Figure 4. Disruption of lamin A multimerization dictates effects on aggregation and abundance.

(A) Map of lamin A missense variant effects on the nuclear circularity feature (grey boxes=missing variants, black dots=synonymous substitutions). Blue to red coloring indicates feature z-score versus the synonymous variant distribution. Above the map, positions are annotated by their participation in multimer contacts (first row, defined below), α-helical average substitution profile (second row, defined below and in Figure S5F), and proline-substitution profile (third row, defined below and in Figure S5E). Linker or coil subdomains are shown directly above the heatmap⁶³. Position-averaged scores are below and amino acid substitution marginal feature z-score distributions are on the right (points depict variants; black lines depict medians).

(B) UMAP of variant profiles (Figure 2H) colored by nuclear circularity score as in (A).

(C) Proline substitutions are shown as triangles on the UMAP shown in (Figure 2H), colored by clustering of the effects of proline substitutions as defined in Figure S5E with legend above.

(D) The number of proline substitutions is plotted for each subdomain⁶³ colored as in (C) with legend above. *** indicates χ² p<0.001.

(E) The number of α-helical positions (defined in Figure S5E) plotted by subdomain⁶³ and colored based on the effect of variants on aggregation or abundance at the position (defined in Figure S5F), with legend above. ** indicates χ² p<0.01.

(F) The number of α-helical positions (defined in Figure S5E) plotted by their participation in structural contacts ((G), see Methods), colored as in (E). Color legend shown above. ** indicates χ² p<0.01.

(G) A11 tetramer structure 6JLB⁶³ (bottom) and the A22 tetramer structure⁶⁴ (top) with positions colored as in (E) (magenta=aggregation-sensitive, light blue=abundance-sensitive, dark blue=low impact, grey=position not profiled, black=position not clustered).

(H) Graphical representation of lamin A processing, localization, aggregation, and degradation, annotated with their relationship to dimerization, multimerization and phenotypic effects as well as variant clusters.