Institute of Biomedical Sciences

Title

Mutations in INPP5K cause a form of congenital muscular dystrophy syndrome overlapping Marinesco-Sjögren Syndrome and the dystroglycanopathies

Poster Number

10

Document Type

Poster

Keywords

Congenital Muscular Dystrophy, Phosphatase, Zebrafish

Publication Date

4-2017

Abstract

Edmund S. Cauley, Daniel P.S. Osborn, Heather L. Pond, Neda Mazaheri, Jeremy Dejardin, Christopher J. Munn, Khaloob Mushref, Isabella Moroni, Maria Barbara Pasanisi, Elizabeth A. Sellars, R. Sean Hill,0, Jennifer N. Partlow,0, 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

A large proportion of patients affected by congenital muscular dystrophies (CMDs) associated with brain and eye phenotypes remain unexplained. Here, we show that mutations in inositol polyphosphate 5-phosphatase K (INPP5K) cause a novel syndrome where CMD is present with short stature, intellectual disability (ID) and cataracts. The clinical presentation resembles both a milder form of dystroglycanopathy and Marinesco-Sjögren Syndrome, a myopathy associated with ID and cataracts. INPP5K, which is also known as Skeletal Muscle and Kidney-enriched Inositol Phosphatase (SKIP), has been involved in phosphatidylinositol phosphate (PIP) metabolism and Akt signaling at the plasma membrane, and in protein processing in the endoplasmic reticulum. It is expressed highly in the muscle and has been implicated as an important factor in myocyte differentiation, but has also shown increased expression in the brain and eyes during fetal development.

Exome sequencing was performed on a group of patients with CMD and reduced dystroglycan glycosylation, and a subset were found to have mutations predicted to be pathogenic in INPP5K. We introduced patient mutations into recombinant INPP5K to assess phosphatase activity and found that mutations ablated or significantly reduced enzyme activity. Zebrafish were then used to investigate the role of INPP5K in muscle, brain, and eye development using morpholino oligonucleotide (MO) injections into fertilized oocytes. MOs were effective in knocking out zebrafish inpp5k and analysis of muscle, brain, and eye tissue showed a consistent phenotype with the patients’ presentation. We have confirmed that mutations in INPP5K lead to a CMD syndrome with features of both dystroglycanopathy and Marinesco-Sjögren Syndrome. While the link to reduced dystroglycan glycosylation remains to be elucidated, INPP5K and PIP processing are critical for muscle, eye and brain development and could represent a novel target for therapy development.

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Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

Open Access

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Comments

To be presented at GW Annual Research Days 2017.

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Mutations in INPP5K cause a form of congenital muscular dystrophy syndrome overlapping Marinesco-Sjögren Syndrome and the dystroglycanopathies

Edmund S. Cauley, Daniel P.S. Osborn, Heather L. Pond, Neda Mazaheri, Jeremy Dejardin, Christopher J. Munn, Khaloob Mushref, Isabella Moroni, Maria Barbara Pasanisi, Elizabeth A. Sellars, R. Sean Hill,0, Jennifer N. Partlow,0, 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

A large proportion of patients affected by congenital muscular dystrophies (CMDs) associated with brain and eye phenotypes remain unexplained. Here, we show that mutations in inositol polyphosphate 5-phosphatase K (INPP5K) cause a novel syndrome where CMD is present with short stature, intellectual disability (ID) and cataracts. The clinical presentation resembles both a milder form of dystroglycanopathy and Marinesco-Sjögren Syndrome, a myopathy associated with ID and cataracts. INPP5K, which is also known as Skeletal Muscle and Kidney-enriched Inositol Phosphatase (SKIP), has been involved in phosphatidylinositol phosphate (PIP) metabolism and Akt signaling at the plasma membrane, and in protein processing in the endoplasmic reticulum. It is expressed highly in the muscle and has been implicated as an important factor in myocyte differentiation, but has also shown increased expression in the brain and eyes during fetal development.

Exome sequencing was performed on a group of patients with CMD and reduced dystroglycan glycosylation, and a subset were found to have mutations predicted to be pathogenic in INPP5K. We introduced patient mutations into recombinant INPP5K to assess phosphatase activity and found that mutations ablated or significantly reduced enzyme activity. Zebrafish were then used to investigate the role of INPP5K in muscle, brain, and eye development using morpholino oligonucleotide (MO) injections into fertilized oocytes. MOs were effective in knocking out zebrafish inpp5k and analysis of muscle, brain, and eye tissue showed a consistent phenotype with the patients’ presentation. We have confirmed that mutations in INPP5K lead to a CMD syndrome with features of both dystroglycanopathy and Marinesco-Sjögren Syndrome. While the link to reduced dystroglycan glycosylation remains to be elucidated, INPP5K and PIP processing are critical for muscle, eye and brain development and could represent a novel target for therapy development.