Abstract| Volume 32, SUPPLEMENT 1, S108, October 2022

P.148 Genotype-phenotype correlations in human diseases caused by mutations of LINC complex-associated genes: a systematic review and meta-summary

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      The linker of nucleoskeleton and cytoskeleton (LINC) complex is a structure that physically connects the nucleus to the cytoskeleton. Mutations in the genes encoding LINC complex proteins give rise to different human diseases with varying phenotypes including cardiac, skeletal muscle, metabolic, or nervous system pathologies. Some of the mechanisms underlying the genotypes and associated phenotypes remain unclear, making it difficult to identify targets for the development of therapies. We systematically reviewed and analysed published mutations affecting LINC complex-associated proteins to determine whether any patterns exist between the genetic sequence variants and clinical phenotypes. This study revealed that LMNA, encoding lamin A/C, is the only LINC-complex associated gene for which mutations frequently cause distinct conditions. We identified a total of 37 different diseases linked to mutations in LMNA. Although there appears to be no obvious genotype-phenotype correlations, clusters of LMNA variants causing striated muscle diseases were found to occur most often in exons 1 and 6, which may disrupt nuclear lamin assembly and lead to a compromised nuclear lamina. We also found that metabolic disease-associated LMNA variants frequently affect the tail domain of lamin A/C, which may hinder interactions between lamin A/C and other proteins. Additionally, a mutation “hot-spot” was identified at exon 6 of EMD, the gene encoding emerin. SYNE1 nonsense mutations also appear to most often cause spinocerebellar ataxia, highlighting the potential for the development of a stop-codon readthrough therapy for the treatment of this disorder. These results provide insight into the varied roles of LINC-complex proteins in human disease and provide direction for clinical diagnosis and future gene-targeted therapy development. Moreover, identifying conditions affected by mutations in different NE proteins may allow for sharing of therapies or therapeutic development strategies.