Bi-allelic Loss-of-Function Mutations in the NPR-C Receptor Result in Enhanced Growth and Connective Tissue Abnormalities Eveline Boudin, Tjeerd R. de.

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Bi-allelic Loss-of-Function Mutations in the NPR-C Receptor Result in Enhanced Growth and Connective Tissue Abnormalities Eveline Boudin, Tjeerd R. de Jong, Tim C.R. Prickett, Bruno Lapauw, Kaatje Toye, Viviane Van Hoof, Ilse Luyckx, Aline Verstraeten, Hugo S.A. Heymans, Eelco Dulfer, Lut Van Laer, Ian R. Berry, Angus Dobbie, Ed Blair, Bart Loeys, Eric A. Espiner, Jan M. Wit, Wim Van Hul, Peter Houpt, Geert R. Mortier The American Journal of Human Genetics Volume 103, Issue 2, Pages 288-295 (August 2018) DOI: 10.1016/j.ajhg.2018.06.007 Copyright © 2018 American Society of Human Genetics Terms and Conditions

Figure 1 Radiographic and Clinical Images of the Hands and Feet (A and B) Radiographs from individual 1 (reproduced with permission from de Jong et al.56). (A) Right hand image taken at the age of 6 years shows an extra epiphysis (indicated by white arrow) at multiple sites. There is also a pseudoepiphysis at the base of the second metacarpal. (B) Right foot image taken at the age of 5 years shows the presence of an extra epiphysis at the head (distal end) of the first metatarsal and the distal ends of the second to fifth proximal phalanges. (C and D) Radiographs from individual 2 (reproduced with permission from de Jong et al.56). Images were taken at the age of 5 years and show the relatively long halluces (D) and extra epiphyses in hands (C) and feet (D). (E) Radiograph of both hands from individual 3 taken at the age of 11 years 8 months. The image shows long and slender tubular bones, especially in both thumbs. The presence of an extra epiphysis is best seen at the distal end of both metacarpals I. (F–I) Radiographic and clinical images of the hands and feet from individual 4. The radiographs were taken at the age of 7 years and 10 months. The tubular bones in the left hand are long and slender, especially the proximal and middle phalanges and metacarpal I, that in addition show an extra epiphysis at their distal end (F). The same pattern is observed in both feet with large metatarsals I and proximal phalanges (G). Clinical photos of the hands (H) and feet (I) show the long fingers and toes, most pronounced for the halluces, which is typical and therefore representative for all affected individuals. The American Journal of Human Genetics 2018 103, 288-295DOI: (10.1016/j.ajhg.2018.06.007) Copyright © 2018 American Society of Human Genetics Terms and Conditions

Figure 2 Cellular Localization of Wild-Type and Mutant (p.Ser148Pro and p.Asp363Val) NPR3 The nuclei are stained blue using DAPI and the cell membrane is marked red using Alexa Fluor wheat germ agglutinin (WGA) 555 (Thermo Fisher Scientific). Images are taken with a Nikon Eclipse Ti-E inverted microscope attached to a microlens-enhanced dual spinning disk confocal system (UltraVIEW VoX; PerkinElmer) equipped with 405, 488, and 561 nm diode lasers for excitation of blue, green, and red and far-red fluorophores, respectively. Magnification 60×. The American Journal of Human Genetics 2018 103, 288-295DOI: (10.1016/j.ajhg.2018.06.007) Copyright © 2018 American Society of Human Genetics Terms and Conditions