PUBLICATION
Mutations in INPP5K, Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment
- Authors
- Wiessner, M., Roos, A., Munn, C.J., Viswanathan, R., Whyte, T., Cox, D., Schoser, B., Sewry, C., Roper, H., Phadke, R., Marini Bettolo, C., Barresi, R., Charlton, R., Bönnemann, C.G., Abath Neto, O., Reed, U.C., Zanoteli, E., Araújo Martins Moreno, C., Ertl-Wagner, B., Stucka, R., De Goede, C., Borges da Silva, T., Hathazi, D., Dell'Aica, M., Zahedi, R.P., Thiele, S., Müller, J., Kingston, H., Müller, S., Curtis, E., Walter, M.C., Strom, T.M., Straub, V., Bushby, K., Muntoni, F., Swan, L.E., Lochmüller, H., Senderek, J.
- ID
- ZDB-PUB-170214-15
- Date
- 2017
- Source
- American journal of human genetics 100(3): 523-536 (Journal)
- Registered Authors
- Keywords
- INPP5K, cognitive impairment, congenital muscular dystrophy, early cataracts, phosphoinositide phosphatase
- MeSH Terms
-
- Adolescent
- Adult
- Alleles
- Animals
- Brain/pathology
- Cataract/genetics*
- Child
- Child, Preschool
- Cognitive Dysfunction/genetics*
- Disease Models, Animal
- Down-Regulation
- Female
- Genome-Wide Association Study
- Humans
- Infant
- Intellectual Disability/genetics
- Magnetic Resonance Imaging
- Male
- Muscle, Skeletal/pathology
- Muscular Dystrophies, Limb-Girdle/genetics*
- Musculoskeletal Abnormalities/genetics*
- Mutation
- Pedigree
- Phosphoric Monoester Hydrolases/genetics*
- Young Adult
- Zebrafish/embryology
- Zebrafish/genetics
- PubMed
- 28190456 Full text @ Am. J. Hum. Genet.
Citation
Wiessner, M., Roos, A., Munn, C.J., Viswanathan, R., Whyte, T., Cox, D., Schoser, B., Sewry, C., Roper, H., Phadke, R., Marini Bettolo, C., Barresi, R., Charlton, R., Bönnemann, C.G., Abath Neto, O., Reed, U.C., Zanoteli, E., Araújo Martins Moreno, C., Ertl-Wagner, B., Stucka, R., De Goede, C., Borges da Silva, T., Hathazi, D., Dell'Aica, M., Zahedi, R.P., Thiele, S., Müller, J., Kingston, H., Müller, S., Curtis, E., Walter, M.C., Strom, T.M., Straub, V., Bushby, K., Muntoni, F., Swan, L.E., Lochmüller, H., Senderek, J. (2017) Mutations in INPP5K, Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment. American journal of human genetics. 100(3):523-536.
Abstract
Phosphoinositides are small phospholipids that control diverse cellular downstream signaling events. Their spatial and temporal availability is tightly regulated by a set of specific lipid kinases and phosphatases. Congenital muscular dystrophies are hereditary disorders characterized by hypotonia and weakness from birth with variable eye and central nervous system involvement. In individuals exhibiting congenital muscular dystrophy, early-onset cataracts, and mild intellectual disability but normal cranial magnetic resonance imaging, we identified bi-allelic mutations in INPP5K, encoding inositol polyphosphate-5-phosphatase K. Mutations impaired phosphatase activity toward the phosphoinositide phosphatidylinositol (4,5)-bisphosphate or altered the subcellular localization of INPP5K. Downregulation of INPP5K orthologs in zebrafish embryos disrupted muscle fiber morphology and resulted in abnormal eye development. These data link congenital muscular dystrophies to defective phosphoinositide 5-phosphatase activity that is becoming increasingly recognized for its role in mediating pivotal cellular mechanisms contributing to disease.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping