scholarly journals Loss-of-function variants of SCN8A in intellectual disability without seizures

2017 ◽  
Vol 3 (4) ◽  
pp. e170 ◽  
Author(s):  
Jacy L. Wagnon ◽  
Bryan S. Barker ◽  
Matteo Ottolini ◽  
Young Park ◽  
Alicia Volkheimer ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Epileptic Encephalopathy ◽  
Site Directed Mutagenesis ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Transmembrane Segments ◽  
Seizure Disorders ◽  
Evolutionarily Conserved ◽  
The Stability ◽  
Established Role

Objective:To determine the functional effect of SCN8A missense mutations in 2 children with intellectual disability and developmental delay but no seizures.Methods:Genomic DNA was analyzed by next-generation sequencing. SCN8A variants were introduced into the Nav1.6 complementary DNA by site-directed mutagenesis. Channel activity was measured electrophysiologically in transfected ND7/23 cells. The stability of the mutant channels was assessed by Western blot.Results:Both children were heterozygous for novel missense variants that altered conserved residues in transmembrane segments of Nav1.6, p.Gly964Arg in D2S6 and p.Glu1218Lys in D3S1. Both altered amino acids are evolutionarily conserved in vertebrate and invertebrate channels and are predicted to be deleterious. Neither was observed in the general population. Both variants completely prevented the generation of sodium currents in transfected cells. The abundance of Nav1.6 protein was reduced by the Glu1218Lys substitution.Conclusions:Haploinsufficiency of SCN8A is associated with cognitive impairment. These observations extend the phenotypic spectrum of SCN8A mutations beyond their established role in epileptic encephalopathy (OMIM#614558) and other seizure disorders. SCN8A should be considered as a candidate gene for intellectual disability, regardless of seizure status.

scholarly journals HSP90 is a chaperone for DLK and is required for axon injury signaling

2018 ◽  
Vol 115 (42) ◽  
pp. E9899-E9908 ◽  
Author(s):  
Scott Karney-Grobe ◽  
Alexandra Russo ◽  
Erin Frey ◽  
Jeffrey Milbrandt ◽  
Aaron DiAntonio
Keyword(s):  
Leucine Zipper ◽  
Axon Regeneration ◽  
Heat Shock Protein 90 ◽  
Hsp90 Inhibitor ◽  
Loss Of Function ◽  
Hsp90 Inhibition ◽  
Axon Injury ◽  
Evolutionarily Conserved ◽  
The Stability

Peripheral nerve injury induces a robust proregenerative program that drives axon regeneration. While many regeneration-associated genes are known, the mechanisms by which injury activates them are less well-understood. To identify such mechanisms, we performed a loss-of-function pharmacological screen in cultured adult mouse sensory neurons for proteins required to activate this program. Well-characterized inhibitors were present as injury signaling was induced but were removed before axon outgrowth to identify molecules that block induction of the program. Of 480 compounds, 35 prevented injury-induced neurite regrowth. The top hits were inhibitors to heat shock protein 90 (HSP90), a chaperone with no known role in axon injury. HSP90 inhibition blocks injury-induced activation of the proregenerative transcription factor cJun and several regeneration-associated genes. These phenotypes mimic loss of the proregenerative kinase, dual leucine zipper kinase (DLK), a critical neuronal stress sensor that drives axon degeneration, axon regeneration, and cell death. HSP90 is an atypical chaperone that promotes the stability of signaling molecules. HSP90 and DLK show two hallmarks of HSP90–client relationships: (i) HSP90 binds DLK, and (ii) HSP90 inhibition leads to rapid degradation of existing DLK protein. Moreover, HSP90 is required for DLK stability in vivo, where HSP90 inhibitor reduces DLK protein in the sciatic nerve. This phenomenon is evolutionarily conserved in Drosophila. Genetic knockdown of Drosophila HSP90, Hsp83, decreases levels of Drosophila DLK, Wallenda, and blocks Wallenda-dependent synaptic terminal overgrowth and injury signaling. Our findings support the hypothesis that HSP90 chaperones DLK and is required for DLK functions, including proregenerative axon injury signaling.

scholarly journals Case Report: Novel mutations in TBC1D24 are associated with autosomal dominant tonic-clonic and myoclonic epilepsy and recessive Parkinsonism, psychosis, and intellectual disability

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 553 ◽  
Author(s):  
Erika Banuelos ◽  
Keri Ramsey ◽  
Newell Belnap ◽  
Malavika Krishnan ◽  
Chris D. Balak ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Autosomal Dominant ◽  
Epileptic Encephalopathy ◽  
Myoclonic Epilepsy ◽  
Compound Heterozygous ◽  
Missense Mutations ◽  
Single Family ◽  
Whole Exome ◽  
Neurological Phenotype ◽  
Syndromic Hearing Loss

Mutations disrupting presynaptic protein TBC1D24 are associated with a variable neurological phenotype, including DOORS syndrome, myoclonic epilepsy, early-infantile epileptic encephalopathy, and non-syndromic hearing loss. In this report, we describe a family segregating autosomal dominant epilepsy, and a 37-year-old Caucasian female with a severe neurological phenotype including epilepsy, Parkinsonism, psychosis, visual and auditory hallucinations, gait ataxia and intellectual disability. Whole exome sequencing revealed two missense mutations in the TBC1D24 gene segregating within this family (c.1078C>T; p.Arg360Cys and c.404C>T; p.Pro135Leu). The female proband who presents with a severe neurological phenotype carries both of these mutations in a compound heterozygous state. The p.Pro135Leu variant, however, is present in the proband’s mother and sibling as well, and is consistent with an autosomal dominant pattern linked to tonic-clonic and myoclonic epilepsy. In conclusion, we describe a single family in which TBC1D24 mutations cause expanded dominant and recessive phenotypes. In addition, we discuss and highlight that some variants in TBC1D24 might cause a dominant susceptibility to epilepsy

scholarly journals Mapping Autosomal Recessive Intellectual Disability: Combined Microarray and Exome Sequencing Identifies 26 Novel Candidate Genes in 192 Consanguineous Families

2016 ◽  
Author(s):  
Ricardo Harripaul ◽  
Nasim Vasli ◽  
Anna Mikhailov ◽  
Muhammad Arshad Rafiq ◽  
Kirti Mittal ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Exome Sequencing ◽  
Autosomal Recessive ◽  
De Novo ◽  
Clinical Diagnostics ◽  
High Yield ◽  
Disease Genes ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Whole Exome

Approximately 1% of the global population is affected by intellectual disability (ID), and the majority receive no molecular diagnosis. Previous studies have indicated high levels of genetic heterogeneity, with estimates of more than 2500 autosomal ID genes, the majority of which are autosomal recessive (AR). Here, we combined microarray genotyping, homozygosity-by-descent (HBD) mapping, copy number variation (CNV) analysis, and whole exome sequencing (WES) to identify disease genes/mutations in 192 multiplex Pakistani and Iranian consanguineous families with non-syndromic ID. We identified definite or candidate mutations (or CNVs) in 51% of families in 72 different genes, including 26 not previously reported for ARID. The new ARID genes include nine with loss-of-function mutations(ABI2, MAPK8, MPDZ, PIDD1, SLAIN1, TBC1D23, TRAPPC6B, UBA7,andUSP44),and missense mutations include the first reports of variants inBDNForTET1associated with ID. The genes identified also showed overlap withde novogene sets for other neuropsychiatric disorders. Transcriptional studies showed prominent expression in the prenatal brain. The high yield of AR mutations for ID indicated that this approach has excellent clinical potential and should inform clinical diagnostics, including clinical whole exome and genome sequencing, for populations in which consanguinity is common. As with other AR disorders, the relevance will also apply to outbred populations.

scholarly journals Variability of Phenotype in Two Sisters with Pyridoxine Dependent Epilepsy

2012 ◽  
Vol 39 (4) ◽  
pp. 516-519 ◽  
Author(s):  
Majid Alfadhel ◽  
Sandra Sirrs ◽  
Paula J. Waters ◽  
András Szeitz ◽  
Eduard Struys ◽  
...  
Keyword(s):  
Differential Diagnosis ◽  
Case Report ◽  
Intellectual Disability ◽  
Genetic Background ◽  
Autosomal Recessive ◽  
Vitamin B ◽  
Missense Mutations ◽  
Compound Heterozygosity ◽  
Speech Delay ◽  
Seizure Disorders

Background:Pyridoxine dependent epilepsy (PDE) is characterized by neonatal epileptic encepahalopathy responsive to pharmacological doses of vitamin B6. Recently an autosomal recessive deficiency in Antiquitin (ALDH7A1), a gene involved in the catabolism of lysine has been identified as the underlying cause.Case report:In 21 and 23 year-old sisters, who had presented with neonatal / early infantile onset seizures, PDE was confirmed by elevated urinary alpha aminoadipic- 6- semialdehyde (α-AASA) excretion and compound heterozygosity for two known ALDH7A1 missense mutations. Although epilepsy was well controlled upon treatment with pyridoxine, thiamine, phenytoin and carbamazepine since early infancy, both had developmental delay with prominent speech delay as children. As adults, despite the same genetic background and early treatment with pyridoxine, their degree of intellectual disability (ID) differed widely. While the older sister's cognitive functions were in the moderate ID range and she was not able to live unattended, the younger sister had only mild ID and was able to live independently.Conclusion:Although seizures are a defining feature of PDE, other disease manifestations can vary widely even within the same family. Adult neurologists should be aware that the diagnosis of PDE can be delayed and PDE should be considered in the differential diagnosis of adults with seizure disorders dating from childhood.

scholarly journals P.120 Case series: Clinical and genetic spectrum of SCN8A-related disorders in British Columbia

2021 ◽  
Vol 48 (s3) ◽  
pp. S53-S53
Author(s):  
M Hebbar ◽  
N Al-Taweel ◽  
I Gill ◽  
C Boelman ◽  
RA Dean ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Case Series ◽  
Autism Spectrum ◽  
Epileptic Encephalopathy ◽  
Clinical Findings ◽  
Loss Of Function ◽  
Treatment Resistant ◽  
Infantile Seizures ◽  
Functional Consequences ◽  
Generation Sequencing

Background: Children with pathogenic variations in SCN8A can present with early infantile epileptic encephalopathy-13, benign familial infantile seizures-5 or intellectual disability alone without epilepsy. In this case series, we discuss six children with variants in SCN8A managed at BC Children’s Hospital. Methods: We describe clinical and genetic results on six individuals with SCN8A variants identified via clinical or research next-generation sequencing. Functional consequences of two SCN8A variants were assessed using electrophysiological analyses in transfected cells. Results: Clinical findings ranged from normal development with well-controlled epilepsy to significant developmental delay with treatment-resistant epilepsy. Phenotypes and genotypes in our cohort are described in the table below. Functional analysis supported gain-of-function in P2 and loss-of-function in P4. Conclusions: Our cohort expands the clinical and genotypic spectrum of SCN8A-related disorders. We establish functional evidence for two missense variants in SCN8A, including LoF variant in a patient with intellectual disability, and autism spectrum disorder without seizures.

scholarly journals The L1624Q Variant in SCN1A Causes Familial Epilepsy Through a Mixed Gain and Loss of Channel Function

2021 ◽  
Vol 12 ◽  
Author(s):  
Laura B. Jones ◽  
Colin H. Peters ◽  
Richard E. Rosch ◽  
Maxine Owers ◽  
Elaine Hughes ◽  
...  
Keyword(s):  
De Novo ◽  
Epileptic Encephalopathy ◽  
Dravet Syndrome ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Gene Encoding ◽  
Channel Function ◽  
Biophysical Analysis ◽  
Gain And Loss ◽  
Patients With Epilepsy

Variants of the SCN1A gene encoding the neuronal voltage-gated sodium channel NaV1.1 cause over 85% of all cases of Dravet syndrome, a severe and often pharmacoresistent epileptic encephalopathy with mostly infantile onset. But with the increased availability of genetic testing for patients with epilepsy, variants in SCN1A have now also been described in a range of other epilepsy phenotypes. The vast majority of these epilepsy-associated variants are de novo, and most are either nonsense variants that truncate the channel or missense variants that are presumed to cause loss of channel function. However, biophysical analysis has revealed a significant subset of missense mutations that result in increased excitability, further complicating approaches to precision pharmacotherapy for patients with SCN1A variants and epilepsy. We describe clinical and biophysical data of a familial SCN1A variant encoding the NaV1.1 L1624Q mutant. This substitution is located on the extracellular linker between S3 and S4 of Domain IV of NaV1.1 and is a rare case of a familial SCN1A variant causing an autosomal dominant frontal lobe epilepsy. We expressed wild-type (WT) and L1642Q channels in CHO cells. Using patch-clamp to characterize channel properties at several temperatures, we show that the L1624Q variant increases persistent current, accelerates fast inactivation onset and decreases current density. While SCN1A-associated epilepsy is typically considered a loss-of-function disease, our results put L1624Q into a growing set of mixed gain and loss-of-function variants in SCN1A responsible for epilepsy.

scholarly journals Loss-of-Function and Gain-of-Function Mutations in KCNQ5 Cause Intellectual Disability or Epileptic Encephalopathy

2017 ◽  
Vol 101 (1) ◽  
pp. 65-74 ◽  
Author(s):  
Anna Lehman ◽  
Samrat Thouta ◽  
Grazia M.S. Mancini ◽  
Sakkubai Naidu ◽  
Marjon van Slegtenhorst ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Epileptic Encephalopathy ◽  
Loss Of Function ◽  
Gain Of Function

Nanobodies restore stability to cancer-associated mutants of tumor suppressor protein p16INK4a

2021 ◽  
Author(s):  
Owen Burbidge ◽  
Martyna W Pastok ◽  
Samantha L Hodder ◽  
Grasilda Zenkeviciute ◽  
Martin EM Noble ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Critical Role ◽  
Tumor Suppressor Protein ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Pharmacological Chaperones ◽  
Binding Interface ◽  
Familial Cancers ◽  
Single Domain Antibodies ◽  
The Stability

We describe the generation and characterization of camelid single-domain antibodies (nanobodies) raised against tumor suppressor protein p16INK4a (p16). p16 plays a critical role in the cell cycle by inhibiting cyclin-dependent kinases CDK4 and CDK6, and it is inactivated in sporadic and familial cancers. The majority of the p16 missense mutations cause loss of function by destabilizing the protein structure. We show that the nanobodies bind p16 with nanomolar affinities and restore the stability of a range of different cancer-associated p16 mutations located at sites throughout the protein. The nanobodies also bind and stabilize p16 in a cellular setting. The crystal structure of a nanobody-p16 complex reveals that the nanobody binds to the opposite face of p16 to the CDK-binding interface permitting formation of a ternary complex. These findings indicate that nanobodies could be used as pharmacological chaperones to determine the consequences of restoring the function of p16 in the cell.

scholarly journals Identification of SETBP1 Mutations by Gene Panel Sequencing in Individuals With Intellectual Disability or With “Developmental and Epileptic Encephalopathy”

2020 ◽  
Vol 11 ◽  
Author(s):  
Emanuela Leonardi ◽  
Elisa Bettella ◽  
Maria Federica Pelizza ◽  
Maria Cristina Aspromonte ◽  
Roberta Polli ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Neurodevelopmental Disorders ◽  
De Novo ◽  
Hot Spot ◽  
Genetic Diagnosis ◽  
Epileptic Encephalopathy ◽  
Gene Panel ◽  
Loss Of Function ◽  
Speech Impairment ◽  
Mild Intellectual Disability

SETBP1 mutations are associated with the Schinzel-Giedion syndrome (SGS), characterized by profound neurodevelopmental delay, typical facial features, and multiple congenital malformations (OMIM 269150). Refractory epilepsy is a common feature of SGS. Loss of function mutations have been typically associated with a distinct and milder phenotype characterized by intellectual disability and expressive speech impairment. Here we report three variants of SETBP1, two novel de novo truncating mutations, identified by NGS analysis of an Intellectual Disability gene panel in 600 subjects with non-specific neurodevelopmental disorders, and one missense identified by a developmental epilepsy gene panel tested in 56 pediatric epileptic cases. The three individuals carrying the identified SETBP1 variants presented mild to severe developmental delay and lacked the cardinal features of classical SGS. One of these subjects, carrying the c.1765C>T (p.Arg589*) mutation, had mild Intellectual Disability with speech delay; the second one carrying the c.2199_2203del (p.Glu734Alafs19*) mutation had generalized epilepsy, responsive to treatment, and moderate Intellectual Disability; the third patient showed a severe cognitive defects and had a history of drug resistant epilepsy with West syndrome evolved into a Lennox-Gastaut syndrome. This latter subject carries the missense c.2572G>A (p.Glu858Lys) variant, which is absent from the control population, reported as de novo in a subject with ASD, and located close to the SETBP1 hot spot for SGS-associated mutations. Our findings contribute to further characterizing the associated phenotypes and suggest inclusion of SETBP1 in the list of prioritized genes for the genetic diagnosis of overlapping phenotypes ranging from non-specific neurodevelopmental disorders to “developmental and epileptic encephalopathy” (DEE).

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