De novo mutation screening in childhood-onset cerebellar atrophy identifies gain-of-function mutations in the CACNA1G calcium channel gene

Abstract Background Mutations in the adenylate cyclase 5 (ADCY5) gene are associated with childhood-onset paroxysmal dyskinesia. Methods We report a new video-documented case of pediatric ADCY5-related dyskinesia with de novo ADCY5 mutation. Results A boy born to nonconsanguineous parents after an uneventful pregnancy had developmental delay and hypotonia. At the age of 7 months, he presented with paroxysmal jerky–choreic–dystonic involuntary movements in wakefulness involving limbs, trunk, and face, exacerbated by emotional stimuli. These episodes gradually worsened in duration and frequency: at the age of 2.5 years, they occurred up to six times per day, and appeared also during sleep in prolonged bouts; the boy also had basal choreoathetoid–dystonic movements, hyperactivity, paraparetic–ataxic gait, generalized hypotonia with brisk tendon reflexes, drooling, and language delay with intellectual disability. Brain magnetic resonance imaging, electroencephalogram, electromyogram, eye review, metabolic investigations, oligoclonal bands, and autoantibodies were normal. Extensive genetic testing had not let to a diagnosis, until a heterozygous de novo mutation c.1252C > T (p.Arg418Trp) was identified in the ADCY5 gene. Clonazepam had partial effectiveness. The boy walked at the age of 3.5 years. At the age of 5 years, the paroxysmal movement disorder has slightly improved. Conclusion ADCY5 mutations should be considered among the differential diagnoses of early-onset paroxysmal choreic–athetosic–myoclonic–dystonic movement disorder involving limbs, trunk, and face, in patients with global neurological impairment with hypotonia and developmental delay. Facial dyskinesias and exacerbation by drowsiness/sleep and emotional stimuli are important clues that may allow a timely recognition of the disorder and avoidance of unnecessary diagnostic investigations.

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A novel de novo mutation inATP1A3and childhood-onset schizophrenia

Molecular Case Studies ◽

10.1101/mcs.a001008 ◽

2016 ◽

Vol 2 (5) ◽

pp. a001008 ◽

Cited By ~ 22

Author(s):

Niklas Smedemark-Margulies ◽

Catherine A. Brownstein ◽

Sigella Vargas ◽

Sahil K. Tembulkar ◽

Meghan C. Towne ◽

...

Keyword(s):

De Novo ◽

De Novo Mutation ◽

Childhood Onset ◽

Childhood Onset Schizophrenia

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Biophysical classification of a CACNA1D de novo mutation as a high-risk mutation for a severe neurodevelopmental disorder

Molecular Autism ◽

10.1186/s13229-019-0310-4 ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 10

Author(s):

Nadja T. Hofer ◽

Petronel Tuluc ◽

Nadine J. Ortner ◽

Yuliia V. Nikonishyna ◽

Monica L. Fernándes-Quintero ◽

...

Keyword(s):

High Risk ◽

Neurodevelopmental Disorders ◽

Developmental Disorder ◽

De Novo ◽

Disease Risk ◽

Neurodevelopmental Disorder ◽

Autism Spectrum ◽

De Novo Mutation ◽

Loss Of Function ◽

Gain Of Function

Abstract Background There is increasing evidence that de novo CACNA1D missense mutations inducing increased Cav1.3 L-type Ca2+-channel-function confer a high risk for neurodevelopmental disorders (autism spectrum disorder with and without neurological and endocrine symptoms). Electrophysiological studies demonstrating the presence or absence of typical gain-of-function gating changes could therefore serve as a tool to distinguish likely disease-causing from non-pathogenic de novo CACNA1D variants in affected individuals. We tested this hypothesis for mutation S652L, which has previously been reported in twins with a severe neurodevelopmental disorder in the Deciphering Developmental Disorder Study, but has not been classified as a novel disease mutation. Methods For functional characterization, wild-type and mutant Cav1.3 channel complexes were expressed in tsA-201 cells and tested for typical gain-of-function gating changes using the whole-cell patch-clamp technique. Results Mutation S652L significantly shifted the voltage-dependence of activation and steady-state inactivation to more negative potentials (~ 13–17 mV) and increased window currents at subthreshold voltages. Moreover, it slowed tail currents and increased Ca2+-levels during action potential-like stimulations, characteristic for gain-of-function changes. To provide evidence that only gain-of-function variants confer high disease risk, we also studied missense variant S652W reported in apparently healthy individuals. S652W shifted activation and inactivation to more positive voltages, compatible with a loss-of-function phenotype. Mutation S652L increased the sensitivity of Cav1.3 for inhibition by the dihydropyridine L-type Ca2+-channel blocker isradipine by 3–4-fold. Conclusions and limitations Our data provide evidence that gain-of-function CACNA1D mutations, such as S652L, but not loss-of-function mutations, such as S652W, cause high risk for neurodevelopmental disorders including autism. This adds CACNA1D to the list of novel disease genes identified in the Deciphering Developmental Disorder Study. Although our study does not provide insight into the cellular mechanisms of pathological Cav1.3 signaling in neurons, we provide a unifying mechanism of gain-of-function CACNA1D mutations as a predictor for disease risk, which may allow the establishment of a more reliable diagnosis of affected individuals. Moreover, the increased sensitivity of S652L to isradipine encourages a therapeutic trial in the two affected individuals. This can address the important question to which extent symptoms are responsive to therapy with Ca2+-channel blockers.

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M190 HETEROZYGOUS DE-NOVO MUTATION OF IKZF1 (IKAROS): WHEN GAIN OF FUNCTION RESULTS IN IMMUNE DYSREGULATION

Annals of Allergy Asthma & Immunology ◽

10.1016/j.anai.2021.08.331 ◽

2021 ◽

Vol 127 (5) ◽

pp. S105

Author(s):

J. Goldman

Keyword(s):

De Novo ◽

Immune Dysregulation ◽

De Novo Mutation ◽

Gain Of Function

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CACNA1A gene de novo mutation causing hemiplegic migraine, coma, and cerebellar atrophy

Neurology ◽

10.1212/wnl.55.7.1040 ◽

2000 ◽

Vol 55 (7) ◽

pp. 1040-1042 ◽

Cited By ~ 89

Author(s):

K. Vahedi ◽

C. Denier ◽

A. Ducros ◽

V. Bousson ◽

C. Levy ◽

...

Keyword(s):

De Novo ◽

Cerebellar Atrophy ◽

De Novo Mutation ◽

Hemiplegic Migraine ◽

Cacna1a Gene

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Biochemical features of primary cells from a pediatric patient with a gain-of-function ODC1 genetic mutation

Biochemical Journal ◽

10.1042/bcj20190294 ◽

2019 ◽

Vol 476 (14) ◽

pp. 2047-2057

Author(s):

Chad R. Schultz ◽

Caleb P. Bupp ◽

Surender Rajasekaran ◽

André S. Bachmann

Keyword(s):

Pediatric Patient ◽

De Novo ◽

Genetic Disorder ◽

Genetic Mutation ◽

Dermal Fibroblasts ◽

The Body ◽

De Novo Mutation ◽

Global Developmental Delay ◽

Gain Of Function ◽

Protein Variant

Abstract We recently described a new autosomal dominant genetic disorder in a pediatric patient caused by a heterozygous de novo mutation in the ornithine decarboxylase 1 (ODC1) gene. The new genetic disorder is characterized by global developmental delay, alopecia, overgrowth, and dysmorphic features. We hypothesized that this new mutation (c.1342 A>T) leads to a C-terminal truncation variant of the ODC protein that is resistant to normal proteasomal degradation, leading to putrescine accumulation in cells. ODC (E.C. 4.1.1.17) is a rate-limiting enzyme in the biosynthesis of polyamines (putrescine, spermidine, and spermine) that plays a crucial role during embryogenesis, organogenesis, and tumorigenesis. In this study, we show that primary dermal fibroblasts derived from a skin biopsy of a 3-year-old patient contain large amounts of ODC protein and putrescine compared with primary dermal (neonatal and adult) fibroblast control cells. Importantly, the accumulated ODC protein variant remained functionally active as we detected exceptionally high ODC enzyme activity in both primary dermal fibroblasts (12–17-fold of controls) and red blood cells (RBCs) (125–137-fold of controls), using a specific 14C radioactive ODC activity assay. Exposure of primary dermal fibroblasts to ODC inhibitor α-difluoromethylornithine (DFMO) reduced the ODC activity and putrescine to levels observed in controls without adversely affecting cell morphology or inducing cell death. In conclusion, our patient and potentially other patients that carry a similar ODC1 gain-of-function mutation might benefit from treatment with DFMO, a drug with a good safety profile, to suppress the exceptionally high ODC activity and putrescine levels in the body.

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Calcium channelopathies and intellectual disability: a systematic review

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-021-01850-0 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Miriam Kessi ◽

Baiyu Chen ◽

Jing Peng ◽

Fangling Yan ◽

Lifen Yang ◽

...

Keyword(s):

Systematic Review ◽

Intellectual Disability ◽

Calcium Channel ◽

Developmental Delay ◽

Cerebellar Atrophy ◽

Dominant Negative ◽

Main Body ◽

Loss Of Function ◽

Gain Of Function ◽

Gain And Loss

Abstract Background Calcium ions are involved in several human cellular processes including corticogenesis, transcription, and synaptogenesis. Nevertheless, the relationship between calcium channelopathies (CCs) and intellectual disability (ID)/global developmental delay (GDD) has been poorly investigated. We hypothesised that CCs play a major role in the development of ID/GDD and that both gain- and loss-of-function variants of calcium channel genes can induce ID/GDD. As a result, we performed a systematic review to investigate the contribution of CCs, potential mechanisms underlying their involvement in ID/GDD, advancements in cell and animal models, treatments, brain anomalies in patients with CCs, and the existing gaps in the knowledge. We performed a systematic search in PubMed, Embase, ClinVar, OMIM, ClinGen, Gene Reviews, DECIPHER and LOVD databases to search for articles/records published before March 2021. The following search strategies were employed: ID and calcium channel, mental retardation and calcium channel, GDD and calcium channel, developmental delay and calcium channel. Main body A total of 59 reports describing 159 cases were found in PubMed, Embase, ClinVar, and LOVD databases. Variations in ten calcium channel genes including CACNA1A, CACNA1C, CACNA1I, CACNA1H, CACNA1D, CACNA2D1, CACNA2D2, CACNA1E, CACNA1F, and CACNA1G were found to be associated with ID/GDD. Most variants exhibited gain-of-function effect. Severe to profound ID/GDD was observed more for the cases with gain-of-function variants as compared to those with loss-of-function. CACNA1E, CACNA1G, CACNA1F, CACNA2D2 and CACNA1A associated with more severe phenotype. Furthermore, 157 copy number variations (CNVs) spanning calcium genes were identified in DECIPHER database. The leading genes included CACNA1C, CACNA1A, and CACNA1E. Overall, the underlying mechanisms included gain- and/ or loss-of-function, alteration in kinetics (activation, inactivation) and dominant-negative effects of truncated forms of alpha1 subunits. Forty of the identified cases featured cerebellar atrophy. We identified only a few cell and animal studies that focused on the mechanisms of ID/GDD in relation to CCs. There is a scarcity of studies on treatment options for ID/GDD both in vivo and in vitro. Conclusion Our results suggest that CCs play a major role in ID/GDD. While both gain- and loss-of-function variants are associated with ID/GDD, the mechanisms underlying their involvement need further scrutiny.

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Case Report of a de Novo Mutation of PCDH19 in Saudi Family Limited to Females

International Journal of Innovative Research in Medical Science ◽

10.23958/ijirms/vol06-i12/1276 ◽

2021 ◽

Vol 6 (12) ◽

pp. 940-943

Author(s):

Rawan Alsheikh, MD ◽

Amal Al-Qassmi, MD

Keyword(s):

De Novo ◽

Somatic Mosaicism ◽

Febrile Illness ◽

Autistic Traits ◽

De Novo Mutation ◽

Epilepsy Syndrome ◽

Childhood Onset ◽

Behavioral Abnormalities ◽

Nucleotide Mutation ◽

Saudi Family

Up to date more than 60 different mutations in PCDH19 have been identified. Most of PCDH19 gene is located in Xq22 and produces nonclustered delta protocadherin. This disorder primarily manifests in heterozygote females due to random X chromosome inactivation leading to somatic mosaicism and abnormal cellular interference between cells with and without delta-protocadherin., but we a heterozygous nucleotide mutation causing amino acid 561 to change from Pro to Ser (p.Pro561Ser). This mutation was de novo, and this alteration was not found in her parents. PCDH19-related epilepsy is a distinct childhood-onset epilepsy syndrome characterized by brief clusters of febrile and afebrile seizures with onset primarily before the age of three years, cognitive impairment, autistic traits, and behavioral abnormalities. We describe the features of a de novo mutation in 3 sibling, presented with early onset of seizure, two of them were controlled and wean off medication was at age of six year and her sister at age of 10 year .The youngest sister still partially controlled on medication, she had seizure only during febrile illness.

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De novo mutation in ELOVL1 causes ichthyosis, acanthosis nigricans, hypomyelination, spastic paraplegia, high frequency deafness and optic atrophy

Journal of Medical Genetics ◽

10.1136/jmedgenet-2018-105711 ◽

2018 ◽

Vol 56 (3) ◽

pp. 164-175 ◽

Cited By ~ 17

Author(s):

Noomi Mueller ◽

Takayuki Sassa ◽

Susanne Morales-Gonzalez ◽

Joanna Schneider ◽

Daniel J Salchow ◽

...

Keyword(s):

Optic Atrophy ◽

Peripheral Vision ◽

De Novo ◽

Competitive Inhibition ◽

Mutation Screening ◽

Expression Patterns ◽

De Novo Mutation ◽

Spastic Paraplegia ◽

Fatty Acid Elongase ◽

And Control

BackgroundVery long-chain fatty acids (VLCFAs) are essential for functioning of biological membranes. ELOVL fatty acid elongase 1 catalyses elongation of saturated and monounsaturated C22-C26-VLCFAs. We studied two patients with a dominant ELOVL1 mutation. Independently, Kutkowska-Kaźmierczak et al. had investigated the same patients and found the same mutation. We extended our study towards additional biochemical, functional, and therapeutic aspects.MethodsWe did mutation screening by whole exome sequencing. RNA-sequencing was performed in patient and control fibroblasts. Ceramide and sphingomyelin levels were measured by LC-MS/MS. ELOVL1 activity was determined by a stable isotope-labelled [13C]malonyl-CoA elongation assay. ELOVL1 expression patterns were investigated by immunofluorescence, in situ hybridisation and RT-qPCR. As treatment option, we investigated VLCFA loading of fibroblasts.ResultsBoth patients carried an identical heterozygous de novo ELOVL1 mutation (c.494C>T, NM_001256399; p.S165F) not deriving from a founder allele. Patients suffered from epidermal hyperproliferation and increased keratinisation (ichthyosis). Hypomyelination of the central white matter explained spastic paraplegia and central nystagmus, while optic atrophy was causative for reduction of peripheral vision and visual acuity. The mutation abrogated ELOVL1 enzymatic activity and reduced ≥C24 ceramides and sphingomyelins in patient cells. Fibroblast loading with C22:0-VLCFAs increased C24:0-ceramides and sphingomyelins. We found competitive inhibition for ceramide and sphingomyelin synthesis between saturated and monounsaturated VLCFAs. Transcriptome analysis revealed upregulation of modules involved in epidermal development and keratinisation, and downregulation of genes for neurodevelopment, myelination, and synaptogenesis. Many regulated genes carried consensus proliferator-activated receptor (PPAR)α and PPARγ binding motifs in their 5’-regions.ConclusionA dominant ELOVL1 mutation causes a neuro-ichthyotic disorder possibly amenable to treatment with PPAR-modulating drugs.

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