scholarly journals SUN-916 Novel Germline p.Gly42Arg MEN1 Missense Mutation in a Family Harboring Very Aggressive Pancreatic Tumor, Hyperparathyroidism and Pituitary Tumor

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Luciana Ansaneli Naves ◽  
Lidiana B Santana ◽  
Isabella Santiago M Miranda ◽  
Isabella Naves Rosa ◽  
Pedro G Mesquita ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Pituitary Tumor ◽  
Variant Calling ◽  
Read Depth ◽  
Test Method ◽  
Missense Mutations ◽  
Inherited Disease ◽  
Exon 2 ◽  
Men 1 ◽  
Large Deletions

Abstract Background.Pancreatic neuroendocrine tumors ocurs in 30-80% of patients with MEN-1, and may be non-functioning and hormone secreting tumors. Non-functioning GEP-NETs are increasingly recognised due to advanced imaging modalities such as endoscopic ultrasound thus became the most common type in MEN1 patients. Several mutations MENIN gene were described, although patients with missense mutations are considered as low-impact mutation carriers.Case report.Index case, female, 47 years old, menarche at age of 16yo, amenorrhea until 23yo, when started continuous oral contraceptives. At age of 45 presented dizziness, paresthesia, cramps, had the diagnosis of Hyperparathyroidism related to multinodular parathyroid hyperplasia (Calcium 14mg/dL, PTH 117 pg/mL) and macroprolactinoma (prolactin 235 ng/mL; pituitary tumor 1.2 X 1.0 cm). All siblings and her mother were recruited and one brother, aged 45 years confirmed the diagnosis of hyperparathyroidism and nephrocalcinosis. Their mother, aged 77 years old, presented abdominal pain, and had the diagnosis of aggressivepancreatic tumor compressing bile duct causing intra and extra-pancreatic dilation, associated with metastatic lymph nodes. She was sunmitted to total pancreato-gastrectomy with esophagus jejunum anastomosis. Genetic screening:MEN1genetic screening for mutations was performed in all patients. In these probands, MLPA analysis was performed to detect large deletions of the MEN1gene, using SALSA MLPA probemix kit P017-D1 according to the manufacturer’s instructions (MRC-Holland, Amsterdam, The Netherlands).DNA was extracted from EDTA-Whole blood using MagNA Pure 24 (Roche). Sequencing libraries were qualified/quantified using TapeStation4200 (Agilent). Test method included coding regions ±10bp flanking intronic sequences of 3921 genes enriched using Kappa HyperPlus Library Preparation Kit (Roche) and SeqCap EZ inherited disease panel (Roche) and sequenced (2x75-bp Mid Output V2 Reagent) using NextSeq-500 (Illumina) (estimated mean coverage-100X). Read alignment, variant calling, variant filtration and annotation were performed with Varstation. SNVs and small indels (20bp) with total-read-depth,10X and variant-read-frequency more than20% found on AIP, APC, CDC73, CDKN1B, DICER1, FH, MAX, MEN1, MET, NF1, PRKAR1A, PTEN, RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, TMEM127, TP53, VHL, WRN genes were analyzed.A missense mutation in exon 2, MEN1:c.124G.C:p.(GLY42Arg) was detected. Discussion and conclusion:MEN1-associated GEP-NETs seem to have a low proliferation rate and long survival has been reported, they should be of particular attention, since they are still the principal cause of death in MEN1 patients.Early screening and diagnosis are crucial for MEN-1 phenotypes.

Congenital afibrinogenemia: identification and expression of a missense mutation in FGB impairing fibrinogen secretion

Blood ◽  
2003 ◽  
Vol 102 (13) ◽  
pp. 4413-4415 ◽  
Author(s):  
Dung Vu ◽  
Paula H. B. Bolton-Maggs ◽  
Jeremy R. Parr ◽  
Michael A. Morris ◽  
Philippe de Moerloose ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Gene Mutations ◽  
Great Majority ◽  
Autosomal Recessive Disorder ◽  
Homozygous Deletion ◽  
Chain Gene ◽  
Missense Mutations ◽  
Exon 2 ◽  
Congenital Afibrinogenemia ◽  
The Media

Abstract Congenital afibrinogenemia is a rare autosomal recessive disorder characterized by complete absence of detectable fibrinogen. We previously identified the first causative mutations for this disease: a homozygous deletion of approximately 11 kb of the fibrinogen α-chain gene (FGA). Subsequent studies revealed that the great majority of afibrinogenemia mutations are localized in FGA, but mutations were also found in FGG and FGB. Apart from 3 missense mutations identified in the C-terminal portion of FGB, all fibrinogen gene mutations responsible for afibrinogenemia are null. In this study, a young boy with afibrinogenemia was found to be a compound heterozygote for 2 mutations in FGB: an N-terminal nonsense mutation W47X (exon 2) and a missense mutation (G444S, exon 8). Coexpression of the FGB G444S mutant cDNA in combination with wild-type FGA and FGG cDNAs demonstrated that fibrinogen molecules containing the mutant β chain are able to assemble but are not secreted into the media, confirming the pathogenic nature of the identified mutation. (Blood. 2003;102:4413-4415)

A Novel Mutation Glyl672→Arg in Type 2A and a Homozygous Mutation in Type 2B von Willebrand Disease

1996 ◽  
Vol 76 (02) ◽  
pp. 253-257 ◽  
Author(s):  
Takeshi Hagiwara ◽  
Hiroshi Inaba ◽  
Shinichi Yoshida ◽  
Keiko Nagaizumi ◽  
Morio Arai ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Novel Mutation ◽  
Point Mutations ◽  
Japanese Patients ◽  
Von Willebrand Disease ◽  
Homozygous Mutation ◽  
Missense Mutations ◽  
Reaction Products ◽  
Type 3 ◽  
Von Willebrand

SummaryGenetic materials from 16 unrelated Japanese patients with von Willebrand disease (vWD) were analyzed for mutations. Exon 28 of the von Willebrand factor (vWF) gene, where point mutations have been found most frequent, was screened by various restriction-enzyme analyses. Six patients were observed to have abnormal restriction patterns. By sequence analyses of the polymerase chain-reaction products, we identified a homozygous R1308C missense mutation in a patient with type 2B vWD; R1597W, R1597Q, G1609R and G1672R missense mutations in five patients with type 2A; and a G1659ter nonsense mutation in a patient with type 3 vWD. The G1672R was a novel missense mutation of the carboxyl-terminal end of the A2 domain. In addition, we detected an A/C polymorphism at nucleotide 4915 with HaeIII. There was no particular linkage disequilibrium of the A/C polymorphism, either with the G/A polymorphism at nucleotide 4391 detected with Hphl or with the C/T at 4891 detected with BstEll.

Mutation Spectrum in Patients with Wiskott-Aldrich Syndrome and X-linked Thrombocytopenia: Identification of Twelve Different Mutations in the WASP Gene

1996 ◽  
Vol 75 (04) ◽  
pp. 546-550 ◽  
Author(s):  
Marianne Schwartz ◽  
Albert Békássy ◽  
Mikael Donnér ◽  
Thomas Hertel ◽  
Stefan Hreidarson ◽  
...  
Keyword(s):  
Base Pair ◽  
Hot Spot ◽  
Missense Mutations ◽  
Nucleotide Substitutions ◽  
Exon 2 ◽  
Wiskott Aldrich Syndrome ◽  
Base Pair Deletion ◽  
Reliable Diagnosis ◽  
Wasp Gene ◽  
Detection Of Mutations

SummaryTwelve different mutations in the WASP gene were found in twelve unrelated families with Wiskott-Aldrich syndrome (WAS) or X-linked thrombocytopenia (XLT). Four frameshift, one splice, one nonsense mutation, and one 18-base-pair deletion were detected in seven patients with WAS. Only missense mutations were found in five patients diagnosed as having XLT. One of the nucleotide substitutions in exon 2 (codon 86) results in an Arg to Cys replacement. Two other nucleotide substitutions in this codon, R86L and R86H, have been reported previously, both giving rise to typical WAS symptoms, indicating a mutational hot spot in this codon. The finding of mutations in the WASP gene in both WAS and XLT gives further evidence of these syndromes being allelic. The relatively small size of the WASP gene facilitates the detection of mutations and a reliable diagnosis of both carriers and affected fetuses in families with WAS or XLT.

scholarly journals Using diverse U.S. beef cattle genomes to identify missense mutations in EPAS1, a gene associated with pulmonary hypertension

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 2003 ◽  
Author(s):  
Michael P. Heaton ◽  
Timothy P.L. Smith ◽  
Jacky K. Carnahan ◽  
Veronica Basnayake ◽  
Jiansheng Qiu ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Beef Cattle ◽  
In Silico ◽  
Read Depth ◽  
Whole Genome Sequence ◽  
Whole Genome ◽  
Missense Mutations ◽  
Protein Variant ◽  
Flight Mass Spectrometry ◽  
Protein Variants

The availability of whole genome sequence (WGS) data has made it possible to discover protein variantsin silico. However, existing bovine WGS databases do not show data in a form conducive to protein variant analysis, and tend to under represent the breadth of genetic diversity in global beef cattle. Thus, our first aim was to use 96 beef sires, sharing minimal pedigree relationships, to create a searchable and publicly viewable set of mapped genomes relevant for 19 popular breeds of U.S. cattle. Our second aim was to identify protein variants encoded by the bovine endothelial PAS domain-containing protein 1 gene (EPAS1), a gene associated with pulmonary hypertension in Angus cattle. The identity and quality of genomic sequences were verified by comparing WGS genotypes to those derived from other methods. The average read depth, genotype scoring rate, and genotype accuracy exceeded 14, 99%, and 99%, respectively. The 96 genomes were used to discover four amino acid variants encoded byEPAS1(E270Q, P362L, A671G, and L701F) and confirm two variants previously associated with disease (A606T and G610S). The sixEPAS1missense mutations were verified with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry assays, and their frequencies were estimated in a separate collection of 1154 U.S. cattle representing 46 breeds. A rooted phylogenetic tree of eight polypeptide sequences provided a framework for evaluating the likely order of mutations and potential impact ofEPAS1alleles on the adaptive response to chronic hypoxia in U.S. cattle. This public, whole genome resource facilitatesin silicoidentification of protein variants in diverse types of U.S. beef cattle, and provides a means of translating WGS data into a practical biological and evolutionary context for generating and testing hypotheses.

scholarly journals Identification of 31 novel mutations in the F8 gene in Spanish hemophilia A patients: structural analysis of 20 missense mutations suggests new intermolecular binding sites

Blood ◽  
2008 ◽  
Vol 111 (7) ◽  
pp. 3468-3478 ◽  
Author(s):  
Adoración Venceslá ◽  
María Ángeles Corral-Rodríguez ◽  
Manel Baena ◽  
Mónica Cornet ◽  
Montserrat Domènech ◽  
...  
Keyword(s):  
Hemophilia A ◽  
Low Density Lipoprotein ◽  
Scavenger Receptor ◽  
Density Lipoprotein ◽  
Missense Mutations ◽  
Factor X ◽  
Novel Mutations ◽  
Large Deletions ◽  
Function Relationship ◽  
The Impact

Abstract Hemophilia A (HA) is an X-linked bleeding disorder caused by a wide variety of mutations in the factor 8 (F8) gene, leading to absent or deficient factor VIII (FVIII). We analyzed the F8 gene of 267 unrelated Spanish patients with HA. After excluding patients with the common intron-1 and intron-22 inversions and large deletions, we detected 137 individuals with small mutations, 31 of which had not been reported previously. Eleven of these were nonsense, frameshift, and splicing mutations, whereas 20 were missense changes. We assessed the impact of the 20 substitutions based on currently available information about FV and FVIII structure and function relationship, including previously reported results of replacements at these and topologically equivalent positions. Although most changes are likely to cause gross structural perturbations and concomitant cofactor instability, p.Ala375Ser is predicted to affect cofactor activation. Finally, 3 further mutations (p.Pro64Arg, p.Gly494Val, and p.Asp2267Gly) appear to affect cofactor interactions with its carrier protein, von Willebrand factor, with the scavenger receptor low-density lipoprotein receptor–related protein (LRP), and/or with the substrate of the FVIIIapi•FIXa (Xase) complex, factor X. Characterization of these novel mutations is important for adequate genetic counseling in HA families, but also contributes to a better understanding of FVIII structure-function relationship.

scholarly journals Incidence of the CHEK2 Germline Mutation and Its Impact on Clinicopathological Features, Treatment Responses, and Disease Course in Patients with Papillary Thyroid Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 470
Author(s):  
Danuta Gąsior-Perczak ◽  
Artur Kowalik ◽  
Krzysztof Gruszczyński ◽  
Agnieszka Walczyk ◽  
Monika Siołek ◽  
...  
Keyword(s):  
Papillary Thyroid Carcinoma ◽  
Thyroid Carcinoma ◽  
Missense Mutation ◽  
Vascular Invasion ◽  
Germline Mutations ◽  
Primary Treatment ◽  
Clinicopathological Characteristics ◽  
Missense Mutations ◽  
Papillary Thyroid ◽  
Treatment Responses

The CHEK2 gene is involved in the repair of damaged DNA. CHEK2 germline mutations impair this repair mechanism, causing genomic instability and increasing the risk of various cancers, including papillary thyroid carcinoma (PTC). Here, we asked whether CHEK2 germline mutations predict a worse clinical course for PTC. The study included 1547 unselected PTC patients (1358 women and 189 men) treated at a single center. The relationship between mutation status and clinicopathological characteristics, treatment responses, and disease outcome was assessed. CHEK2 mutations were found in 240 (15.5%) of patients. A CHEK2 I157T missense mutation was found in 12.3%, and CHEK2 truncating mutations (IVS2 + 1G > A, del5395, 1100delC) were found in 2.8%. The truncating mutations were more common in women (p = 0.038), and were associated with vascular invasion (OR, 6.91; p < 0.0001) and intermediate or high initial risk (OR, 1.92; p = 0.0481) in multivariate analysis. No significant differences in these parameters were observed in patients with the I157T missense mutation. In conclusion, the CHEK2 truncating mutations were associated with vascular invasion and with intermediate and high initial risk of recurrence/persistence. Neither the truncating nor the missense mutations were associated with worse primary treatment response and outcome of the disease.

Jimpy-4J Mouse Has a Missense Mutation in Exon 2 of the Plp Gene

1997 ◽  
Vol 19 (4) ◽  
pp. 337-341 ◽  
Author(s):  
Gail B. Pearsall ◽  
Nancy L. Nadon ◽  
Merrill K. Wolf ◽  
Susan Billings-Gagliardi
Keyword(s):  
Missense Mutation ◽  
Exon 2 ◽  
I Gene

scholarly journals Identification of a novel pathogenic missense mutation in PRPF31 using whole exome sequencing: a case report

2018 ◽  
Vol 103 (6) ◽  
pp. 761-767 ◽  
Author(s):  
Laura Bryant ◽  
Olga Lozynska ◽  
Anson Marsh ◽  
Tyler E Papp ◽  
Lucas van Gorder ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Missense Mutation ◽  
Whole Exome Sequencing ◽  
Protein Trafficking ◽  
Protein Misfolding ◽  
Autosomal Dominant ◽  
Null Alleles ◽  
Incomplete Penetrance ◽  
Missense Mutations ◽  
Whole Exome

BackgroundVariants in PRPF31, which encodes pre-mRNA processing factor 31 homolog, are known to cause autosomal-dominant retinitis pigmentosa (adRP) with incomplete penetrance. However, the majority of mutations cause null alleles, with only two proven pathogenic missense mutations. We identified a novel missense mutation in PRPF31 in a family with adRP.MethodsWe performed whole exome sequencing to identify possible pathogenic mutations in the proband of a family with adRP. Available affected family members had a full ophthalmological evaluation including kinetic and two-colour dark adapted static perimetry, electroretinography and multimodal imaging of the retina. Two patients had evaluations covering nearly 20 years. We carried out segregation analysis of the probable mutation, PRPF31 c.590T>C. We evaluated the cellular localisation of the PRPF31 variant (p.Leu197Pro) compared with the wildtype PRPF31 protein.ResultsPRPF31 c.590T>C segregated with the disease in this four-generation autosomal dominant pedigree. There was intrafamilial variability in disease severity. Nyctalopia and mid-peripheral scotomas presented from the second to the fourth decade of life. There was severe rod >cone dysfunction. Visual acuity (VA) was relatively intact and was maintained until later in life, although with marked interocular asymmetries. Laboratory studies showed that the mutant PRPF31 protein (p.Leu197Pro) does not localise to the nucleus, unlike the wildtype PRPF31 protein. Instead, mutant protein resulted in punctate localisation to the cytoplasm.Conclusionsc.590T>C is a novel pathogenic variant in PRPF31 causing adRP with incomplete penetrance. Disease may be due to protein misfolding and associated abnormal protein trafficking to the nucleus.

Abstract TP269: Distinct Molecular Mechanisms of Htra1 Mutants in Manifesting Heterozygotes With Carasil

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Hiroaki Nozaki ◽  
Taisuke Kato ◽  
Megumi Nihonmatsu ◽  
Yohei Saito ◽  
Ikuko Mizuta ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Molecular Mechanisms ◽  
Small Vessel Disease ◽  
Gel Filtration ◽  
Gene Mutations ◽  
Missense Mutations ◽  
Inherited Disease ◽  
Wild Type ◽  
Vessel Disease ◽  
Activation Cascade

Introduction: Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), an autosomal recessive inherited cerebral small vessel disease (CSVD), involves severe leukoaraiosis, multiple lacunar infarcts, early-onset alopecia, and spondylosis deformans. High-temperature requirement serine peptidase A1 (HTRA1) gene mutations cause CARASIL by decreasing HTRA1 protease activity. Although CARASIL is a recessive inherited disease, heterozygous mutations in the HTRA1 gene were recently identified in 11 families with CSVD. Because CSVD is frequently observed in elderly individuals, it is unclear which mutants truly contribute to CSVD pathogenesis. Here, we found heterozygous mutations in the HTRA1 gene in individuals with CSVD and investigated the differences in biochemical characteristics between these mutant HTRA1s and mutant HTRA1s observed in homozygotes. Methods: We recruited 113 unrelated index patients with clinically diagnosed CSVD. The coding sequences of the HTRA1 gene were analyzed. We evaluated HTRA1 protease activities using casein assays and oligomeric HTRA1 formation using gel filtration chromatography. Results: We found 4 heterozygous missense mutations in the HTRA1 gene (p.G283E, p.P285L, p.R302Q, and p.T319I) in 6 patients from 113 unrelated index patients and in 2 siblings in 2 unrelated families with p.R302Q. These mutant HTRA1s showed markedly decreased protease activities and inhibited wild-type HTRA1 activity, whereas 2 of 3 mutant HTRA1s reported in CARASIL (A252T and V297M) did not inhibit wild- type HTRA1 activity. Wild-type HTRA1 forms trimers; however, G283E and T319I HTRA1, observed in manifesting heterozygotes, did not form trimers. P285L and R302Q HTRA1s formed trimers, but their mutations were located in domains that are important for trimer-associated HTRA1 activation; in contrast, A252T and V297M HTRA1s, which have been observed in CARASIL, also formed trimers but had mutations outside the domains important for trimer- associated HTRA1 activation. Conclusions: The mutant HTRA1s observed in manifesting heterozygotes might result in an impaired HTRA1 activation cascade of HTRA1 or be unable to form stable trimers.

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