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

2021 ◽  
Vol 127 (5) ◽  
pp. S105
Author(s):  
J. Goldman
Keyword(s):  
De Novo ◽  
Immune Dysregulation ◽  
De Novo Mutation ◽  
Gain Of Function

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

2020 ◽  
Vol 11 (1) ◽  
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.

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

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.

scholarly journals Efficacy of tocilizumab therapy in a patient with severe pancytopenia associated with a STAT3 gain-of-function mutation

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Wenjie Wang ◽  
Luyao Liu ◽  
Xiaoying Hui ◽  
Ying Wang ◽  
Wenjing Ying ◽  
...  
Keyword(s):  
T Cells ◽  
Next Generation Sequencing ◽  
B Cells ◽  
Early Onset ◽  
De Novo ◽  
Gene Sequencing ◽  
Immune Dysregulation ◽  
Effector Memory ◽  
Gain Of Function ◽  
Generation Sequencing

Abstract Background We aimed to report the clinical characteristics, immunological features, and treatment of one patient with a de novo STAT3 gain-of-function mutation identified by next generation sequencing. We investigated the efficacy of tocilizumab therapy in immune dysregulation diseases caused by STAT3 mutation. Results The patient was a 16-year-old girl. She presented with recurrent respiratory infections and chronic diarrhea after birth. She had life-threatening autoimmune pancytopenia at 14 years old. After receiving glucocorticoid therapy, she developed diabetes. However, her pancytopenia relapsed when the glucocorticoid was tapered. Next-generation sequencing showed a de novo heterozygous mutation in the STAT3 gene, c.1261G > A (p. G421R), which was previously described as a gain-of-function mutation. After tocilizumab therapy, her pancytopenia fully resolved, and insulin and glucocorticoid therapies were gradually discontinued within 12 months. She had lymphopenia and an inverted CD4/CD8 ratio before therapy. Lymphocyte subpopulation analysis indicated an expansion of effector memory CD4+, effector memory CD8+ and central memory CD4+ T cells. The proportions of memory B cells and naive CD4+ T cells were decreased, and the proportion of naïve B cells was increased. None of the abnormal lymphocytic changes improved significantly. STAT3 GOF mutations were identified by next gene sequencing in those with early-onset multi-organ autoimmunity. Including our patient, 13 patients with STAT3 GOF mutations received targeted treatment. Twelve of them were treated with tocilizumab alone or combination tocilizumab with JAK inhibitor, and ten patients improved. Conclusions Gene sequencing should be performed for patients with early-onset refractory or multiorgan immune dysregulation diseases. Targeted drugs can effectively improve the clinical problems associated with STAT3 gain-of-function mutations, while nontargeted immunosuppressive therapy is usually insufficient.

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

Brain ◽  
2018 ◽  
Vol 141 (7) ◽  
pp. 1998-2013 ◽  
Author(s):  
Jean Chemin ◽  
Karine Siquier-Pernet ◽  
Michaël Nicouleau ◽  
Giulia Barcia ◽  
Ali Ahmad ◽  
...  
Keyword(s):  
Calcium Channel ◽  
De Novo ◽  
Mutation Screening ◽  
Cerebellar Atrophy ◽  
De Novo Mutation ◽  
Childhood Onset ◽  
Gain Of Function ◽  
Channel Gene

scholarly journals Gain-of-function GABRB3 variants identified in vigabatrin-hypersensitive epileptic encephalopathies

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Nathan L Absalom ◽  
Vivian W Y Liao ◽  
Kavitha Kothur ◽  
Dinesh C Indurthi ◽  
Bruce Bennetts ◽  
...  
Keyword(s):  
De Novo ◽  
Drug Effects ◽  
Receptor Expression ◽  
Aminobutyric Acid ◽  
Loss Of Function ◽  
Molecular Phenotype ◽  
Gain Of Function ◽  
Gene Encoding ◽  
Epileptic Encephalopathies ◽  
Receptor Phenotype

Abstract Variants in the GABRB3 gene encoding the β3-subunit of the γ-aminobutyric acid type A ( receptor are associated with various developmental and epileptic encephalopathies. Typically, these variants cause a loss-of-function molecular phenotype whereby γ-aminobutyric acid has reduced inhibitory effectiveness leading to seizures. Drugs that potentiate inhibitory GABAergic activity, such as nitrazepam, phenobarbital or vigabatrin, are expected to compensate for this and thereby reduce seizure frequency. However, vigabatrin, a drug that inhibits γ-aminobutyric acid transaminase to increase tonic γ-aminobutyric acid currents, has mixed success in treating seizures in patients with GABRB3 variants: some patients experience seizure cessation, but there is hypersensitivity in some patients associated with hypotonia, sedation and respiratory suppression. A GABRB3 variant that responds well to vigabatrin involves a truncation variant (p.Arg194*) resulting in a clear loss-of-function. We hypothesized that patients with a hypersensitive response to vigabatrin may exhibit a different γ-aminobutyric acid A receptor phenotype. To test this hypothesis, we evaluated the phenotype of de novo variants in GABRB3 (p.Glu77Lys and p.Thr287Ile) associated with patients who are clinically hypersensitive to vigabatrin. We introduced the GABRB3 p.Glu77Lys and p.Thr287Ile variants into a concatenated synaptic and extrasynaptic γ-aminobutyric acid A receptor construct, to resemble the γ-aminobutyric acid A receptor expression by a patient heterozygous for the GABRB3 variant. The mRNA of these constructs was injected into Xenopus oocytes and activation properties of each receptor measured by two-electrode voltage clamp electrophysiology. Results showed an atypical gain-of-function molecular phenotype in the GABRB3 p.Glu77Lys and p.Thr287Ile variants characterized by increased potency of γ-aminobutyric acid A without change to the estimated maximum open channel probability, deactivation kinetics or absolute currents. Modelling of the activation properties of the receptors indicated that either variant caused increased chloride flux in response to low concentrations of γ-aminobutyric acid that mediate tonic currents. We therefore propose that the hypersensitivity reaction to vigabatrin is a result of GABRB3 variants that exacerbate GABAergic tonic currents and caution is required when prescribing vigabatrin. In contrast, drug strategies increasing tonic currents in loss-of-function variants are likely to be a safe and effective therapy. This study demonstrates that functional genomics can explain beneficial and adverse anti-epileptic drug effects, and propose that vigabatrin should be considered in patients with clear loss-of-function GABRB3 variants.

scholarly journals De novo TRPV4 Leu619Pro variant causes a new channelopathy characterised by giant cell lesions of the jaws and skull, skeletal abnormalities and polyneuropathy

2021 ◽  
pp. jmedgenet-2020-107427
Author(s):  
Aviel Ragamin ◽  
Carolina C Gomes ◽  
Karen Bindels-de Heus ◽  
Renata Sandoval ◽  
Angelia V Bassenden ◽  
...  
Keyword(s):  
Giant Cell ◽  
De Novo ◽  
Neuromuscular Disorders ◽  
Somatic Mosaicism ◽  
Ion Leakage ◽  
Gain Of Function ◽  
Therapeutic Modalities ◽  
Organ Systems ◽  
Heterozygous Variant ◽  
Systemic Disorder

BackgroundPathogenic germline variants in Transient Receptor Potential Vanilloid 4 Cation Channel (TRPV4) lead to channelopathies, which are phenotypically diverse and heterogeneous disorders grossly divided in neuromuscular disorders and skeletal dysplasia. We recently reported in sporadic giant cell lesions of the jaws (GCLJs) novel, somatic, heterozygous, gain-of-function mutations in TRPV4, at Met713.MethodsHere we report two unrelated women with a de novo germline p.Leu619Pro TRPV4 variant and an overlapping systemic disorder affecting all organs individually described in TRPV4 channelopathies.ResultsFrom an early age, both patients had several lesions of the nervous system including progressive polyneuropathy, and multiple aggressive giant cell-rich lesions of the jaws and craniofacial/skull bones, and other skeletal lesions. One patient had a relatively milder disease phenotype possibly due to postzygotic somatic mosaicism. Indeed, the TRPV4 p.Leu619Pro variant was present at a lower frequency (variant allele frequency (VAF)=21.6%) than expected for a heterozygous variant as seen in the other proband, and showed variable regional frequency in the GCLJ (VAF ranging from 42% to 10%). In silico structural analysis suggests that the gain-of-function p.Leu619Pro alters the ion channel activity leading to constitutive ion leakage.ConclusionOur findings define a novel polysystemic syndrome due to germline TRPV4 p.Leu619Pro and further extend the spectrum of TRPV4 channelopathies. They further highlight the convergence of TRPV4 mutations on different organ systems leading to complex phenotypes which are further mitigated by possible post-zygotic mosaicism. Treatment of this disorder is challenging, and surgical intervention of the GCLJ worsens the lesions, suggesting the future use of MEK inhibitors and TRPV4 antagonists as therapeutic modalities for unmet clinical needs.

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