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

Fuller, H; Storey, E


E Storey


Mutations in genes encoding proteins associated with the linker of nucleoskel-eton and cytoskeleton (LINC) complex within the nuclear envelope cause dif-ferent diseases with varying phenotypes including skeletal muscle, cardiac, metabolic, or nervous system pathologies. There is some understanding of the structure of LINC complex-associated proteins and how they interact, but it is unclear how mutations in genes encoding them can cause the same disease, and different diseases with different phenotypes. Here, published mutations in LINC complex-associated proteins were systematically reviewed and ana-lyzed to ascertain whether patterns exist between the genetic sequence vari-ants and clinical phenotypes. This revealed LMNA is the only LINC complex-associated gene in which mutations commonly cause distinct conditions, and there are no clear genotype-phenotype correlations. Clusters of LMNA vari-ants causing striated muscle disease are located in exons 1 and 6, and metabol-ic disease-associated LMNA variants are frequently found in the tail of lamin A/C. Additionally, exon 6 of the emerin gene, EMD, may be a mutation “hot-spot”, and diseases related to SYNE1, encoding nesprin-1, are most often caused by nonsense type mutations. These results provide insight into the di-verse roles of LINC-complex proteins in human disease and provide direction for future gene-targeted therapy development.

Acceptance Date Dec 13, 2022
Publication Date Dec 15, 2022
Journal Cells
Publisher MDPI
Keywords LINC complex; nuclear envelope; laminopathies; lamin A; C; LMNA; SYNE1; EMD; nesprin; emerin
Publisher URL
Additional Information © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (


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