Fig. 1.

Pedigrees, gingival fibromatosis and craniofacial features, and KCNQ1 structure. a (I) Pedigree of the large Finnish family showing autosomal dominant growth hormone deficiency and maternally inherited gingival fibromatosis. The genotype (wild-type (WT) or p.(Arg116Leu)) is given. The samples included in the linkage analysis are indicated in italics, and samples included in whole-genome sequencing are underlined. Two additional families with the same disease but another mutation in KCNQ1, p.(Pro369Leu), were identified: a Finnish trio (II) and a family (III) originating from Argentina. Note that the index patient in pedigree III has a de novo mutation. b Maternally inherited gingival fibromatosis is shown together with the craniofacial features of the twin boys belonging to family II. c Schematic of the KCNQ1 channel protein and the location of the two missense mutations in the 3D channel structure. The schematic shows the membrane domain, with helical segments S0–S6 and the intracellular domain, divided into a membrane-proximal module (helices A–B) bound by CaM and a distal module (helices C–D), responsible for tetramerization. Filled circles with labels show the positions of the mutations, Arg116Leu and Pro369Leu. The double lines depict the plasma membrane. Below the schematic is a molecular graphics depiction of the Kv7.1/CaM channel complex as based on the cryo EM Xenopus structure (PDB code: 5VMS)¹¹. The channel subunits are colored green, cyan, and teal. CaM is colored pink and shown with a surface representation on the right side. Gray spheres are Ca²⁺ ions. Again, the straight lines denote the probable location of the plasma membrane. The residues that undergo mutation are drawn as CPK atoms and are labeled. One channel subunit of the tetramer and its respective CaM molecule have not been drawn in order to facilitate visualization. The helix D tetrameric coiled-coil⁶² was not observed in the cryo EM study due to flexibility in the linker between it and helix C and hence not drawn here