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

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

De novo and biallelic DEAF1 variants cause a phenotypic spectrum.

PURPOSE: To investigate the effect of different DEAF1 variants on the phenotype of patients with autosomal dominant and recessive inheritance patterns and on DEAF1 activity in vitro. METHODS: We assembled a cohort of 23 patients with de novo and biallelic DEAF1 variants, described the genotype-phenotype correlation, and investigated the differential effect of de novo and recessive variants on transcription assays using DEAF1 and Eif4g3 promoter luciferase constructs. RESULTS: The proportion of the most prevalent phenotypic features, including intellectual disability, speech delay, motor delay, autism, sleep disturbances, and a high pain threshold, were not significantly different in patients with biallelic and pathogenic de novo DEAF1 variants. However, microcephaly was exclusively observed in patients with recessive variants (p < 0.0001). CONCLUSION: We propose that different variants in the DEAF1 gene result in a phenotypic spectrum centered around neurodevelopmental delay. While a pathogenic de novo dominant variant would also incapacitate the product of the wild-type allele and result in a dominant-negative effect, a combination of two recessive variants would result in a partial loss of function. Because the clinical picture can be nonspecific, detailed phenotype information, segregation, and functional analysis are fundamental to determine the pathogenicity of novel variants and to improve the care of these patients

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

Duplicated zebrafish (<i>Danio rerio</i>) inositol phosphatases <i>inpp5ka</i> and <i>inpp5kb</i> diverged in expression pattern and function

AbstractOne hurdle in the development of zebrafish models of human disease is the presence of multiple zebrafish orthologs resulting from whole genome duplication in teleosts. Mutations in Inositol polyphosphate 5-phosphatase K (INPP5K) lead to a syndrome characterized by variable presentation of intellectual disability, brain abnormalities, cataracts, muscle disease, and short stature. INPP5K is a phosphatase acting at position 5 of phosphoinositides to control their homeostasis and is involved in insulin signaling, cytoskeletal regulation, and protein trafficking. Previously, our group and others have replicated the human phenotypes in zebrafish knockdown models by targeting both INPP5K orthologs inpp5ka and inpp5kb. Here, we show that inpp5ka is the more closely related orthologue to human INPP5K. While both inpp5ka and inpp5kb mRNA expression levels follow a similar trend in the developing head, eyes, and tail, inpp5ka is much more abundantly expressed in these tissues than inpp5kb. In situ hybridization revealed a similar trend, also showing unique localization of inpp5kb in the pineal gland indicating different transcriptional regulation. We also found that inpp5kb has lost its catalytic activity against its preferred substrate, PtdIns(4,5)P2. Since most human mutations are missense changes disrupting phosphatase activity, we propose that loss of inpp5ka alone can be targeted to recapitulate the human presentation. In addition, we show that the function of inpp5kb has diverged from inpp5ka and may play a novel role in the zebrafish.</jats:p

Duplicated zebrafish (Danio rerio) inositol phosphatases inpp5ka and inpp5kb diverged in expression pattern and function

AbstractOne hurdle in the development of zebrafish models of human disease is the presence of multiple zebrafish orthologs resulting from whole genome duplication in teleosts. Mutations in inositol polyphosphate 5-phosphatase K (INPP5K) lead to a syndrome characterized by variable presentation of intellectual disability, brain abnormalities, cataracts, muscle disease, and short stature. INPP5K is a phosphatase acting at position 5 of phosphoinositides to control their homeostasis and is involved in insulin signaling, cytoskeletal regulation, and protein trafficking. Previously, our group and others have replicated the human phenotypes in zebrafish knockdown models by targeting both INPP5K orthologs inpp5ka and inpp5kb. Here, we show that inpp5ka is the more closely related orthologue to human INPP5K. While both inpp5ka and inpp5kb mRNA expression levels follow a similar trend in the developing head, eyes, and tail, inpp5ka is much more abundantly expressed in these tissues than inpp5kb. In situ hybridization revealed a similar trend, also showing unique localization of inpp5kb in the pineal gland and retina indicating different transcriptional regulation. We also found that inpp5kb has lost its catalytic activity against its preferred substrate, PtdIns(4,5)P2. Since most human mutations are missense changes disrupting phosphatase activity, we propose that loss of inpp5ka alone can be targeted to recapitulate the human presentation. In addition, we show that the function of inpp5kb has diverged from inpp5ka and may play a novel role in the zebrafish.</jats:p