Mutations in INPP5K , Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment

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.

INPP5K variant causes autosomal recessive congenital cataract in a Pakistani family

“…Class II larvae had reduction both in AChR cluster size and density of neuromuscular junction synapses (Figure B). Class III was the most severe form with less elegant branching on the myotome, no AChR clusters, along with structural aberrations in myofibers (Figure B), a phenotype resembles with the results obtained from zebrafish morphants . In our study, majority of the inpp5ka mutants belongs to the class I (46%), while 23% and 30% embryos were in class II and III, respectively.…”

“…Electromyography revealed a range of variability in muscle fiber diameter, shape and rarely centered dispersed nuclei in few patients . However, these clinical findings were highly variable, even among the 9 affected individuals homozygous for the same p.(Ile50Thr) variant of INPP5K . Like these reported individuals, all 3 affected of LUCC15 had bilateral CC, and electromyography of individual V:5 revealed normal sensory and motor nerve conduction with irritable myopathic changes in the muscles.…”

“…Zebrafish inpp5ka morphants are reported to have severely disorganized cortex, and small lens, thin and wavy myofibers in skeletal muscles with reduced synaptic junctions . Our inpp5ka germline mutants had highly variable lens and skeletal muscle abnormalities (Figure ).…”

“…According to family medical history, all 3 affected individuals had bilateral CC. While this study was in progress, variants in INPP5K were reported to cause congenital muscular dystrophy, intellectual disability, along with cataract in families from diverse populations . Therefore, we re‐evaluated all LUCC15 participating members to identify signs and symptoms of muscular dystrophy and intellectual disability.…”

“…The clinical index of these patients, include early onset bilateral cataract, delayed development, muscular atrophy, mild intellectual impairment, high serum creatinine kinase, aldolase, and alkaline phosphatase levels. Electromyography revealed a range of variability in muscle fiber diameter, shape and rarely centered dispersed nuclei in few patients . However, these clinical findings were highly variable, even among the 9 affected individuals homozygous for the same p.(Ile50Thr) variant of INPP5K .…”