scholarly journals ANGPTL6 genetic variants are an underlying cause of familial intracranial aneurysms

Neurology ◽  
2020 ◽  
pp. 10.1212/WNL.0000000000011125
Author(s):  
Isabel C Hostettler ◽  
Benjamin O’Callaghan ◽  
Enrico Bugiardini ◽  
Emer O’Connor ◽  
Jana Vandrovcova ◽  
...  
Keyword(s):  
Family History ◽  
Genetic Variants ◽  
Intracranial Aneurysms ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Small Subset ◽  
Missense Mutations ◽  
Class Iii ◽  
Exon 2 ◽  
History Of

Background and Purpose:To understand the role of the angiopoietin-like 6 gene (ANGPTL6) in intracranial aneurysms (IA) we investigated its role in a large cohort of familial IAs.Methods:Inclusion of individuals with family history of IA recruited to the Genetic and Observational Subarachnoid Haemorrhage (GOSH) study. The ANGPTL6 gene was sequenced using Sanger sequencing. Identified genetic variants were compared to a control population.Results:We found six rare ANGPTL6 genetic variants in 9/275 individuals with a family history of IA (3.3%), none of them were present in controls: Five missense and one nonsense mutation leading to a premature stop codon. One of these had been previously reported: c.392A>T (p.Glu131Val) on exon 2, another was very close: c.332G>A (p.Arg111His). Two further genetic variants lie within the fibrinogen-like domain of the ANGPTL6 gene, which may influence function or level of the ANGPTL6 protein. The last two missense mutations lie within the coiled-coil domain of the ANGPTL6 protein. All genetic variants were well conserved across species.Conclusion:ANGPTL6 genetic variants are an important cause of IA. Defective or lack of ANGPTL6 protein is therefore an important factor in blood vessel proliferation leading to IA; dysfunction of this protein is likely to cause abnormal proliferation or weakness of vessel walls. With these data, not only do we emphasise the importance of screening familial IA cases for ANGPTL6 and other genes involved in IA, but also highlight the ANGPTL6 pathway as a potential therapeutic target.Classification of Evidence:This is a Class III study showing some specificity of presence of the ANGPTL6 gene variant as a marker of familial intracranial aneurysms in a small subset of those with familial aneurysms.

Current implications for the efficacy of noninvasive screening for occult intracranial aneurysms in patients with a family history of aneurysms

1995 ◽  
Vol 83 (1) ◽  
pp. 42-49 ◽  
Author(s):  
Nancy A. Obuchowski ◽  
Michael T. Modic ◽  
Michele Magdinec
Keyword(s):  
Family History ◽  
Natural History ◽  
Life Expectancy ◽  
Intracranial Aneurysms ◽  
Positive Family History ◽  
Aneurysm Rupture ◽  
Average Life Expectancy ◽  
Content Type ◽  
Rupture Rate ◽  
History Of

✓ Although the technology exists for accurate noninvasive screening for intracranial aneurysms, the efficacy of screening depends on several key parameters of the natural history of aneurysms. Recent studies suggest that the prevalence of intracranial aneurysms may reach 20% in the subpopulation of patients with a family history of these lesions; other key parameters are less certain. The authors investigated factors that impact the efficacy of screening to establish interim guidelines. Three plausible models for the natural history of aneurysms were constructed. For each model the monetary cost of screening and the average gain in life expectancy were computed for a range of screening ages and prevalence rates. It is shown that the efficacy of screening depends on the pattern of aneurysm rupture. If aneurysms develop and rupture rapidly, then screening has no benefit. On the other hand, if aneurysms remain at risk for some time after formation, then screening may improve average life expectancy depending on when it occurs. The authors recommend that patients with a positive family history of aneurysms who are 30 years of age or younger be screened. This recommendation is based on the belief that the gains attributable to screening, assuming a constant rupture rate, outweigh the losses attributable to screening using a decreasing rupture rate model.

scholarly journals Exome Sequencing Identifies A Nonsense Variant in DAO Associated With Reduced Energy Expenditure in American Indians

2020 ◽  
Vol 105 (11) ◽  
Author(s):  
Paolo Piaggi ◽  
Çiğdem Köroğlu ◽  
Anup K Nair ◽  
Jeff Sutherland ◽  
Yunhua L Muller ◽  
...  
Keyword(s):  
Energy Expenditure ◽  
Exome Sequencing ◽  
American Indians ◽  
Genetic Variants ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Dopamine Synthesis ◽  
Acid Oxidase ◽  
Pima Indians ◽  
Amino Acid Oxidase

Abstract Background Obesity and energy expenditure (EE) are heritable and genetic variants influencing EE may contribute to the development of obesity. We sought to identify genetic variants that affect EE in American Indians, an ethnic group with high prevalence of obesity. Methods Whole-exome sequencing was performed in 373 healthy Pima Indians informative for 24-hour EE during energy balance. Genetic association analyses of all high-quality exonic variants (≥5 carriers) was performed, and those predicted to be damaging were prioritized. Results Rs752074397 introduces a premature stop codon (Cys264Ter) in DAO and demonstrated the strongest association for 24-hour EE, where the Ter allele associated with substantially lower 24-hour EE (mean lower by 268 kcal/d) and sleeping EE (by 135 kcal/d). The Ter allele has a frequency = 0.5% in Pima Indians, whereas is extremely rare in most other ethnic groups (frequency < 0.01%). In vitro functional analysis showed reduced protein levels for the truncated form of DAO consistent with increased protein degradation. DAO encodes D-amino acid oxidase, which is involved in dopamine synthesis which might explain its role in modulating EE. Conclusion Our results indicate that a nonsense mutation in DAO may influence EE in American Indians. Identification of variants that influence energy metabolism may lead to new pathways to treat human obesity. Clinical Trial Registration Number NCT00340132.

Mutations of TET2 and JAK2 but Not CBL Are Detectable in a High Portion of Patients with Refractory Anemia with Ring Sideroblasts and Thrombocytosis (RARS-T).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1766-1766
Author(s):  
Johanna Flach ◽  
Sonja Schindela ◽  
Frank Dicker ◽  
Susanne Schnittger ◽  
Alexander Kohlmann ◽  
...  
Keyword(s):  
Microarray Analysis ◽  
Stop Codon ◽  
Myeloproliferative Neoplasms ◽  
Premature Stop Codon ◽  
Jak2v617f Mutation ◽  
Refractory Anemia ◽  
Missense Mutations ◽  
Myeloid Malignancies ◽  
Ring Sideroblasts ◽  
Equity Ownership

Abstract Abstract 1766 Poster Board I-792 Refractory anemia with ring sideroblasts and thrombocytosis (RARS-T) forms a provisional entity within the category of MDS/MPN-U in the 2008 WHO classification. Although the identification of the JAK2V617F mutation was an important first step in distinguishing this entity from other hematological diseases, further genetic characterization is necessary. We performed comprehensive cytogenetic and molecular genetic investigations including targeted analysis of JAK2V617F, TET2, MPLW515 and CBL, markers known to be altered in MPN, as well as genome-wide single nucleotide polymorphism microarray analysis (SNP-A) in 23 RARS-T patients who fulfilled WHO 2008 diagnostic criteria. The JAK2V617F mutation was detectable in 15 out of 19 analyzed patients (78.9%), four of which were homozygous. However, our patients neither carried a MPLW515 mutation nor mutations in exons 8 or 9 of CBL genes. These genes were recently described to be mainly mutated in myeloproliferative neoplasms. In addition, conventional cytogenetic analysis did not reveal any recurrent cytogenetic abnormalities in RARS-T patients. We also performed SNP microarray analysis in a subset of 10 RARS-T patients. Although we did neither observe recurrent chromosomal gains or losses nor recurring regions of UPD, one patient showed a deletion spanning a 1.3 Mb region on the long arm of chromosome 4 (start: 105,497,200 bp from pter; end: 106,825,780 bp from pter). The deleted region contained TET2, a gene recently found to be altered in many subtypes of myeloid malignancies. To further clarify the 4q24 deletion detected by SNP-A analysis we performed fluorescence in situ hybridization (FISH). 20 out of 100 analyzed interphase nuclei and three metaphases showed only one signal for the probe spanning the TET2 gene in this patient. Interphase FISH with the TET2 probe was performed in nine additional cases not analyzed by SNP arrays due to a lack of material, but no additional case showing a deletion was detected. In addition to FISH, we performed TET2 sequencing in 19/23 RARS-T patients. TET2 mutations were detected in 5/19 patients (26%), of which 3/5 also presented the JAK2V617F mutation, whereas the remaining 2/5 did neither show JAK2V617F nor MPL nor CBL mutations. The five patients showed 6 individually different TET2 mutations. Three were nonsense and two missense mutations. One patient displayed a frameshift mutation leading to a premature stop codon. In summary, RARS-T patients demonstrated a high frequency of both JAK2 and TET2 mutations. Together with the less common MPL mutations described by others RARS-T presents a variety of mutations that overlap with the spectrum of mutations seen in MPN and other myeloid malignancies. Thus, a combination of molecular markers including JAK2 and TET2 should be investigated to more precisely describe RARS-T as an independent disease entity. Disclosures Flach: MLL Munich Leukemia Laboratory: Employment. Schindela:MLL Munich Leukemia Laboratory: Employment. Dicker:MLL Munich Leukemia Laboratory: Employment. Schnittger:MLL Munich Leukemia Laboratory: Equity Ownership. Kohlmann:MLL Munich Leukemia Laboratory: Employment. Weiss:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership.

scholarly journals A new mutation at exon 2 of hprt1 locus causing Lesch-Nyhan Syndrome.

2015 ◽  
Vol 3 (1) ◽  
pp. 18-21
Author(s):  
Adriana María Gil Zapata ◽  
Adriana Castillo Pico ◽  
Leonor Gusmão ◽  
António Amorim ◽  
Fernando Rodríguez Sanabria
Keyword(s):  
Genetic Counseling ◽  
Inborn Error ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Dna Fragments ◽  
Hprt Gene ◽  
New Mutation ◽  
Exon 2 ◽  
The Family ◽  
Hypoxanthine Guanine Phosphoribosyl Transferase

Introduction: Lesch-Nyhan síndrome (LNS) is an X-linked recessive inborn error of metabolism, due to deficiency of the enzyme Hypoxanthine-guanine-phosphoribosyl transferase (HGPRT; EC.2.4.2.8) resulting in hyperuricemia, neurological and behavioural disturbances. In the present work, we report the results of the study of a Colombian family, where LNS was previously clinically and biochemically diagnosed. Material and Methods: The full HPRT gene, including 9 exons and 8 introns, was amplified on eight separate DNA fragments. Both strands, forward and reverse, of the amplified DNA fragments were analyzed and the obtained sequences were compared with those deposited at National Center for Biotechnology Information. Results and conclusions: Sequence analysis allowed the detection of new LNS causing mutation, an adenine deletion in exon 2 of HPRT1 gene resulting in a frameshift which determines a premature stop codon. This study, besides adding a new mutation to the already large spectrum of disease causing variation at HPRT, allows therefore providing genetic counseling for the family as well as prenatal diagnosis.

scholarly journals Erratum: clinical and molecular characteristics of patients with 46,xy dsd due to nr5a1 gene mutations (Probl Endokrinol (Mosk). 2020 Sep 16;66(3):62-69. Russian. doi: 10.14341/probl12445)

2021 ◽  
Vol 67 (6) ◽  
pp. 124-126
Author(s):  
N. Yu. Kalinchenko ◽  
A. A. Kolodkina ◽  
N. Yu. Raygorodskaya ◽  
A. N. Tiulpakov
Keyword(s):  
Stop Codon ◽  
Premature Stop Codon ◽  
Gene Mutations ◽  
Synonymous Substitution ◽  
Molecular Characteristics ◽  
Missense Mutations ◽  
Reading Frame ◽  
Splicing Site

n the article some corrections were needed. Abstract: “Heterozygous SF1 variants were found in 36 out of 310 (11.6%) of cases, among them 15 were not previously described”. has been corrected to read “Heterozygous SF1 variants were found in 36 out of 310 (11.6%) of cases, among them 22 were not previously described”. Results: “Heterozygous SF1 variants were found in 36 out of 310 (11.6%) of cases, among them 15 were not previously described”, has been corrected to read “Heterozygous SF1 variants were found in 36 out of 310 (11.6%) of cases, among them 22 were not previously described”. Among the newly identified variants in the NR1A1 gene, two lead to the premature stop codon -p. Y197X and p. Y25X, two lead to a shift in the reading frame-p. N385fs and p. L245fs, which does not allow us to doubt their pathogenicityAmong the previously undescribed variant changes, 5 missense mutations (p. C283Y, p. C283B, p.H24Q, p.M126K, p.E81K) and 1  synonymous substitution affecting the splicing site (E330E) were evaluated as pathogenic, and 5 others as probably pathogenic.Has been corrected to read: Among the newly identified variants in the NR1A1 gene, two lead to the premature stop codon -p. Y197X and p. Y25X, two lead to a shift in the reading frame — p.N385SfsX10 and p.L245AfsX53, which does not allow us to doubt their pathogenicity Among the previously undescribed variants, 5 missense mutations (p.C283Y, p.С283F, p.H24Q, p.M126K, p.A82T) and 1 synonymous substitution affecting the splicing site (E330E) were predicted as pathogenic, and 5 others as probably pathogenic by calculating pathogenicity. The authors apologize for these errors. 

scholarly journals Genetic variants associated with addictive behavior in Colombian addicted and non-addicted to heroin or cocaine

2013 ◽  
pp. 19-25 ◽  
Author(s):  
Carlos Isaza ◽  
Julieta Henao ◽  
Leonardo Beltrán ◽  
Liliana Porras-Hurtado ◽  
Martha Gonzalez ◽  
...  
Keyword(s):  
Substance Abuse ◽  
Family History ◽  
Genetic Variants ◽  
Illicit Drugs ◽  
Age Of Onset ◽  
Addictive Behavior ◽  
Control Group ◽  
Abcb1 Gene ◽  
History Of ◽  
Pcr Techniques

Objective: Determine the prevalence and compare some genetic markers involved in addictive behavior in agroup of addicts to derivative of coca (cocaine/crack) or heroin and a control group of non-addicted peoplematched for gender, age and ethnicity. Methods: A 120 addicts and 120 non-addicts Colombian male were surveyed and genotyped for 18 polymorphismof the OPRM1, DRD2, DRD4, SLC6A3, SLC6A4, ABCB1, DβH and CYP2B6 genes. For the identificationof alleles markers were used mini-sequencing and fragment multiplex PCR techniques; ethnicity of cases and controls was analyzed with 61 AIMs. Results: The age of onset use of heroin or coca derivatives (cocaine/crack) was 16.5±6 yrs and 99.2% of them consume several illicit drugs. It showed that controls and addicts belong to the same ethnic group. Significant differences between addicts and controls in relation to schooling, marital status, social security family history of substance abuse (p<0.001), Int8-VNTR SLC6A3 gene (p= 0.015) and SNP 3435C>T ABCB1 gene (p= 0.001)were found. Conclusion: The present results indicate that the VNTR-6R polymorphism of the gene SLC6A3 and the genotype 3435CC in the ABCB1 gene, are both associated with addictive behavior to heroin or cocaine.

GATA1 Mutations in Clonal Disorders of Children with and without Down Syndrome.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4314-4314
Author(s):  
Isis Q. Magalhaes ◽  
Alessandra Splendore ◽  
Mariana Emerenciano ◽  
Iris Ferrari ◽  
Maria S. Pombo-de-Oliveira
Keyword(s):  
Down Syndrome ◽  
Trisomy 21 ◽  
Genomic Dna ◽  
Stop Codon ◽  
Pediatric Population ◽  
Premature Stop Codon ◽  
Genetic Changes ◽  
Exon 2 ◽  
Gata1 Mutation ◽  
Proliferative Advantage

Abstract Down Syndrome (DS) children are 10–20 times folder likely to develop acute leukemia (AL) within the first four years of life compared to general pediatric population. Recently acquired somatic mutations in GATA1 gene on chromosome X have been described in most cases of DS AML and congenital TMD of DS carry the same type of mutations in exon 2 of GATA1. Here we report the preliminary results of GATA1 mutation in AL with and without DS children. The aim of this study is to provide insights in the relationships of GATA1 mutations and trisomy 21 in leukemogenesis process. GATA1 mutations were assayed in genomic DNA in 34 children with DS and AL, 2 with transient myeloproliferative disorder (TMD), 3 with myelodisplastic syndrome. Sequential sample including 2 pre-diagnosis in neonate period and 1 year before diagnosis were available in two children and 40 randomly selected DS children without known hematological disorder. A rare case of a non-DS neonate with TMD and clonal trisomy 21 were also examined. Genomic DNA was extracted and the exon 2 of GATA1 was PCR amplified as described by Wechsler et al. PCR products were sequenced in both directions and analyzed in a MegaBACE 1000 automated sequencer. Presently, GATA 1 mutations were found in 7 cases of AL, in all TMD cases with DS and none MDS case of DS. Interesting, a neonate girl with no phenotypic features of DS, but TMD features whose karyotype revealed 47, XX, +21/46, XX mosaics. A G-to-T transversion was detected which is predicted to result in a premature stop codon (c.119G>T; p.Glu67X) at the time of onset of TMD. However this same mutation was not detcted at 5 years of age.To our knowledge, this is the first reported case of TMD without DS with a detected GATA1 mutation. The presence of both somatically acquired abnormalities probably confers a proliferative advantage to the cell, resulting in TMD. We postulated in this case that both genetic abnormalities were temporary because of the non self-renewing nature of the progenitor that first had a non-disjunction event and this progenitor and the proliferative clone eventually disappeared. Therefore, even the proliferative advantage that the combination of trisomy 21 and GATA1 mutation confer, maintenance of these genetic changes are necessary for full leukemic transformation and persistence.

Mutations in Apoptosis-related Gene, PDCD10, Cause Cerebral Cavernous Malformation 3

Neurosurgery ◽  
2005 ◽  
Vol 57 (5) ◽  
pp. 1008-1013 ◽  
Author(s):  
Bulent Guclu ◽  
Ali K. Ozturk ◽  
Katie L. Pricola ◽  
Kaya Bilguvar ◽  
Dana Shin ◽  
...  
Keyword(s):  
Family History ◽  
High Throughput Screening ◽  
Stop Codon ◽  
Positive Family History ◽  
Linkage Data ◽  
Cavernous Malformations ◽  
History Of ◽  
Temperature Gradient Capillary Electrophoresis ◽  
Exon 9 ◽  
Molecular Pathophysiology

Abstract OBJECTIVE: To identify the CCM3 gene in a population of 61 families with a positive family history of cerebral cavernous malformations (CCM), 8 of which had suggestive linkage to the CCM3 locus. METHODS: We searched for mutations within the CCM3 interval using a high-throughput screening technique, temperature-gradient capillary electrophoresis. Mutations detected by this device were subsequently sequenced, and the results were analyzed. RESULTS: A recent study by Bergametti et al. established Programmed Cell Death 10 (PDCD10) as the gene responsible for CCM3. We hereby confirm PDCD10 as the CCM3 gene by reporting four novel mutations in 61 CCM families. Two of these mutations were identical and produced a stop codon in exon 7. Another two resulted in frameshift mutations in exon 6, although the mutations occurred at different points along the exon. The last mutation caused a frameshift in exon 9. Of note, mutations in these families completely cosegregated with the trait. Three of the five families had prior linkage data suggestive of the CCM3 locus, whereas the remaining two were identified in index patients with a positive family history but no linkage data. CONCLUSION: Our data establish PDCD10 as the gene responsible for CCM in families linking to the CCM3 locus. The discovery of the third gene involved in inherited forms of CCM, after KRIT1 and Malcavernin, is an important step toward dissecting the molecular pathophysiology of this disease.

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