Mutations in INPP5K Cause a Form of Congenital Muscular Dystrophy Overlapping Marinesco-Sjögren Syndrome and Dystroglycanopathy Daniel P.S. Osborn, Heather.

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Mutations in INPP5K Cause a Form of Congenital Muscular Dystrophy Overlapping Marinesco-Sjögren Syndrome and Dystroglycanopathy Daniel P.S. Osborn, Heather L. Pond, Neda Mazaheri, Jeremy Dejardin, Christopher J. Munn, Khaloob Mushref, Edmund S. Cauley, Isabella Moroni, Maria Barbara Pasanisi, Elizabeth A. Sellars, R. Sean Hill, Jennifer N. Partlow, Rebecca K. Willaert, Jaipreet Bharj, Reza Azizi Malamiri, Hamid Galehdari, Gholamreza Shariati, Reza Maroofian, Marina Mora, Laura E. Swan, Thomas Voit, Francesco J. Conti, Yalda Jamshidi, M. Chiara Manzini The American Journal of Human Genetics Volume 100, Issue 3, Pages 537-545 (March 2017) DOI: 10.1016/j.ajhg.2017.01.019 Copyright © 2017 Terms and Conditions

Figure 1 Mutations in INPP5K Severely Disrupt Protein Function (A) Pedigrees of families 1 to 4 where five autosomal-recessive alleles in INPP5K have been identified by exome sequencing. (B) Four missense mutations are localized to the phosphatase domain in INPP5K, while a C-terminal frameshift affects the last actin ruffle targeting domain. (C) Protein conservation in the four INPP5K amino acids altered by the identified missense mutations. Percent conservation (cons) to the human gene is shown and asterisk (∗) indicates conservation across all species listed. (D) Phosphatase activity was measured by using malachite green dye to detect GST-INPP5K-mediated phosphate release in the presence of the soluble lipid substrate PI(4,5)P2 diC8, showing that all reported mutations compromise the enzymatic activity of INPP5K. Results of three independent experiments were presented as mean ± standard deviation. See Table 1 for numeric values. The American Journal of Human Genetics 2017 100, 537-545DOI: (10.1016/j.ajhg.2017.01.019) Copyright © 2017 Terms and Conditions

Figure 2 Muscular Dystrophy and Loss of Dystroglycan Glycosylation in Subjects S2 and S3 (A and B) Haematoxylin and eosin (H&E) staining (A) from normal control subject (con) and subject S2 and Gomori trichrome staining (B) from control (con) and subject S3. Both biopsies show great fiber size variability, and increased perimysial connective tissue and regenerating fibers are indicated by arrows in S2. Scale bar represents 100 μm. (C) Immunostaining of α-dystroglycan glycosylation in muscle biopsies from S2 and S3, showing reduced and irregular protein expression in the affected individuals compared to the control subject (con). Scale bar represents 50 μm. The American Journal of Human Genetics 2017 100, 537-545DOI: (10.1016/j.ajhg.2017.01.019) Copyright © 2017 Terms and Conditions

Figure 3 Knockdown of inpp5ka in Zebrafish Causes Defective Eye Development and Muscle Formation (A) General morphological abnormalities were observed in inpp5ka morphant embryos at 4 dpf, compared to control morpholino (MO) or uninjected control age-matched embryos. Scale bar represents 500 μm. (B) Aberrant eye development was observed in inpp5ka morphant wax sections stained with H&E; eyes were observed reduced in size and downwardly oriented. Scale bar represents 200 μm. (C) Structural analysis of the lens, by staining for α-crystallin, identifies disorganization in inpp5ka morphant embryos. In addition, abnormal medial nuclei retention was observed in inpp5ka morphant lens, as marked by DNA stain Hoechst. Scale bar represents 50 μm. (D) Birefringence of inpp5ka morphant embryos reveals decreased muscle integrity compared to uninjected or control MO-injected embryos at 4 dpf. Scale bar represents 200 μm. (E) Analysis of muscle fiber and neuromuscular junction formation using Phalloidin (Red, F-actin) and alpha-Bungarotoxin (Green, AChR), respectively, reveals misaligned myofibers and reduced NMJ arborization in morphants. Scale bar represents 100 μm. The American Journal of Human Genetics 2017 100, 537-545DOI: (10.1016/j.ajhg.2017.01.019) Copyright © 2017 Terms and Conditions

Figure 4 Zebrafish Loss of inpp5ka Results in Disorganized Myofibrils and Insufficient Sarcomere Assembly, as Analyzed by Transmission Electron Microscopy (A) Assessment of sarcomere assembly at the ultrastructural level shows less compact myobrils, short sarcomere length, and undefined regional divisions. Scale bar represents 2 μm. (B) High-magnification image of sarcomere assembly indicates the loss of defined anisotropic (black bracket) and isotropic (blue bracket) bands in morphant embryos. T-tubules are also notably smaller than control embryos (arrows). Scale bar represents 2 μm. (C) Muscle fiber attachments at the somite borders presented disorganized and weak unions with the myoseptum in morphants embryos. Scale bar represents 1 μm. (D) Top panel shows a schematic diagram of the Triad assembly, composed of the sarcoplasmic reticulum (SR) and T-tubule (T) sandwiched between muscle fibers (MF). Middle and lower panels show representative triad morphology for control and inpp5ka morphant fish, respectively. (E) Triad size was quantified using the combined area of SR and T per triad. Con 58.2 ± SEM 7.254; n = 10, inpp5kaMO 28.3 ± SEM 2.371; n = 10. ∗∗p ≤ 0.01, as analyzed by an unpaired t test. The American Journal of Human Genetics 2017 100, 537-545DOI: (10.1016/j.ajhg.2017.01.019) Copyright © 2017 Terms and Conditions