Mutations in the Gene Encoding the Calcium-Permeable Ion Channel TRPV4 Produce Spondylometaphyseal Dysplasia, Kozlowski Type and Metatropic Dysplasia

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Mutations in the Gene Encoding the Calcium-Permeable Ion Channel TRPV4 Produce Spondylometaphyseal Dysplasia, Kozlowski Type and Metatropic Dysplasia Deborah Krakow, Joris Vriens, Natalia Camacho, Phi Luong, Hannah Deixler, Tara L. Funari, Carlos A. Bacino, Mira B. Irons, Ingrid A. Holm, Laurie Sadler, Ericka B. Okenfuss, Annelies Janssens, Thomas Voets, David L. Rimoin, Ralph S. Lachman, Bernd Nilius, Daniel H. Cohn The American Journal of Human Genetics Volume 84, Issue 3, Pages 307-315 (March 2009) DOI: 10.1016/j.ajhg.2009.01.021 Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 1 Radiographs of Individuals with SMDK with TRPV4 Mutations Reference numbers are indicated above each column of radiographs. The ages of the subjects were 5 years (R07-490), 3 years (R72-010), 9 years (R03-404), and 8 months (R08-216). (A–D) Anteroposterior (A/P) radiographs of the chest in four subjects, demonstrating the variability of the scoliosis from mild to more severe. The arrow in (C) shows the overfaced pedicles (lamina are seen medial to the vertebral edge). (E–G) Lateral radiographs of the vertebrae showing flattened vertebrae (platyspondyly) and irregular margins. (H) Lateral radiograph of the cervical vertebrae showing a small, irregular C1 vertebra (odontoid hypoplasia, arrow), a finding similar to metatropic dysplasia. (I–K) A/P radiographs of the pelvis showing slightly flared ilia, wide epiphyseal plates, and mildly irregular acetabulae (arrows). (L) A/P radiograph of lower extremity showing slightly widened metaphyses with normal epiphyses, somewhat reminiscent of metatropic dysplasia. (M–P) A/P hand radiographs demonstrating the marked carpal ossification delay (arrows) for each subject's respective age. The American Journal of Human Genetics 2009 84, 307-315DOI: (10.1016/j.ajhg.2009.01.021) Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 2 Radiographs of Metatropic Dysplasia in the Newborn Period Reference numbers for the cases are indicated on each image. (A and C) Body A/P radiographs in two cases showing severe platyspondyly (wafer-like), anterior and posterior rib cupping, widened ileum, and markedly flared proximal and distal femoral metaphyses (dumbbell-shaped femora). (B) Lateral cervical spine radiograph demonstrating odontoid hypoplasia and hypoplasia of the cervical vertebral bodies with cervical kyphosis (arrows). (D and E) Lateral lower-extremity radiograph showing characteristic irregular tali and calcanei (arrows) frequently seen in metatropic dysplasia. (F) A/P radiograph of the upper extremity showing highly irregular metaphyses with popcorn appearance (arrow). The American Journal of Human Genetics 2009 84, 307-315DOI: (10.1016/j.ajhg.2009.01.021) Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 3 Basal Activity of TRPV4 Wild-Type and TRPV4 Mutants (A–D) Basal currents through wild-type TRPV4 (A), D333G (B), R594H (C), and A716S (D) transfected HEK cells in response to a voltage step protocol (40 mV steps from −80 mV to +200 mV). (E) Average basal inward and outward currents at −150 and +150 mV in wild-type TRPV4 (n = 8), D333G (n = 12), R594H (n = 16) and A716S (n = 9) expressing HEK cells. ∗ indicates significant differences when compared with cells expressing wild-type TRPV4 (one-sided Student's t test, p < 0.05). Error bars represent means ± SE (standard error). The American Journal of Human Genetics 2009 84, 307-315DOI: (10.1016/j.ajhg.2009.01.021) Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 4 Effect of TRPV4 Mutagenesis on Activation of TRPV4 by Different Activation Stimuli (A–D) Effect of stimulation with 2 μM 4αPDD on internal fluorescence ratio in wild-type TRPV4 (A), D333G (B), R594H (C), and A716S (D) transfected HEK cells. (E) Basal internal fluorescence ratio, which is a reference for the basal [Ca2+]i, in nontransfected (NT) and the wild-type TRPV4 and TRPV4 mutant transfected cells, D333G, R594H, and A716S. (F–H) Average increase in fluorescence ratio in response to 4αPDD (2 μM) (F), a hypotonic stimulus (HTS) (G), and 10 μM arachidonic acid (AA) (H). For every condition, n > 24 in at least three independent recordings. ∗ indicates significant differences when compared with cells expressing wild-type TRPV4 (one-sided Student's t test, p < 0.05). Error bars represent means ± SE. The American Journal of Human Genetics 2009 84, 307-315DOI: (10.1016/j.ajhg.2009.01.021) Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 5 Diagram of the TRPV4 Molecule The locations of the mutations relative to the domains of the molecule for autosomal-dominant brachyolmia, spondylometaphyseal dysplasia, Kozlowski type, and metatropic dysplasia. The American Journal of Human Genetics 2009 84, 307-315DOI: (10.1016/j.ajhg.2009.01.021) Copyright © 2009 The American Society of Human Genetics Terms and Conditions