Investigating diagnostic sequencing techniques for CADASIL diagnosis

Dunn, Paul J.; Maksemous, Neven; Smith, Robert A.; Sutherland, Heidi G.; Haupt, Larisa M.; Griffiths, Lyn R.

doi:10.1186/s40246-019-0255-x

Cited by 14 publications

(11 citation statements)

References 58 publications

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“…Among the non-AD risk genes, such as Notch Receptor 3 ( NOTCH3 ), Leucine-rich repeat kinase 2 ( LRRK2 ), and microtubule-associated protein tau ( MAPT ), several variants appeared, too. A rare mutation, Leu1518Met, was observed in NOTCH3 , but its role in neurodegenerative diseases remained unclear [ 18 ]. Additionally, a common variant was observed in MAPT (Tyr441His), and three common variants appeared in LRRK2 (Arg50His, Ser1647Thr, and Met2397Thr) ( Supplementary Table S2 ).…”

Section: Resultsmentioning

confidence: 99%

PSEN2 Thr421Met Mutation in a Patient with Early Onset Alzheimer’s Disease

Yang

Bagyinszky

et al. 2022

IJMS

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Presenilin-2 (PSEN2) mutation Thr421Met was identified from a 57-years old patient with early onset Alzheimer’s disease (EOAD) for the first time in Korea. Previously, this mutation was discovered in an EOAD patient in Japan without a change on amyloid production from the cellular study. Both Korean and Japanese patients developed the disease in their 50s. Memory loss was prominent in both cases, but no additional clinical information was available on the Japanese patient. Magnetic resonance imaging (MRI) images of the Korean patient revealed asymmetric atrophies in both temporo-parietal lobes. In addition, amyloid positron emission tomography (PET) also revealed amyloid deposits in the gray matter of the temporo-parietal lobes asymmetrically. PSEN2 Thr421 was conserved among a majority of vertebrates (such as zebras, elephants, and giant pandas); hence, Thr421 could play an important role in its functions and any mutations could cause detrimental ramifications in its interactions. Interestingly, PSEN2 Thr421 could have homology with PSEN1 Thr440, as PSEN1 T440del mutations were reported from patients with AD or dementia with Lewy bodies. Hence, the changed amino acid from threonine to methionine of PSEN2 Thr421 could cause significant structural alterations in causing local protein dynamics, leading to its pathogenicity in EOAD. Lastly, PSEN2 Thr421Met may interact with other mutations in neurodegenerative disease related genes, which were found in the proband patient, such as ATP binding cassette subfamily A member 7 (ABCA7), Notch Receptor 3 (NOTCH3), or Leucine-rich repeat kinase 2 (LRRK2). These interactions of pathway networks among PSEN2 and other disease risk factors could be responsible for the disease phenotype through other pathways. For example, PSEN2 and ABCA7 may impact amyloid processing and reduce amyloid clearance. Interaction between PSEN2 and NOTCH3 variants may be associated with abnormal NOTCH signaling and a lower degree of neuroprotection. Along with LRRK2 variants, PSEN2 Thr421Met may impact neurodegeneration through Wnt related pathways. In the future, cellular studies of more than one mutation by CRISPR-Cas9 method along with biomarker profiles could be helpful to understand the complicated pathways.

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Section: Resultsmentioning

confidence: 99%

PSEN2 Thr421Met Mutation in a Patient with Early Onset Alzheimer’s Disease

Yang

Bagyinszky

et al. 2022

IJMS

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“…These findings suggest that Notch1 and Hes1 molecules are potential biomarkers for mild and moderate/severe TB, providing a basis for adjunctive diagnosis and monitoring of disease efficacy. Previous research has identified Notch3 as a diagnostic marker for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) ( 32 , 33 ), while DLL1 has shown utility in diagnosing tuberculous meningitis ( 12 ). Although no other Notch signaling molecules have been identified as biomarkers for other diseases, the regulation of immune cells function and cytokines secretion by Notch signaling molecules can affect the outcome of TB disease.…”

Section: Discussionmentioning

confidence: 99%

The potential value of Notch1 and DLL1 in the diagnosis and prognosis of patients with active TB

Xie

Chen

et al. 2023

Front. Immunol.

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ObjectivesThe Notch signaling pathway has been implicated in the pathogenesis of active tuberculosis (TB), and Th1-type cell-mediated immunity is essential for effective control of mycobacterial infection. However, it remains unclear whether Notch signaling molecules (Notch1, DLL1, and Hes1) and Th1-type factors (T-bet and IFN-γ) can serve as biomarkers for tracking the progression of active TB at different stages along with peripheral blood white blood cell (WBC) parameters.MethodsA total of 60 participants were enrolled in the study, including 37 confirmed TB patients (mild (n=17), moderate/severe (n=20)) and 23 healthy controls. The mRNA expression of Notch1, DLL1, Hes1, T-bet and IFN-γ in the peripheral blood mononuclear cells (PBMCs) of the subjects was measured by RT-qPCR, then analyzed for differences. Receiver Operating Characteristic curve (ROC) was used to assess the effectiveness of each factor as a biomarker in identifying lung injury.ResultsWe found that mRNA expression levels of Notch1, DLL1, and Hes1 were upregulated in active TB patients, with higher levels observed in those with moderate/severe TB than those with mild TB or without TB. In contrast, mRNA levels of T-bet and IFN-γ were downregulated and significantly lower in mild and moderate/severe cases. Furthermore, the combiROC analysis of IFN-γ and the percentage of lymphocytes (L%) among WBC parameters showed superior discriminatory ability compared to other factors for identifying individuals with active TB versus healthy individuals. Notably, Notch pathway molecules were more effective than Th1-type factors and WBC parameters in differentiating mild and moderate/severe cases of active TB, particularly in the combiROC model that included Notch1 and Hes1.ConclusionsOur study demonstrated that Notch1, Hes1, IFN-γ, and L% can be used as biomarkers to identify different stages of active TB patients and to monitor the effectiveness of treatment.

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“…NGS allows for millions of small fragments of DNA to be sequenced at once, allowing for entire gene sets or even the whole genome to be investigated, rather than targeted exons or regions. 15,62,63 Several research groups have reported increased diagnostic rates for several neurological diseases, through the use of whole exome sequencing (WES) [64][65][66] and targeted gene panels. [67][68][69] WES analysis has shown that not all suspected HM cases have exonic mutations in the known FHM genes, 30,31 or genes that cause overlapping disorders, which suggests that additional genes or other factors as yet unknown are causative of HM, 12 some of which may be revealed through WES or whole genome sequencing and structural analysis.…”

Section: Hemiplegic Migrainementioning

confidence: 99%

Exploring the Hereditary Nature of Migraine

Bron¹,

Sutherland²,

Griffiths³

2021

NDT

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Migraine is a common neurological disorder which affects 15-20% of the population; it has a high socioeconomic impact through treatment and loss of productivity. Current forms of diagnosis are primarily clinical and can be difficult owing to comorbidity and symptom overlap with other neurological disorders. As such, there is a need for better diagnostic tools in the form of genetic testing. Migraine is a complex disorder, encompassing various subtypes, and has a large genetic component. Genetic studies conducted on rare monogenic subtypes, including familial hemiplegic migraine, have led to insights into its pathogenesis via identification of causal mutations in three genes (CACNA1A, ATP1A2 and SCN1A) that are involved in transport of ions at synapses and glutamatergic transmission. Study of familial migraine with aura pedigrees has also revealed other causal genes for monogenic forms of migraine. With respect to the more common polygenic form of migraine, large genome-wide association studies have increased our understanding of the genes, pathways and mechanisms involved in susceptibility, which are largely involved in neuronal and vascular functions. Given the preponderance of female migraineurs (3:1), there is evidence to suggest that hormonal or X-linked components can also contribute to migraine, and the role of genetic variants in mitochondrial DNA in migraine has been another avenue of exploration. Epigenetic studies of migraine have shown links between hormonal variation and alterations in DNA methylation and gene expression. While there is an abundance of preliminary studies identifying many potentially causative migraine genes and pathways, more comprehensive genomic and functional analysis to better understand mechanisms may aid in better diagnostic and treatment outcomes.

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Investigating diagnostic sequencing techniques for CADASIL diagnosis

Cited by 14 publications

References 58 publications

PSEN2 Thr421Met Mutation in a Patient with Early Onset Alzheimer’s Disease

PSEN2 Thr421Met Mutation in a Patient with Early Onset Alzheimer’s Disease

The potential value of Notch1 and DLL1 in the diagnosis and prognosis of patients with active TB

Exploring the Hereditary Nature of Migraine

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