DNM1 encephalopathy

Objective:To evaluate the phenotypic spectrum caused by mutations in dynamin 1 (DNM1), encoding the presynaptic protein DNM1, and to investigate possible genotype-phenotype correlations and predicted functional consequences based on structural modeling.Methods:We reviewed phenotypic data of 21 patients (7 previously published) with DNM1 mutations. We compared mutation data to known functional data and undertook biomolecular modeling to assess the effect of the mutations on protein function.Results:We identified 19 patients with de novo mutations in DNM1 and a sibling pair who had an inherited mutation from a mosaic parent. Seven patients (33.3%) carried the recurrent p.Arg237Trp mutation. A common phenotype emerged that included severe to profound intellectual disability and muscular hypotonia in all patients and an epilepsy characterized by infantile spasms in 16 of 21 patients, frequently evolving into Lennox-Gastaut syndrome. Two patients had profound global developmental delay without seizures. In addition, we describe a single patient with normal development before the onset of a catastrophic epilepsy, consistent with febrile infection-related epilepsy syndrome at 4 years. All mutations cluster within the GTPase or middle domains, and structural modeling and existing functional data suggest a dominant-negative effect on DMN1 function.Conclusions:The phenotypic spectrum of DNM1-related encephalopathy is relatively homogeneous, in contrast to many other genetic epilepsies. Up to one-third of patients carry the recurrent p.Arg237Trp variant, which is now one of the most common recurrent variants in epileptic encephalopathies identified to date. Given the predicted dominant-negative mechanism of this mutation, this variant presents a prime target for therapeutic intervention.

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Biallelic and monoallelic variants in PLXNA1 are implicated in a novel neurodevelopmental disorder with variable cerebral and eye anomalies

Genetics in Medicine ◽

10.1038/s41436-021-01196-9 ◽

2021 ◽

Author(s):

Gabriel C. Dworschak ◽

Jaya Punetha ◽

Jeshurun C. Kalanithy ◽

Enrico Mingardo ◽

Haktan B. Erdem ◽

...

Keyword(s):

Developmental Delay ◽

De Novo ◽

Neurodevelopmental Disorder ◽

Structural Modeling ◽

Dominant Negative ◽

Dominant Negative Effect ◽

Global Developmental Delay ◽

Downstream Signaling ◽

Negative Effect

Abstract Purpose To investigate the effect of PLXNA1 variants on the phenotype of patients with autosomal dominant and recessive inheritance patterns and to functionally characterize the zebrafish homologs plxna1a and plxna1b during development. Methods We assembled ten patients from seven families with biallelic or de novo PLXNA1 variants. We describe genotype–phenotype correlations, investigated the variants by structural modeling, and used Morpholino knockdown experiments in zebrafish to characterize the embryonic role of plxna1a and plxna1b. Results Shared phenotypic features among patients include global developmental delay (9/10), brain anomalies (6/10), and eye anomalies (7/10). Notably, seizures were predominantly reported in patients with monoallelic variants. Structural modeling of missense variants in PLXNA1 suggests distortion in the native protein. Our zebrafish studies enforce an embryonic role of plxna1a and plxna1b in the development of the central nervous system and the eye. Conclusion We propose that different biallelic and monoallelic variants in PLXNA1 result in a novel neurodevelopmental syndrome mainly comprising developmental delay, brain, and eye anomalies. We hypothesize that biallelic variants in the extracellular Plexin-A1 domains lead to impaired dimerization or lack of receptor molecules, whereas monoallelic variants in the intracellular Plexin-A1 domains might impair downstream signaling through a dominant-negative effect.

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De novo Mutations in NALCN Cause a Syndrome of Congenital Contractures of the Limbs and Face with Hypotonia, and Developmental Delay

10.1101/013656 ◽

2015 ◽

Author(s):

Jessica X Chong ◽

Margaret J McMillin ◽

Kathryn M Shively ◽

Anita E Beck ◽

Colby T Marvin ◽

...

Keyword(s):

Exome Sequencing ◽

Developmental Delay ◽

De Novo ◽

Dominant Negative ◽

Protein Domain ◽

Dominant Negative Effect ◽

Global Developmental Delay ◽

Missense Mutations ◽

Severe Intellectual Disability ◽

Dominant Condition

Freeman-Sheldon syndrome, or distal arthrogryposis type 2A (DA2A), is an autosomal dominant condition caused by mutations in MYH3 and characterized by multiple congenital contractures of the face and limbs and normal cognitive development. We identified a subset of five simplex cases putatively diagnosed with “DA2A with severe neurological abnormalities” in which the proband had Congenital Contractures of the LImbs and FAce, Hypotonia, and global Developmental Delay often resulting in early death, a unique condition that we now refer to as CLIFAHDD syndrome. Exome sequencing identified missense mutations in sodium leak channel, nonselective (NALCN) in four families with CLIFAHDD syndrome. Using molecular inversion probes to screen NALCN in a cohort of 202 DA cases as well as concurrent exome sequencing of six other DA cases revealed NALCN mutations in ten additional families with “atypical” forms of DA. All fourteen mutations were missense variants predicted to alter amino acid residues in or near the S5 and S6 pore-forming segments of NALCN, highlighting the functional importance of these segments. In vitro functional studies demonstrated that mutant NALCN nearly abolished the expression of wildtype NALCN, suggesting that mutations that cause CLIFAHDD syndrome have a dominant negative effect. In contrast, homozygosity for mutations in other regions of NALCN has been reported in three families with an autosomal recessive condition characterized mainly by hypotonia and severe intellectual disability. Accordingly, mutations in NALCN can cause either a recessive or dominant condition with varied though overlapping phenotypic features perhaps depending on the type of mutation and affected protein domain(s).

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DNM1 Gene and Its Related Epileptic Phenotypes

Journal of Pediatric Neurology ◽

10.1055/s-0041-1727258 ◽

2021 ◽

Author(s):

Milena Motta ◽

Maria Chiara Consentino ◽

Alessandra Fontana ◽

Laura Sciuto ◽

Raffaele Falsaperla ◽

...

Keyword(s):

Developmental Delay ◽

De Novo ◽

Wide Spectrum ◽

Intractable Epilepsy ◽

Gene Mutations ◽

Infantile Spasms ◽

Dominant Negative ◽

Dominant Negative Effect ◽

De Novo Mutations ◽

Negative Effect

AbstractThe phenotypic variety associated to mutations in dynamin 1 (DNM1), codifying the presynaptic protein DNM1 has been increasingly reported, mainly related to encephalopathy with intractable epilepsy; currently, it is known the phenotype related to DNM1 gene mutations is relatively homogeneous with developmental delay, hypotonia, and epilepsy characterized by infantile spasms and possible progression to Lennox-Gastaut syndrome. By examining all the papers published until 2020 (18 articles), we compared data from 30 patients (extrapolated from 5 papers) with DNM1 mutations, identifying 26 patients with de novo mutations in DNM1. Nine patients (33.3%) reported the recurrent mutation p.Arg237Trp. A usual phenotype observed comprises severe to deep developmental delay and muscular hypotonia in all patients with epilepsy beginning with infantile spasms, which often evolved into Lennox-Gastaut syndrome. Data about GTPase or central domains mutations, and existing structural modeling and functional suggest a dominant negative effect on DMN1 function. Generally genetic epilepsies consist of a wide spectrum of clinical features, unlike that, DNM1-related CNS impairment phenotype is quite uniform. In up to one third of patients it has been found variant p.Arg237Trp, which is one of the most frequent variant detected in epileptic encephalopathies. The understanding of DNM1 function opens up the chance that this gene would become a new therapeutic target for epilepsies.

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239-kb Microdeletion Spanning KMT2E in a Child with Developmental Delay: Further Delineation of the Phenotype

Molecular Syndromology ◽

10.1159/000516635 ◽

2021 ◽

pp. 1-6

Author(s):

Konstantina Kosma ◽

Konstantinos Varvagiannis ◽

Anastasios Mitrakos ◽

Maria Tsipi ◽

Joanne Traeger-Synodinos ◽

...

Keyword(s):

Developmental Delay ◽

De Novo ◽

Neurodevelopmental Disorder ◽

Dominant Negative ◽

Dominant Negative Effect ◽

Chromosomal Microarray ◽

Global Developmental Delay ◽

Common Mechanism ◽

Facial Dysmorphism ◽

Gi Symptoms

Pathogenic KMT2E variants underly O'Donnell-Luria-Rodan syndrome, a recently described neurodevelopmental disorder characterized by global developmental delay, variable degrees of intellectual disability, and subtle facial dysmorphism. Less common findings include autism, seizures, gastrointestinal (GI) problems, and abnormal head circumference. Occurrence of mostly truncating variants as well as the similar phenotype observed in individuals with deletions spanning KMT2E suggest haploinsufficiency of this gene as a common mechanism for the disorder, while a gain-of-function or dominant-negative effect cannot be ruled out for some missense variants. Deletions reported in the literature encompass several additional known or presumed haploinsufficient genes, thus leading to more complex phenotypes. Here, we describe a male with antenatal onset hydronephrosis, hypotonia, global developmental delay, prominent GI symptoms as well as facial dysmorphism. Chromosomal microarray revealed a 239-kb de novo microdeletion spanning KMT2E and LHFPL3. Clinical presentation of our proband, harboring one of the smallest deletions of the region confirms the core features of this disorder, suggests GI symptoms as a prominent finding in affected individuals while expanding the phenotypic spectrum to abnormalities of the urinary tract.

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An ensemble of toxic channel types underlies the severity of the de novo variant G375R of the human BK channel

10.1101/2021.12.22.473917 ◽

2021 ◽

Author(s):

Yanyan Geng ◽

Ping Li ◽

Alice Butler ◽

Bill Wang ◽

Lawrence Salkoff ◽

...

Keyword(s):

Neuronal Excitability ◽

De Novo ◽

Bk Channels ◽

Bk Channel ◽

Dominant Negative ◽

Dominant Negative Effect ◽

De Novo Mutations ◽

Negative Effect ◽

De Novo Variant ◽

Heteromeric Channels

De novo mutations play a prominent role in neurodevelopmental diseases including autism, schizophrenia, and intellectual disability. Many de novo mutations are dominant and so severe that the afflicted individuals do not reproduce, so the mutations are not passed into the general population. For multimeric proteins, such severity may result from a dominant-negative effect where mutant subunits assemble with WT to produce channels with adverse properties. Here we study the de novo variant G375R heterozygous with the WT allele for the large conductance voltage- and Ca2+-activated potassium (BK) channel, Slo1. This variant has been reported to produce devastating neurodevelopmental disorders in three unrelated children. If mutant and WT subunits assemble randomly to form tetrameric BK channels, then ~6% of the assembled channels would be wild type (WT), ~88% would be heteromeric incorporating from 1-3 mutant subunits per channel, and ~6% would be homomeric mutant channels consisting of four mutant subunits. To test this hypothesis, we analyzed the biophysical properties of single BK channels in the ensemble of channels expressed following a 1:1 injection of mutant and WT cRNA into oocytes. We found ~3% were WT channels, ~85% were heteromeric channels, and ~12% were homomeric mutant channels. All of the heteromeric channels as well as the homomeric mutant channels displayed toxic properties, indicating a dominant negative effect of the mutant subunits. The toxic channels were open at inappropriate negative voltages, even in the absence of Ca2+, which would lead to altered cellular function and decreased neuronal excitability.

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A Restricted Repertoire of De Novo Mutations in ITPR1 Cause Gillespie Syndrome with Evidence for Dominant-Negative Effect

The American Journal of Human Genetics ◽

10.1016/j.ajhg.2016.03.018 ◽

2016 ◽

Vol 98 (5) ◽

pp. 981-992 ◽

Cited By ~ 44

Author(s):

Meriel McEntagart ◽

Kathleen A. Williamson ◽

Jacqueline K. Rainger ◽

Ann Wheeler ◽

Anne Seawright ◽

...

Keyword(s):

De Novo ◽

Dominant Negative ◽

Dominant Negative Effect ◽

De Novo Mutations ◽

Negative Effect

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A familial case of CAMK2B mutation with variable expressivity

SAGE Open Medical Case Reports ◽

10.1177/2050313x21990982 ◽

2021 ◽

Vol 9 ◽

pp. 2050313X2199098

Author(s):

Paige Heiman ◽

Sarah Drewes ◽

Lina Ghaloul-Gonzalez

Keyword(s):

Intellectual Disability ◽

De Novo ◽

Neurodevelopmental Disorder ◽

Clinical Manifestations ◽

Cerebellar Atrophy ◽

Global Developmental Delay ◽

De Novo Mutations ◽

Phenotypic Spectrum ◽

Behavioral Abnormalities ◽

Intrafamilial Variability

Variants in CAMK2-associated genes have recently been implicated in neurodevelopmental disorders and intellectual disability. The clinical manifestations reported in patients with mutations in these genes include intellectual disability (ranging from mild to severe), global developmental delay, seizures, delayed speech, behavioral abnormalities, hypotonia, episodic ataxia, progressive cerebellar atrophy, visual impairments, and gastrointestinal issues. Phenotypic heterogeneity has been postulated. We present a child with neurodevelopmental disorder caused by a pathogenic CAMK2B variant inherited from a healthy mother. A more mildly affected sib was determined to have the same variant. Monoallelic mutations in CAMK2B in patients have previously only been reported as de novo mutations. This report adds to the clinical phenotypic spectrum of the disease and demonstrates intrafamilial variability of expression of a CAMK2B mutation.

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Clinical and molecular analysis of three families with autosomal dominant neurohypophyseal diabetes insipidus associated with a novel and recurrent mutations in the vasopressin-neurophysin II gene

Acta Endocrinologica ◽

10.1530/eje.0.1460649 ◽

2002 ◽

pp. 649-656 ◽

Cited By ~ 26

Author(s):

J Rutishauser ◽

P Kopp ◽

MB Gaskill ◽

TJ Kotlar ◽

GL Robertson

Keyword(s):

Diabetes Insipidus ◽

Autosomal Dominant ◽

De Novo ◽

Index Patient ◽

Dominant Negative ◽

Dominant Negative Effect ◽

Heterozygous Mutation ◽

Posterior Pituitary ◽

Recurrent Mutations ◽

Neurophysin Ii

OBJECTIVE: To test further the hypothesis that autosomal dominant neurohypophyseal diabetes insipidus (adFNDI) is caused by heterozygous mutations in the vasopressin-neurophysin II (AVP-NPII) gene that exert a dominant negative effect by producing a precursor that misfolds, accumulates and eventually destroys the neurosecretory neurons. METHODS: Antidiuretic function, magnetic resonance imaging (MRI) of the posterior pituitary and AVP-NPII gene analysis were performed in 10 affected members of three unreported families with adFNDI. RESULTS: As in previously studied patients, adFNDI apparently manifested after birth, was due to a partial or severe deficiency of AVP, and was associated with absence or diminution of the hyperintense MRI signal normally emitted by the posterior pituitary, and with a heterozygous mutation in the AVP-NPII gene. In family A, a transition 275G-->A, which predicts replacement of cysteine 92 by tyrosine (C92Y), was found in the index patient, but not in either parent, indicating that it arose de novo. The six affected members of family B had a transversion 160G-->C, which predicts replacement of glycine 54 by arginine (G54R). It appeared de novo in the oldest affected member, and was transmitted in a dominant manner. In family C, six of 15 living affected members were tested and all had a novel transition, 313T-->C, which predicts replacement of cysteine 105 by arginine (C105R). It, too, was transmitted in a dominant manner. As in other patients with adFNDI, the amino acids replaced by the mutations in these three families are known to be particularly important for correct and efficient folding of the precursor. CONCLUSIONS: These findings are consistent with the malfolding/toxicity hypothesis underlying the pathogenesis of adFNDI. Moreover, they illustrate the value of genetic analysis in all patients who develop idiopathic diabetes insipidus in childhood, even if no other family members are affected.

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Heterozygous Missense Pathogenic Variants Within the Second Spectrin Repeat of SPTBN2 Lead to Infantile-Onset Cerebellar Ataxia

Journal of Child Neurology ◽

10.1177/0883073819878917 ◽

2019 ◽

Vol 35 (2) ◽

pp. 106-110 ◽

Cited By ~ 1

Author(s):

Andrea Accogli ◽

Judith St-Onge ◽

Nassima Addour-Boudrahem ◽

Joël Lafond-Lapalme ◽

Alexandre Dionne Laporte ◽

...

Keyword(s):

Cognitive Impairment ◽

Cerebellar Ataxia ◽

De Novo ◽

Dominant Negative ◽

Dominant Negative Effect ◽

Adult Onset ◽

Spinocerebellar Ataxias ◽

Spectrin Repeat ◽

Missense Variants ◽

Pathogenic Variants

The term spinocerebellar ataxia encompasses a heterogeneous group of neurodegenerative disorders due to pathogenic variants in more than 100 genes, underlying 2 major groups of ataxia: autosomal dominant cerebellar ataxias (ADCA, also known as spinocerebellar ataxias [SCAs]) due to heterozygous variants or polyglutamine triplet expansions leading to adult-onset ataxia, and autosomal recessive spinocerebellar ataxias (ARCAs, also known as SCARs) due to biallelic variants, usually resulting in more severe and earlier-onset cerebellar ataxia. Certain ataxia genes, including SPTBN2 which encodes β-III spectrin, are responsible for both SCA and SCAR, depending on whether the pathogenic variant occurs in a monoallelic or biallelic state, respectively. Accordingly, 2 major phenotypes have been linked to SPTBN2: pathogenic heterozygous in-frame deletions and missense variants result in an adult-onset, slowly progressive ADCA (SCA5) through a dominant negative effect, whereas biallelic loss-of-function variants cause SCAR14, an allelic disorder characterized by infantile-onset cerebellar ataxia and cognitive impairment. Of note, 2 heterozygous missense variants (c.1438C>T, p.R480 W; c.1309C>G, p.R437G), both lying in the second spectrin repeat of SPTBN2, have been linked to infantile-onset cerebellar ataxia, similar to SCAR14. Here, we report a novel de novo heterozygous pathogenic missense variant (c.1310G>A) in SPTBN2 in a child with infantile-onset cerebellar ataxia and mild cognitive impairment. This variant affects the same R437 residue of the second spectrin repeat but results in a different amino acid change (p.R437Q). We review previously reported cases and discuss possible pathomechanisms responsible for the early-onset cerebellar phenotype due to disease-causing variants in the second spectrin repeat.

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