Mutations in INPP5K Cause a Form of Congenital Muscular Dystrophy Overlapping Marinesco-Sjögren Syndrome and Dystroglycanopathy

Abstract

Congenital muscular dystrophies display a wide phenotypic and genetic heterogeneity. The combination of clinical, biochemical, and molecular genetic findings must be considered to obtain the precise diagnosis and provide appropriate genetic counselling. Here we report five individuals from four families presenting with variable clinical features including muscular dystrophy with a reduction in dystroglycan glycosylation, short stature, intellectual disability, and cataracts, overlapping both the dystroglycanopathies and Marinesco-Sjögren syndrome. Whole-exome sequencing revealed homozygous missense and compound heterozygous mutations in INPP5K in the affected members of each family. INPP5K encodes the inositol polyphosphate-5-phosphatase K, also known as SKIP (skeletal muscle and kidney enriched inositol phosphatase), which is highly expressed in the brain and muscle. INPP5K localizes to both the endoplasmic reticulum and to actin ruffles in the cytoplasm. It has been shown to regulate myoblast differentiation and has also been implicated in protein processing through its interaction with the ER chaperone HSPA5/BiP. We show that morpholino-mediated inpp5k loss of function in the zebrafish results in shortened body axis, microphthalmia with disorganized lens, microcephaly, reduced touch-evoked motility, and highly disorganized myofibers. Altogether these data demonstrate that mutations in INPP5K cause a congenital muscular dystrophy syndrome with short stature, cataracts, and intellectual disability.

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.…”

“…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 .…”

“…Here, we describe a multiplex Pakistani family (LUCC15) with CC co‐segregating with a missense variant in the INPP5K (OMIM 607875) in an autosomal recessive fashion. INPP5K, abundantly expressed in human skeletal muscles and kidney, is involved in dephosphorylation of PtdIns, regulation of the actin cytoskeleton, and myoblasts differentiation . Recently, mutations in INPP5K have been associated with congenital muscular dystrophies together with CC, therefore, we utilized a zebrafish loss‐of‐function allele to further explore the role of INPP5K in the lens and skeletal muscles development.…”