Genetics Research
rs28931591
Serine 284 → Leucine
Gene: CHRNA4 — Cholinergic Receptor Nicotinic Alpha 4 Subunit
Chr 20:63350560
20q13.33
Missense Variant
Population Frequencies0
No frequency data stored yet.
Studies8
Unread Studies8 ▼
1
The α4β2 nAChRs are crucial ion channels that control neurotransmitter release and play a role in various physiologic and pathologic processes. CHRNA4 encodes the α4-nAChRs, while CHRNB2 encodes the β2-nAChRs. Recent studies have found different variants of α4β2-nAChRs in individuals with conditions such as AD, ADHD, ALS, PD, and brain abnormalities. We conducted a scoping review following a six-stage methodology structure and adhering to PRISMA guidelines. We systematically reviewed articles using relevant keywords up to October 2, 2023. In this summary, we cover the clinical symptoms reported, the genes and protein structure of CHRNA4 and CHRNB2, mutations in these genes, inheritance patterns, the functional impact of mutations and polymorphisms in CHRNA4 and CHRNB2, and the epidemiology of these diseases. Recent research indicates that nAChRs may play a significant role in neurodegenerative disorders, possibly impacting neuronal function through yet undiscovered regulatory pathways. Studying how nAChRs interact with disease-related aggregates in neurodegenerative conditions may lead to new treatment options for these disorders.
2
The objective of this dissertation is to assess the bioequivalence of generic drugs. Patients with epilepsy complain about more seizures and side effects after brand-generic or generic-generic switching of an anti-epileptic drug (AED). Generic brittleness (GB) is the familiar notion that, upon switching between AEDs of pharmaceutical equivalents, a patient experiences negative outcome. Aim 1 is to probe the individual patient attributes thought to predispose a patient to generic brittleness. At the University of Maryland Medical Center, 148 patients from the outpatient epilepsy clinic were recruited for an observational case-control study.
3
A patient was denoted to be generic brittle (GB) if they had a negative opinion about generics (e.g. prior history of a switch problem) or took the innovator brand of their most problematic anti-epileptic drug (AED) when generic was available. The aim of this hypothesis-generating study was to assess possible genetic and physiologic differences between GB and not GB patients with epilepsy.
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Background: Cys‐loop receptors control neuronal excitability in the brain and their dysfunction results in numerous neurological disorders. Recently, six missense variants in GABRA2, a member of this family, have been associated with early infantile epileptic encephalopathy (EIEE). We identified a novel de novo missense variant in GABRA2 in a patient with EIEE and performed protein structural analysis of the seven variants. / Methods: The novel variant was identified by trio whole‐genome sequencing. We performed protein structural analysis of the seven variants, and compared them to previously reported pathogenic mutations at equivalent positions in other Cys‐loop receptors. Additionally, we studied the distribution of disease‐associated variants in the transmembrane helices of these proteins. / Results: The seven variants are in the transmembrane domain, either close to the desensitization gate, the activation gate, or in inter‐subunit interfaces. Six of them have pathogenic mutations at equivalent positions in other Cys‐loop receptors, emphasizing the importance of these residues. Also, pathogenic mutations are more common in the pore‐lining helix, consistent with this region being highly constrained for variation in control populations. / Conclusion: Our study reports a novel pathogenic variant in GABRA2, characterizes the regions where pathogenic mutations are in the transmembrane helices, and underscores the value of considering sequence, evolutionary, and structural information as a strategy for variant interpretation of novel missense mutations.
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Purpose Genetics of Sleep-related Hypermotor Epilepsy (SHE) includes mutations in several genes that cumulatively account for 30 % of families. This approximate estimate comes from different case-series, each focused on the screening of a single gene. We systematically investigated a large cohort of SHE patients to estimate the frequency of pathogenic variants in the main genes thus far implicated in this epilepsy syndrome. Methods We selected familial and isolated cases diagnosed with clinical/confirmed SHE who underwent genetic analysis by comparable next generation sequencing (NGS) techniques (WES/ multigene epilepsy panel). The identified heterozygous variants were classified according to the American College of Medical Genetics and Genomics guidelines. Results We included 103 SHE patients (M/F:61/42) who underwent NGS. Sixteen (15.5 %) were familial cases, 16.5 % had focal cortical dysplasia (FCD). We identified three pathogenic variants in CHRNA4 (2.9 %, CI: 0.6–8.3 %), two of whom novel; one pathogenic variant in KCNT1 (1 %, CI: 0.02–5.29 %); four loss-of-function variants in DEPDC5 (3.9 %, CI: 1.1–9.7 %), one of whom never reported; finally, one missense change in NPRL2 (1 %, CI: 0.02–5.29 %), already reported as pathogenic. Three out of the four patients with DEPDC5 variants had FCD. Conclusions The overall frequency of pathogenic variants in our SHE cohort was 8.7 %, 19 % and 7 % considering familial and sporadic cases, respectively. Pathogenic variants in the GATOR1-complex genes account for 5 % of the cases. DEPDC5 shows the highest variants frequency, especially in patients with genetic-structural etiology. From a practical perspective, analysis of this gene is recommended even in isolated cases, because of possible implications for patient management.
6
Sleep-related Hypermotor Epilepsy (SHE) is a genetically heterogeneous epilepsy syndrome. Differences in epilepsy phenotype/endophenotype were associated with mutations in specific genes. However, the genes identified so far cumulatively account for 25% of cases. Moreover, systematic neuropsychological investigations on comprehensive SHE cohorts are lacking. This study provides an accurate clinical, genetic and neuropsychological characterization of a large cohort of patients diagnosed with SHE according to reliable diagnostic criteria. A subgroup underwent a preliminary screening, partly performed by dHPLC to exclude mutations in CHRNA4, CHRNB2, CHRNA2. Using a number of genetic strategies, we identified causative mutations in 10.4% of our cases. The mutation frequencies were 2.3% for KCNT1 (CI: 0.3-8.1%), 5.9% for GATOR1-complex genes (CI: 2.0-13.3%), 3.1% for CHRNA4 (CI: 0.6-8.8%) and 1.7% for SCN1A (CI 0-8.9%). WES analysis allowed the identification of a novel epilepsy gene, NPRL2, coding a component of GATOR1, a negative regulator of mTOR pathway. Altogether, mutations in the GATOR1 complex genes DEPDC5 and NPRL2 account for the majority of our cases (6%). Genotype-phenotype correlations confirmed their association with focal cortical dysplasia, higher rates of drug-resistance, aura and seizures in wakefulness, with relevant implications in diagnostic and treatment strategies. Moreover, we confirm that mutations in KCNT1 are implicated in severe forms with intellectual disability and psychiatric disorders. The unexpected detection of CHRNA4 mutations highlighted the low sensitivity of dHPLC assay. The systematic neuropsychological study showed that neurocognitive deficits are not uncommon in SHE. Mutated patients scored significantly lower at WAIS, supporting a crucial role of genetics in cognitive deficit by different biological mechanisms and molecular pathways. About 47% of patients of normal intelligence showed some degree of cognitive dysfunction. The profile of neuropsychological impairment was characterized by significant worse scores in verbal IQ, deficits in memory and in selected executive functions, with preserved shifting abilities and cognitive flexibility.
7
Idiopathic epilepsies are common and devastating neurological disorders in which genetic background and physiopathological mechanisms underlying the clinical phenotype are not fully characterized yet. These diseases are assumed to have a strong genetic component, being monogenic or oligo/polygenic with different recurrence risks in the same family. However, even in monogenic epilepsy, additional genes and environmental factors may modulate its expression, thus resulting in incomplete penetrance and variable phenotype. Ethiology, phenotypic manifestations and prognosis are indeed highly heterogeneous. Idiopathic epilepsies represent about 30-40% of all epilepsies in childhood and 20% in adults. Most of them are complex diseases: patients may shift from one phenotype to another during their lifetime and parents affected by one form may have children suffering from another epileptic syndrome. The identification of genes responsible for distinct epilepsy syndromes or influencing the risk for epilepsy has important implications, for both research and clinical purposes. In this work we studied the genetic bases of two different epilepsies: nocturnal frontal lobe epilepsy (NFLE/ADNFLE) and febrile seizures (FS/GEFS+). In the case of the NFLE/ADNFLE phenotype, we performed a mutational screening of known genes, including CRH and its promoter, in a sample of both sporadic and familial patients. The study allowed the identification of: an already known mutation in the CHRNA4 gene (p.Ser284Leu) originated de novo in one NFLE patient; three unknown variants in the CRH promoter in both sporadic and familial patients which we demonstrated to not cosegregate with the disease; one unknown missense mutation in the coding portion of the CRH gene (p.Pro30Arg) in one ADNFLE patient. By functional in vitro analysis we demonstrated that the p.Pro30Arg causes impairment in the production and release of the CRH hormone. This impairment could be related to an altered capability of patients to respond quickly to stress agents. Finally, by analyzing candidate genes encoding the orexin system we demonstrated an unlikely role of this system in the 2 pathogenesis of ADNFLE: none of the patients has mutations in the three genes. In the study of FS/GEFS+ phenotype, the role of the SCN1A gene was evaluated. Several intronic and exonic polymorphisms were detected. In the case of unknown intronic variants, an in silico analysis revealed that these variations do not introduce or remove any splicing sites. Interestingly, we found in a patient two missense mutations: the already known p.Thr297Ile and the unknown p.Arg1525Gln. These two variants co-segregated with the pathology being present in all …
8
Nocturnal frontal lobe epilepsy (NFLE) is a focal epilepsystarting in childhood and persisting into young adulthood.Affected individuals are typically of normal intelligence, butrare cases with intellectual disability and⁄or psychiatricdisorders have been reported (Derry et al., 2008).Sporadic and familial forms of NFLE do not show clinicaldifferences (Combi et al., 2004). Mutations in genes encod-ing three subunits of the neuronal nicotinic acetylcholinereceptor and variations affecting the promoter of the geneencoding the corticotropin releasing hormone have beenassociated with autosomal dominant NFLE (ADNFLE)(Combi et al., 2004, 2005). These mutations are absent inthe majority of ADNFLE families and in nearly all sporadiccases. The proportion of cases caused by de novo mutationsis unknown (Hirose and Kurahashi, 2010).A mutation screening of CHRNA2, CHRNA4, CHRNB2and CRH genes has been performed in an Italian cohort of 28NFLE sporadic patients by sequencing the whole codingregion of each gene. All patients underwent a video-polysomnographic analysis and neurological examinationallowing the correct diagnosis of NFLE. All patients signedan informed consent and the study was approved by theinstitution ethical committee.The study allowed the identification of a c.851C>T muta-tion (numbering referred to ENST00000370263 sequence),resulting in a p.Ser284Leu substitution in the CHRNA4 gene.The mutation (dbSNP:rs28931591) was found as a missenseheterozygous in a single patient and absent in both parents.This is a 25-year-old woman of Italian origin with a negativefamily history for epilepsy and parasomnias. Segregation of30 highly polymorphic microsatellite markers spread acrossthe genome was in concordance with paternity and confirmedthat the mutation was originated de novo. From age 7 thepatient had nocturnal episodes while asleep, characterizedby a sudden elevation of the trunk generally associated withdystonic posturing of both arms. She had no memory of theepisodes, but was fully conscious at the end of the seizures.Seizures occurred almost every night and could last from10 to more than 60 s. She never complained of subjectivemanifestations either during sleep or during wakefulness.Seizures did not respond to different drugs in monotherapy orin association.Neurological examination and magnetic resonance imag-ing (MRI) were normal. Video-electroencephalographic(EEG) analysis showed the occurrence of ictal frontalrhythmic slow waves, more evident on the right side.The identified mutation was reported previously in threeADNFLE families (Cho et al., 2003; Hirose et al., 1999;Rozycka et al., 2003) and in a Lebanese woman diagnosedinitially as a sporadic case who subsequently had an affectedson (Phillips et al., 2000). However, the phenotype of thepresent NFLE case appears slightly different from the onereported previously for the p.Ser284Leu mutation: in fact, allprevious cases showed mental retardation or intellectualdisabilities(Choet al.,2003;Phillipset al.,2000),whilenormalintellectandgoodschoolperformanceweredocumentedinthepresent case. Conversely, no pathological variants wereidentified in the CRH, CHRNA2 and CHRNB2 genes.This study describes the first Italian NFLE case with aCHRNA4 mutation and contributes new data suggesting theopportunity of performing both genetic testing and counsel-ling for sporadic cases. Two observations are worthy of note:first, the patient with the CHRNA4 mutation has a typicalform of NFLE without particular distinctive clinical aspects;secondly, the CHRNA4 Ser284 seems to be a hot point formutation. This amino acid was indeed found mutated eitherto Phe or Leu and associated with a cytosine guaninedinucleotide (CpG) hypermutable site (Hwang et al., 2011).In conclusion, the present study highlights that all sporadiccases should be screened for de novo mutations in knownADNFLE genes with special focus at the CHRNA4 Ser284and that clinical data are of no help in evaluating theeffectiveness of a genetic test.DECLARATIONS OF INTERESTThe authors have received no personal compensation, noresearch support, no stocks, stock options and royalties, andhave not been involved in legal proceedings during the last2 years. None of the author has conflicts of interest on thispaper.Veronica Sansoni
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