Mutational Analysis of PHEX Gene in X-Linked Hypophosphatemia1

Hypophosphatemic rickets is commonly an X-linked dominant disorder (XLH or HYP) associated with a renal tubular defect in phosphate transport and bone deformities. The XLH gene, referred to as PHEX, or formerly as PEX (phosphate regulating gene with homologies to endopeptidases on the X-chromosome), encodes a 749-amino acid protein that putatively consists of an intracellular, transmembrane, and extracellular domain. PHEX mutations have been observed in XLH patients, and we have undertaken studies to characterize such mutations in 46 unrelated XLH kindreds and 22 unrelated patients with nonfamilial XLH by single stranded conformational polymorphism and DNA sequence analysis. We identified 31 mutations (7 nonsense, 6 deletions, 2 deletional insertions, 1 duplication, 2 insertions, 4 splice site, 8 missense, and 1 within the 5′ untranslated region), of which 30 were scattered throughout the putative extracellular domain, together with 6 polymorphisms that had heterozygosity frequencies ranging from less than 1% to 43%. Single stranded conformational polymorphism was found to detect more than 60% of these mutations. Over 20% of the mutations were observed in nonfamilial XLH patients, who represented de novo occurrences of PHEX mutations. The unique point mutation (a→g) of the 5′untranslated region together with the other mutations indicates that the dominant XLH phenotype is unlikely to be explained by haplo-insufficiency or a dominant negative effect.

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DNM1 encephalopathy

Neurology ◽

10.1212/wnl.0000000000004152 ◽

2017 ◽

Vol 89 (4) ◽

pp. 385-394 ◽

Cited By ~ 31

Author(s):

Sarah von Spiczak ◽

Katherine L. Helbig ◽

Deepali N. Shinde ◽

Robert Huether ◽

Manuela Pendziwiat ◽

...

Keyword(s):

Functional Data ◽

De Novo ◽

Structural Modeling ◽

Dominant Negative ◽

Dominant Negative Effect ◽

Global Developmental Delay ◽

Epilepsy Syndrome ◽

De Novo Mutations ◽

Phenotypic Data ◽

Phenotypic Spectrum

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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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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Epilepsy and neurobehavioral abnormalities in mice with a KCNB1 pathogenic variant that alters conducting and non-conducting functions of KV2.1

10.1101/770206 ◽

2019 ◽

Author(s):

Nicole A. Hawkins ◽

Sunita N. Misra ◽

Manuel Jurado ◽

Nicholas C. Vierra ◽

Kimberly Nguyen ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Plasma Membrane ◽

De Novo ◽

Pathogenic Variant ◽

Repetitive Behaviors ◽

Dominant Negative ◽

Dominant Negative Effect ◽

Delayed Rectifier ◽

Eeg Abnormalities ◽

Surface Ecg

AbstractDevelopmental and epileptic encephalopathies (DEE) are a group of severe epilepsies that usually present with intractable seizures, developmental delay and are at a higher risk for premature mortality. Numerous genes have been identified as a monogenic cause of DEE, including KCNB1. The voltage-gated potassium channel KV2.1, encoded by KCNB1, is primarily responsible for delayed rectifier potassium currents that are important regulators of excitability in electrically excitable cells, including neurons and cardiomyocytes. The de novo pathogenic variant KCNB1-p.G379R was identified in an infant with epileptic spasms, atonic, focal and tonic-clonic seizures that were refractory to treatment with standard antiepileptic drugs. Previous work demonstrated deficits in potassium conductance, but did not assess non-conducting functions. To determine if the G379R variant affected clustering at endoplasmic reticulum-plasma membrane junctions KV2.1-G379R was expressed in HEK293T cells. KV2.1-G379R expression did not induce formation of endoplasmic reticulum-plasma membrane junctions, and co-expression of KV2.1-G379R with KV2.1-WT lowered induction of these structures relative to KV2.1-WT alone, suggesting a dominant negative effect. To model this variant in vivo, we introduced Kcnb1G379R into mice using CRISPR/Cas9 genome editing. We characterized neurological and neurobehavioral phenotypes of Kcnb1G379R/+ (Kcnb1R/+) and Kcnb1G379R/G379R (Kcnb1R/R) mice, and screened for cardiac abnormalities. Immunohistochemistry studies on brains from Kcnb1+/+ (WT), Kcnb1R/+ and Kcnb1R/R mice revealed genotype-dependent differences in the levels and subcellular localization of KV2.1, with reduced plasma membrane expression of the KV2.1-G379R protein, consistent with in vitro data. Kcnb1R/+ and Kcnb1R/R mice displayed profound hyperactivity, repetitive behaviors, impulsivity and reduced anxiety. In addition, both Kcnb1R/+ and Kcnb1R/R mice exhibited abnormal interictal EEG abnormalities, including isolated spike and slow waves. Spontaneous seizure events were observed in Kcnb1R/R mice during exposure to novel environments and/or handling, while both Kcnb1R/+ and Kcnb1R/R mutants were more susceptible to induced seizures. Kcnb1R/+ and Kcnb1R/R mice exhibited prolonged rate-corrected QT interval on surface ECG recording. Overall, the Kcnb1G379R mice recapitulate many features observed in individuals with DEE due to pathogenic variants in KCNB1. This new mouse model of KCNB1 associated DEE will be valuable for improving the understanding of the underlying pathophysiology and will provide a valuable tool for the development of therapies to treat this pharmacoresistant DEE.

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Mutational analysis of PRDM1 indicates a tumor-suppressor role in diffuse large B-cell lymphomas

Blood ◽

10.1182/blood-2005-09-3778 ◽

2006 ◽

Vol 107 (10) ◽

pp. 4090-4100 ◽

Cited By ~ 162

Author(s):

Wayne Tam ◽

Mario Gomez ◽

Amy Chadburn ◽

Joong W. Lee ◽

Wing C. Chan ◽

...

Keyword(s):

Tumor Suppressor ◽

B Cell ◽

Rna Editing ◽

Zinc Finger Protein ◽

De Novo ◽

Mutational Analysis ◽

Genetic Defect ◽

B Cell Lymphoma ◽

Dominant Negative ◽

Large B Cell

The PR (PRDI-BF1-RIZ) domain zinc finger protein 1 (PRDM1) is a transcription repressor with a pivotal role in plasma-cell differentiation. We identified clonal inactivating mutations in PRDM1 in the diffuse large B-cell lymphoma (DLBCL) cell line OCI-Ly3 and in 8 of 35 de novo clinical DLBCL samples. The mutational spectrum consists predominantly (7 cases) of single-nucleotide mutations affecting consensus splice donor sites, some of which are recurrent, that lead to splicing aberrations and premature translation termination. In 2 of these cases, point mutations appear to be caused by RNA editing with G-to-A and U-to-G conversions. Other mutations include frame-shift deletion and chromosomal inversion. Except for one mutant, which may act as a dominant-negative, all mutations are associated with either deletion or silencing of the paired PRDM1 allele. This study identifies PRDM1 inactivation as a recurrent genetic defect in DLBCL cells and establishes PRDM1 as a potential tumor suppressor gene in DLBCL. Moreover, it implies inhibition of terminal differentiation as a pathogenetic pathway in DLBCL, particularly for the activated B-cell–like DLBCL. It also demonstrates for the first time the potential role of RNA editing in lymphomagenesis.

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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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Loss–of–function variants in the KCNQ5 gene are associated with genetic generalized epilepsies

10.1101/2021.04.20.21255696 ◽

2021 ◽

Author(s):

Johanna Krueger ◽

Julian Schubert ◽

Josua Kegele ◽

Audrey Labalme ◽

Miaomiao Mao ◽

...

Keyword(s):

Mammalian Cells ◽

De Novo ◽

Surface Expression ◽

Epileptic Encephalopathy ◽

Dominant Negative ◽

Dominant Negative Effect ◽

K Channel ◽

Loss Of Function ◽

Normal Surface ◽

Missense Variants

Objective: De novo missense variants in KCNQ5, encoding the voltage–gated K+ channel KV7.5, have been described as a cause of developmental and epileptic encephalopathy (DEE) or intellectual disability (ID). We set out to identify disease–related KCNQ5 variants in genetic generalized epilepsy (GGE) and their underlying mechanisms. Methods: 1292 families with GGE were studied by next-generation sequencing. Whole–cell patch–clamp recordings, biotinylation and phospholipid overlay assays were performed in mammalian cells combined with docking and homology modeling. Results: We identified three deleterious heterozygous missense variants, one truncation and one splice site alteration in five independent families with GGE with predominant absence seizures, two variants were also associated with mild to moderate ID. All three missense variants displayed a strongly decreased current density indicating a loss–of–function (LOF). When mutant channels were co–expressed with wild–type (WT) KV7.5 or KV7.5 and KV7.3 channels, three variants also revealed a significant dominant–negative effect on WT channels. Other gating parameters were unchanged. Biotinylation assays indicated a normal surface expression of the variants. The p.Arg359Cys variant altered PI(4,5)P2–interaction, presumably in the non–conducting preopen–closed state. Interpretation: Our study indicates that specific deleterious KCNQ5 variants are associated with GGE, partially combined with mild to moderate ID. The disease mechanism is a LOF partially with dominant–negative effects through functional, rather than trafficking deficits. LOF of KV7.5 channels will reduce the M–current, likely resulting in increased excitability of KV7.5–expressing neurons. Further studies on a network level are necessary to understand which circuits are affected and how the variants induce generalized seizures.

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Type of TP53 Mutations Affects Subclonal Configuration and Selection Pressure for Acquisition of Additional Hits in Contralateral Alleles

Blood ◽

10.1182/blood-2020-140058 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 25-25

Author(s):

Carmelo Gurnari ◽

Vera Adema ◽

Hassan Awada ◽

Simona Pagliuca ◽

Cassandra M Kerr ◽

...

Keyword(s):

Selection Pressure ◽

Double Mutant ◽

Hematopoietic Cell Transplantation ◽

De Novo ◽

Genetic Alterations ◽

Dominant Negative ◽

Dominant Negative Effect ◽

Tp53 Mutations ◽

Myeloid Neoplasms ◽

The Impact

Somatic TP53 mutations are found in 10% of adult patients with MDS and de novo AML and in up to 20% of patients with therapy-related myeloid neoplasms. TP53 status is associated with complex karyotype (CK), aberrations of chromosome 5 and poor survival. Moreover, mutated TP53 (TP53MT) may be an indication for hematopoietic cell transplantation, but also predictive of relapse following the procedure, making this particular category of myeloid neoplasms (MN) a conundrum of clinical management. Unlike other tumor suppressor genes, missense (ms) mutations within the DNA-binding domain (DBD) are the most common genetic alterations in TP53 gene representing up to 80% of somatic hits, with involvement of canonical hotspots (R175H, Y220C, M237I, R248Q, R273H, R282W) in around 30% of cases. A loss-of-function (LOF) dominant-negative effect (DN) may explain the ability of TP53MT to interfere with wild type (WT) functions. Moreover, TP53 germ line (GL) mutations are responsible for Li-Fraumeni syndrome, and GL contamination may also exist in adult MN. Here we comprehensively characterize TP53MT MNs to better dissect the role of specific mutational configurations and identify the selective forces affecting outcomes in this poor prognostic MN category. A total of 764 TP53 mutations were found in 632 MN patients. Ms mutations were the most common (75%) followed by frameshift (11%), splice site (7%), nonsense (5%) and insertion/deletions (2%), with 20% of patients harboring more than 1 lesion. Topographical annotation revealed that ms mutations typically (98%) occurred within the DBD (residues 102-292) and only 2% occurred outside this region (vs. 28% in case of truncating mutations, p<.0001). Overall, 22% of patients displayed a mutation in the canonical hotspot regions. Among TP53MT, 36 cases (6%) were of possible GL origin. Focusing on the somatic lesions, a male preponderance (1.42 vs. 1.1 M:F, p=.0069) and a younger age at presentation (median 68.9 vs 71, p<.00001) were found in WT vs. mutant cases, which were also less enriched in coincident de novo leukemia-driver genes mutations (e.g. NPM1, FLT3). When compared to WT MN, TP53MT cases were more likely to have CK (8% vs. 70%, p<.00001), del(5q) (4% vs. 40%, p<.00001), del(7q)/-7 (6% vs. 18%, p<.00001) and trisomy 8 (8% vs. 49%, p<.00001). Of note, deletion of the TP53 locus was found in 27% of mutated cases vs only 1% of WT counterparts (p<.00001). Conversely, 77% of all MN cases with CK had either TP53 mutations (61%), del(17p) (3%) or both (36%). When classifying patients according to TP53 genomic context (30% single vs. 70% double hit, defined as a presence of biallelic, hemizigous or UPD configuration) progressive inactivation had an adverse impact on survival (p<.0001). We then hypothesized that truncating (frameshift/nonsense/deletion) alterations require additional hits as the presence of one allele may be partially protective. Consequently, the VAF for these lesions may be a result of a UPD in a smaller fraction of cells; biallelic truncation hits thus may be truly biallelic rather than clonally mosaic, which can be demonstrated only by single cell DNA sequencing. In contrast, DN mutations in canonical hotspots decrease the function beyond 50% of the activity, with further inactivation would having less of an effect, thus exerting less selection pressure for acquisition of additional lesions. Indeed, second truncating hits (including UPD and del(17p)) were common (30%), while none of the dominant ms hits had a double-mutant hotspot configuration (vs. 14% of non-canonical ms double mutant), and these canonical dominant hits were less likely to be paired with del(17p) or truncating mutations (8%). Only 25% of CK had a WT configuration of TP53, consistent with our theory that dominant ms hits were more likely to be present without del(17p). It is possible that the inability to assert clear survival differences according to the number or types of TP53 lesions may be due to an inability to resolve the intraclonal configuration of mutations using VAF calculations. We also conclude that non-canonical ms mutations (many of them classified as VUS) may have a variable impact, with functional consequences ranging from those that are less severe than truncations to various degrees of negative dominance. Analyses of the impact of ms mutations on TP53 tetramers (which may contain various doses of mutant vs WT monomer), will shed further light on the biology of TP53MT MN. Disclosures Voso: Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sekeres:Takeda/Millenium: Consultancy; BMS: Consultancy; Pfizer: Consultancy. Carraway:Abbvie: Other: Independent Advisory Committe (IRC); Stemline: Consultancy, Speakers Bureau; ASTEX: Other: Independent Advisory Committe (IRC); BMS: Consultancy, Other: Research support, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Takeda: Other: Independent Advisory Committe (IRC). Maciejewski:Alexion, BMS: Speakers Bureau; Novartis, Roche: Consultancy, Honoraria.

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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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