Mutations in the Transmembrane Natriuretic Peptide Receptor NPR-B Impair Skeletal Growth and Cause Acromesomelic Dysplasia, Type Maroteaux Cynthia F.

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Mutations in the Transmembrane Natriuretic Peptide Receptor NPR-B Impair Skeletal Growth and Cause Acromesomelic Dysplasia, Type Maroteaux Cynthia F. Bartels, Hülya Bükülmez, Pius Padayatti, David K. Rhee, Conny van Ravenswaaij-Arts, Richard M. Pauli, Stefan Mundlos, David Chitayat, Ling-Yu Shih, Lihadh I. Al-Gazali, Sarina Kant, Trevor Cole, Jenny Morton, Valérie Cormier-Daire, Laurence Faivre, Melissa Lees, Jeremy Kirk, Geert R. Mortier, Jules Leroy, Bernhard Zabel, Chong Ae Kim, Yanick Crow, Nancy E. Braverman, Focco van den Akker, Matthew L. Warman The American Journal of Human Genetics Volume 75, Issue 1, Pages 27-34 (July 2004) DOI: 10.1086/422013 Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 1 Schematic depiction of an endochondral growth plate, with resting, proliferative, prehypertrophic, and hypertrophic zones noted. Ligands or ligand families known to regulate endochondral growth (e.g., IGF, FGF, and BMP) are shown at left. Note that CNP is expressed by proliferative and prehypertrophic chondrocytes. Sites of expression of the two CNP receptors are shown at right. NPR-B is expressed in proliferative and prehypertrophic chondrocytes, whereas NPR-C is expressed in prehypertrophic and hypertrophic chondrocytes. Systemic growth factors are noted above. Although some interactions between secreted growth factors are known (see, e.g., Minina et al. 2002), the interplay between most endocrine- and paracrine-signaling systems is still not delineated. The American Journal of Human Genetics 2004 75, 27-34DOI: (10.1086/422013) Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 2 Clinical and radiographic features of AMDM. A, Side photograph of an adult male with AMDM, whose hand photograph is in panel B. Note the short stature, the shortening of the extremities, and the bowing of the forearm. C, Hand radiograph of a child with AMDM, whose hand photograph is in panel D. Note the shortening and widening of metacarpals and phalanges. E, Hand radiograph of an adult carrier of AMDM, whose height is 145 cm (4 ft, 9 in) and whose hand photograph is in panel F. Note the normal shape and proportion of the skeletal elements. The American Journal of Human Genetics 2004 75, 27-34DOI: (10.1086/422013) Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 3 Schematic diagram of the dimeric NPR-B receptor, highlighting sites containing putative disease-causing missense mutations and a truncation mutation that would not be predicted to cause nonsense-mediated mRNA decay. Also depicted are the ECD, transmembrane helices (TM), the kinase homology domain (KHD), the coiled-coil (CC) region, and the guanylyl cyclase (GC) domain. Mutations are P32T (1), W115G (2), D176E (3), T297M (4), Y338C (5), A409T (6), G413E (7), Y708C (8), R776W (9), R957C (10), G959A (11), and R1020fsX1025 (12). A, Close-up view of four mutation sites (4–7) in the ECD. B, Close-up view of the W115G and D176E mutation sites. C, Close-up view of the Y708C and R776W mutation sites in the KHD. D, Close-up view of the modeled NPR-B GC domain dimer showing R957C, G959A, and R1020fsX1025. The red ribbon indicates the portion of NPR-B that is missing in R1020fsX1025. Note that, for clarity, only one of the nucleotide substrate analogs, derived from the template 1CUL kinase domain structure, is shown (dark blue), including the two magnesium ions (black). The American Journal of Human Genetics 2004 75, 27-34DOI: (10.1086/422013) Copyright © 2004 The American Society of Human Genetics Terms and Conditions