scholarly journals Comprehensive Analysis of LIN28A in Chinese Patients With Early Onset Parkinson’s Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiaojing Gu ◽  
Yanbing Hou ◽  
Yongping Chen ◽  
Ruwei Ou ◽  
Bei Cao ◽  
...  
Keyword(s):  
Early Onset ◽  
Chinese Patient ◽  
Chinese Patients ◽  
Loss Of Function ◽  
Developmental Defects ◽  
Functional Studies ◽  
Whole Exome ◽  
Increased Risk ◽  
Related Phenotype ◽  
Early Onset Parkinson’S Disease

A loss-of-function variant in Lin-28 Homolog A gene (LIN28A p. R192G, rs558060339) has been identified in two East Asian ancestry patients with early-onset PD (EOPD). Functional studies revealed that such a variant could lead to developmental defects and PD-related phenotype, and the phenotypes could be rescued after correction of the variant. The aim of the study was to screen the variants of LIN28A in Chinese patients with EOPD. A total of 682 EOPD patients were sequenced with whole exome sequencing and the coding and flanking region of LIN28A were analyzed. We identified a rare coding variant, p. P182L, of LIN28A in a Chinese patient with EOPD. Moreover, we also found a 3′-UTR polymorphism (rs4659441) to be associated with an increased risk for PD. However, our rare variant burden analysis did not support a role for LIN28A as a major causal gene for PD.

scholarly journals Comprehensive Analysis of LIN28A in Chinese Patients with Early Onset Parkinson’s Disease

2021 ◽  
Author(s):  
Xiaojing Gu ◽  
Yanbing Hou ◽  
Yongping Chen ◽  
Ruwei Ou ◽  
Bei Cao ◽  
...  
Keyword(s):  
Early Onset ◽  
Chinese Patient ◽  
Chinese Patients ◽  
Loss Of Function ◽  
Developmental Defects ◽  
Functional Studies ◽  
Whole Exome ◽  
Increased Risk ◽  
Related Phenotype ◽  
Early Onset Parkinson’S Disease

Abstract A loss-of-function variant in Lin-28 Homolog A gene (LIN28A p.R192G, rs558060339) has been identified in two East Asian ancestry patients with early-onset PD (EOPD). Functional studies revealed that such variant could lead to developmental defects and PD-related phenotype, and the phenotypes could be rescued after correction of the variant. The aim of the study was to screen the variants of LIN28A in Chinese patients with EOPD. A total of 682 EOPD patients were sequenced with whole exome sequencing and the coding and flanking region of LIN28A were analyzed. We identified a rare coding variant-p.P182L of LIN28A in a Chinese patient with EOPD. Moreover, we also found a 3’-UTR polymorphism(rs4659441) to be associated with an increased risk for PD. However, our rare variant burden analysis did not support a role for LIN28A as a major causal gene for PD.

scholarly journals CARMIL2 Deficiency Presenting as Very Early Onset Inflammatory Bowel Disease

2019 ◽  
Vol 25 (11) ◽  
pp. 1788-1795 ◽  
Author(s):  
Thomas Magg ◽  
Anna Shcherbina ◽  
Duran Arslan ◽  
Mukesh M Desai ◽  
Sarah Wall ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Early Onset ◽  
Mononuclear Cells ◽  
Severe Disease ◽  
Effector Memory ◽  
Loss Of Function ◽  
Peripheral Blood Mononuclear ◽  
Whole Exome ◽  
Inflammatory Bowel

Abstract Background Children with very early onset inflammatory bowel diseases (VEO-IBD) often have a refractory and severe disease course. A significant number of described VEO-IBD-causing monogenic disorders can be attributed to defects in immune-related genes. The diagnosis of the underlying primary immunodeficiency (PID) often has critical implications for the treatment of patients with IBD-like phenotypes. Methods To identify the molecular etiology in 5 patients from 3 unrelated kindred with IBD-like symptoms, we conducted whole exome sequencing. Immune workup confirmed an underlying PID. Results Whole exome sequencing revealed 3 novel CARMIL2 loss-of-function mutations in our patients. Immunophenotyping of peripheral blood mononuclear cells showed reduction of regulatory and effector memory T cells and impaired B cell class switching. The T cell proliferation and activation assays confirmed defective responses to CD28 costimulation, consistent with CARMIL2 deficiency. Conclusion Our study highlights that human CARMIL2 deficiency can manifest with IBD-like symptoms. This example illustrates that early diagnosis of underlying PID is crucial for the treatment and prognosis of children with VEO-IBD.

scholarly journals Phosphodiesterase 2A and 3B variants are associated with primary aldosteronism

2021 ◽  
Vol 28 (1) ◽  
pp. 1-13
Author(s):  
Marcela Rassi-Cruz ◽  
Andrea G Maria ◽  
Fabio R Faucz ◽  
Edra London ◽  
Leticia A P Vilela ◽  
...  
Keyword(s):  
Primary Aldosteronism ◽  
Early Onset ◽  
Zona Glomerulosa ◽  
Unilateral Adrenalectomy ◽  
Transfected Cells ◽  
Functional Studies ◽  
Protein Levels ◽  
Whole Exome ◽  
Hyperplastic Tissue ◽  
Bilateral Adrenal Hyperplasia

Abstract Familial primary aldosteronism (PA) is rare and mostly diagnosed in early-onset hypertension (HT). However, ‘sporadic’ bilateral adrenal hyperplasia (BAH) is the most frequent cause of PA and remains without genetic etiology in most cases. Our aim was to investigate new genetic defects associated with BAH and PA. We performed whole-exome sequencing (paired blood and adrenal tissue) in six patients with PA caused by BAH that underwent unilateral adrenalectomy. Additionally, we conducted functional studies in adrenal hyperplastic tissue and transfected cells to confirm the pathogenicity of the identified genetic variants. Rare germline variants in phosphodiesterase 2A (PDE2A) and 3B (PDE3B) genes were identified in three patients. The PDE2A heterozygous variant (p.Ile629Val) was identified in a patient with BAH and early-onset HT at 13 years of age. Two PDE3B heterozygous variants (p.Arg217Gln and p.Gly392Val) were identified in patients with BAH and HT diagnosed at 18 and 33 years of age, respectively. A strong PDE2A staining was found in all cases of BAH in zona glomerulosa and/or micronodules (that were also positive for CYP11B2). PKA activity in frozen tissue was significantly higher in BAH from patients harboring PDE2A and PDE3B variants. PDE2A and PDE3B variants significantly reduced protein expression in mutant transfected cells compared to WT. Interestingly, PDE2A and PDE3B variants increased SGK1 and SCNN1G/ENaCg at mRNA or protein levels. In conclusion, PDE2A and PDE3B variants were associated with PA caused by BAH. These novel genetic findings expand the spectrum of genetic etiologies of PA.

scholarly journals The clinical, immunological and genetic features of 12 Chinese patients with STAT3 mutation

2020 ◽  
Author(s):  
Li Lin ◽  
Ying Wang ◽  
Bijun Sun ◽  
Luyao Liu ◽  
Wenjing Ying ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Immunoglobulin E ◽  
Clinical Symptoms ◽  
Elevated Serum ◽  
Chinese Patients ◽  
Onset Age ◽  
Loss Of Function ◽  
Peripheral Blood Mononuclear ◽  
Whole Exome ◽  
Genetic Features

Abstract Background: Loss-of-function (LOF) mutation in signal transducer and activator of transcription 3 (STAT3) was one of the causes of the hyper immunoglobulin E (IgE) syndrome (HIES), while gain-of-function mutation (GOF) in STAT3 leads to immune dysregulation diseases. We retrospectively report 11 LOF STAT3 patients and 1 GOF STAT3 patient and illustrate their onset age, common clinical symptoms, immunologic and molecular manifestation. Methods: 12 patients were enrolled in our study. Serum immunoglobulins, lymphocyte subset detection and whole-exome sequencing were performed. Results: The median onset age of STAT3-deficient patients was 1.89 years. Eczema, recurrent respiratory infection, apparent fever, abscesses and Staphylococcus aureus infection was the classical manifestation. Elevated serum IgE level is not entirely unanimous with high eosinophils counts. Moderate viral DNA was also measured in peripheral blood mononuclear cells. We noticed that c. 1144C>T was the most common spot, followed by c.1311C>A. Additionally, c.1311C>A and c. 1826G>C are two novel mutations. Eight patients obtained a notable improvement after received intravenous immunoglobulin (IVIG). Conclusion: We believe IVIG may help reduce the opportunity of infection in STAT3-deficient patients. Significant variance at onset age probably is a great challenge for clinicians and urgently needs early diagnosis and treatment.

scholarly journals Biallelic DAB1 Variants Are Associated With Mild Lissencephaly and Cerebellar Hypoplasia

2021 ◽  
Vol 7 (2) ◽  
pp. e558
Author(s):  
Daphne J. Smits ◽  
Rachel Schot ◽  
Martina Wilke ◽  
Marjon van Slegtenhorst ◽  
Marie Claire Y. de Wit ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Splice Variants ◽  
Brain Mri ◽  
Cerebellar Vermis ◽  
Compound Heterozygous ◽  
Loss Of Function ◽  
Functional Studies ◽  
Pathogenic Variants ◽  
Whole Exome

ObjectiveWe aimed to identify pathogenic variants in a girl with epilepsy, developmental delay, cerebellar ataxia, oral motor difficulty, and structural brain abnormalities with the use of whole-exome sequencing.MethodsWhole-exome trio analysis and molecular functional studies were performed in addition to the clinical findings and neuroimaging studies.ResultsBrain MRI showed mild pachygyria, hypoplasia of the cerebellar vermis, and abnormal foliation of the cerebellar vermis, suspected for a variant in one of the genes of the Reelin pathway. Trio whole-exome sequencing and additional functional studies were performed to identify the pathogenic variants. Trio whole-exome sequencing revealed compound heterozygous splice variants in DAB1, both affecting the highly conserved functional phosphotyrosine-binding domain. Expression studies in patient-derived cells showed loss of normal transcripts, confirming pathogenicity.ConclusionsWe conclude that these variants are very likely causally related to the cerebral phenotype and propose to consider loss-of-function DAB1 variants in patients with RELN-like cortical malformations.

scholarly journals A Novel Loss-of-Function MKRN3 Variant in a Chinese Patient With Familial Precocious Puberty: A Case Report and Functional Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Xueling Yin ◽  
Junqi Wang ◽  
Tianting Han ◽  
Zhang Tingting ◽  
Yuhong Li ◽  
...  
Keyword(s):  
Case Report ◽  
Precocious Puberty ◽  
Transcriptional Activity ◽  
Central Precocious Puberty ◽  
Chinese Patient ◽  
Functional Study ◽  
Loss Of Function ◽  
Pediatric Endocrinology ◽  
Functional Studies ◽  
Clinical Pediatric

Background: Central precocious puberty (CPP) is one of the most common and complex problems in clinical pediatric endocrinology practice. Mutation of the MKRN3 gene can cause familial CPP.Methods and Results: Here we reported a Chinese patient bearing a novel MKRN3 mutation (c.G277A/p.Gly93Ser) and showing the CPP phenotype. Functional studies found that this mutation of MKRN3 attenuated its autoubiquitination, degradation, and inhibition on the transcriptional activity of GNRH1, KISS1, and TAC3 promoters.Conclusion: MKRN3 (Gly93Ser) is a loss-of-function mutation, which attenuates the inhibition on GnRH1-related signaling, suggesting that this mutant can lead to central precocious puberty.

Presenilin 1 and APP Gene Mutations in Early-Onset AD Families from a Southeast Region of China

2020 ◽  
Vol 17 (6) ◽  
pp. 540-546
Author(s):  
Jiajia Zhou ◽  
Yi Chen ◽  
Fanxia Meng ◽  
Kan Zhang ◽  
Xiaoyan Liu ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Early Onset ◽  
Chinese Population ◽  
Gene Mutations ◽  
Splice Mutation ◽  
Chinese Patients ◽  
Presenilin 1 ◽  
Whole Exome ◽  
Presenilin 2 ◽  
App Gene

Background: Early-Onset Familial Alzheimer’s Disease (EOFAD) has been reported to be associated with Presenilin 1 (PSEN1), Presenilin 2 (PSEN2), and Amyloid Precursor Protein (APP) genes. The spectrum of mutations in Chinese patients with EOFAD was rarely investigated. Objective: To investigate the spectrum of mutations in patients with EOFAD in Chinese population. Methods: We performed whole-exome sequencing and described relevant clinical features in a total of 67 subjects from 3 families with EOFAD. Results: A splice mutation (p.S290C) in PSEN1 and a missense mutation (p.V717I) in APP were identified. Conclusion: The variant p. S290C (c.869-2>G) in PSEN1 in Chinese EOAD family revealed different clinical phenotypes when compared with that of Europeans.

scholarly journals Loss of function mutations in CCDC32 cause a congenital syndrome characterized by craniofacial, cardiac and neurodevelopmental anomalies

2020 ◽  
Vol 29 (9) ◽  
pp. 1489-1497 ◽  
Author(s):  
Tamar Harel ◽  
John N Griffin ◽  
Thomas Arbogast ◽  
Tanner O Monroe ◽  
Flavia Palombo ◽  
...  
Keyword(s):  
Molecular Basis ◽  
Congenital Malformations ◽  
Mammalian Cell Culture ◽  
Zebrafish Embryos ◽  
Loss Of Function ◽  
Zebrafish Model ◽  
Functional Studies ◽  
Whole Exome ◽  
Cilia Formation ◽  
Congenital Syndrome

Abstract Despite the wide use of genomics to investigate the molecular basis of rare congenital malformations, a significant fraction of patients remains bereft of diagnosis. As part of our continuous effort to recruit and perform genomic and functional studies on such cohorts, we investigated the genetic and mechanistic cause of disease in two independent consanguineous families affected by overlapping craniofacial, cardiac, laterality and neurodevelopmental anomalies. Using whole exome sequencing, we identified homozygous frameshift CCDC32 variants in three affected individuals. Functional analysis in a zebrafish model revealed that ccdc32 depletion recapitulates the human phenotypes. Because some of the patient phenotypes overlap defects common to ciliopathies, we asked if loss of CCDC32 might contribute to the dysfunction of this organelle. Consistent with this hypothesis, we show that ccdc32 is required for normal cilia formation in zebrafish embryos and mammalian cell culture, arguing that ciliary defects are at least partially involved in the pathomechanism of this disorder.

scholarly journals Whole-exome sequencing identifies multiple loss-of-function mutations of NF-κB pathway regulators in nasopharyngeal carcinoma

2016 ◽  
Vol 113 (40) ◽  
pp. 11283-11288 ◽  
Author(s):  
Hong Zheng ◽  
Wei Dai ◽  
Arthur Kwok Leung Cheung ◽  
Josephine Mun Yee Ko ◽  
Rebecca Kan ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Somatic Mutations ◽  
Cytidine Deaminase ◽  
Cycle Phase ◽  
Loss Of Function ◽  
Functional Studies ◽  
Whole Exome ◽  
Multiple Loss

Nasopharyngeal carcinoma (NPC) is an epithelial malignancy with a unique geographical distribution. The genomic abnormalities leading to NPC pathogenesis remain unclear. In total, 135 NPC tumors were examined to characterize the mutational landscape using whole-exome sequencing and targeted resequencing. An APOBEC cytidine deaminase mutagenesis signature was revealed in the somatic mutations. Noticeably, multiple loss-of-function mutations were identified in several NF-κB signaling negative regulators NFKBIA, CYLD, and TNFAIP3. Functional studies confirmed that inhibition of NFKBIA had a significant impact on NF-κB activity and NPC cell growth. The identified loss-of-function mutations in NFKBIA leading to protein truncation contributed to the altered NF-κB activity, which is critical for NPC tumorigenesis. In addition, somatic mutations were found in several cancer-relevant pathways, including cell cycle-phase transition, cell death, EBV infection, and viral carcinogenesis. These data provide an enhanced road map for understanding the molecular basis underlying NPC.

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