941), have also been reported.
Summary of Experimental Evidence (1 point): The mechanism for disease is hypothesized to be biallelic loss-of-function, with mutant protein unable to regulate TREK-1 and potentially causing altered skeletal muscle development. However, without further functional studies and potential models, the exact pathogenic mechanisms or other affected pathways are not yet known. This gene-disease association is supported by limited experimental evidence. POPDC3 is uniquely expressed in skeletal and cardiac muscle, providing evidence towards an association with this muscle-affecting disorder. A Zebrafish knock-out mutant model demonstrated ventral tail curvature and dystrophic changes in myofibers, indicating a function related to muscle tissue, however the limited similarity between this model and human probands as well as the question regarding the type of pathogenic mechanism limits the reliability.
In summary, there is moderate evidence (7.8 points) to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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