One missense mutation in exon 2 of the PAX5 gene in Iran

Abstract BACKGROUND AND AIM von Hippel-Lindau (VHL) disease is a hereditary disease which manifest central nervous system (CNS) hemangioblastoma, retinal angioma, renal cell carcinoma (RCC), pheochromocytoma, endolymphatic sac tumor, and pancreas cyst. The VHL gene is located at 3p25.3 and is corresponding to 213 amino acids. Genotype-phenotype correlation analyses of VHL disease have been recently reported from several foreign countries, but the genotype-phenotype correlation has not been characterized since above 10 years ago. Therefore, this study aimed to evaluate the VHL mutation spectrum and genotype-phenotype correlations in Japanese VHL patients. METHODS Blood samples of 111 unrelated families of VHL disease were collected and DNAs were extracted. Direct sequencing and real-time PCR analysis were performed. Consequently, the clinical manifestations and family histories of the subjects were evaluated. RESULTS We identified VHL mutations as follows: missense 47; deletion 17; insertion 5; nonsense 8; splice-site 9; larger deletion 25. At hot-spot codon 167, 4 minsense mutations were identified, with Arg167Trp, 4 cases; Arg167Gln2, 2 cases. At codon 155, splice-site mutations were identified at 6 cases. Mutation sites were distributed in exon 1, 45; exon 2, 21; exon 3, 36. Large deletions were distributed in exon 1 & 2, 1; exon 2& 3, 1; all exons, 11. Genotype-phenotype correlation analysis revealed that age-specific risk and number of CNS hemangioblastoma were significantly higher in subjects carrying missense mutation within HIF-α binding site or non-missense mutation (P < 0.05). In addition, penetrance of RCC was significantly higher in subjects carrying non-missense mutation (P < 0.05). CONCLUSIONS The results of this study were similar to the previous foreign studies. This study provides insight into the genotype-phenotype correlation in that amino acids substitutions in the HIF- α binding and non-sense mutations may predispose VHL patients to age-related risk and number of CNS hemangioblastoma.

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Metabolic abnormalities in G6PC3-deficient human neutrophils result in severe functional defects

Blood Advances ◽

10.1182/bloodadvances.2020002225 ◽

2020 ◽

Vol 4 (23) ◽

pp. 5888-5901

Author(s):

Christopher McKinney ◽

Michael Ellison ◽

Natalie J. Briones ◽

Angelina Baroffio ◽

John Murphy ◽

...

Keyword(s):

Missense Mutation ◽

Bacterial Infections ◽

Neutrophil Function ◽

Functional Improvement ◽

Human Neutrophils ◽

Compound Heterozygous ◽

Cd11b Expression ◽

Exon 2 ◽

Metabolic Defects ◽

Functional Defects

Abstract Severe congenital neutropenia type 4 (SCN-4) is an autosomal recessive condition in which mutations in the G6PC3 gene encoding for the catalytic 3 subunit of glucose-6-phosphatase-β result in neutropenia, neutrophil dysfunction, and other syndromic features. We report a child with SCN-4 caused by compound heterozygous mutations in G6PC3, a previously identified missense mutation in exon 6 (c.758G>A[p.R235H]), and a novel missense mutation in exon 2 (c.325G>A[p.G109S]). The patient had recurrent bacterial infections, inflammatory bowel disease, neutropenia, and intermittent thrombocytopenia. Administration of granulocyte colony–stimulating factor (G-CSF) resolved the neutropenia and allowed for detailed evaluation of human neutrophil function. Random and directed migration by the patient’s neutrophils was severely diminished. Associated with this were defects in CD11b expression and F-actin assembly. Bactericidal activity at bacteria/neutrophil ratios >1:1 was also diminished and was associated with attenuated ingestion. Superoxide anion generation was <25% of control values, but phox proteins appeared quantitatively normal. Extensive metabolomics analysis at steady state and upon incubation with stable isotope–labeled tracers (U-13C-glucose, 13C,15N-glutamine, and U-13C-fructose) demonstrated dramatic impairments in early glycolysis (hexose phosphate levels), hexosemonophosphate shunt (required for the generation of the NADPH), and the total adenylate pool, which could explain the dramatic cell dysfunction displayed by the patient’s neutrophils. Preliminary experiments with fructose supplementation to bypass the enzyme block demonstrated that the metabolic profile could be reversed, but was not sustained long enough for functional improvement. In human deficiency of G6PC3, metabolic defects resulting from the enzyme deficiency account for diverse neutrophil functional defects and present a major risk of infection.

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Missense Mutation in Exon 2 of SLC36A1 Responsible for Champagne Dilution in Horses

PLoS Genetics ◽

10.1371/journal.pgen.1000195 ◽

2008 ◽

Vol 4 (9) ◽

pp. e1000195 ◽

Cited By ~ 30

Author(s):

Deborah Cook ◽

Samantha Brooks ◽

Rebecca Bellone ◽

Ernest Bailey

Keyword(s):

Missense Mutation ◽

Exon 2

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Identification of a new missense mutation in exon 2 of the human hypoxanthine phosphoribosyltransferase gene (HPRTIsar): A further example of clinical heterogeneity in HPRT deficiencies

Human Mutation ◽

10.1002/humu.1380050413 ◽

1995 ◽

Vol 5 (4) ◽

pp. 341-344 ◽

Cited By ~ 2

Author(s):

R. Burgemeister ◽

E. Rötzer ◽

W. Gutensohn ◽

M. Gehrke ◽

W. Schiel

Keyword(s):

Missense Mutation ◽

Hypoxanthine Phosphoribosyltransferase ◽

Clinical Heterogeneity ◽

Exon 2

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Identification of Novel LNK Mutations In Patients with Chronic Myeloproliferative Neoplasms and Related Disorders

Blood ◽

10.1182/blood.v116.21.315.315 ◽

2010 ◽

Vol 116 (21) ◽

pp. 315-315

Author(s):

Stephen T. Oh ◽

Jacob M. Zahn ◽

Carol D. Jones ◽

Bing Zhang ◽

Mignon L. Loh ◽

...

Keyword(s):

Missense Mutation ◽

Negative Feedback ◽

Myeloproliferative Neoplasms ◽

Premature Stop Codon ◽

Feedback Regulation ◽

Jak2 V617f ◽

Sh2 Domain ◽

Negative Feedback Regulation ◽

Exon 2 ◽

Stat Signaling

Abstract Abstract 315 Introduction: Dysregulated JAK-STAT signaling in chronic myeloproliferative neoplasms (MPNs) has primarily been attributed to activating mutations in tyrosine kinases. However, JAK-STAT activation can be demonstrated in some patients lacking JAK2 or MPL mutations, suggesting alteration of other regulatory elements in this pathway. One regulator of JAK-STAT signaling is LNK (SH2B3), an adapter protein that contains a proline-rich N-terminal dimerization domain (Pro/DD), a pleckstrin homology (PH) domain (plasma membrane localization), and an SH2 domain. LNK binds to cytokine receptors (e.g. MPL, EPOR) and JAK2 via its SH2 domain, inhibiting downstream STAT activation and providing critical negative feedback regulation. LNK-/- mice exhibit features consistent with an MPN phenotype. We recently reported the first human disease-related LNK mutations in two JAK2 V617F-negative MPN patients (Oh et al, Blood, Aug 12, 2010). One patient with primary myelofibrosis (PMF) exhibited a 5 base-pair (bp) deletion and missense mutation (DEL) leading to a premature stop codon and loss of the PH and SH2 domains. A second patient with essential thrombocythemia (ET) was found to have a missense mutation (E208Q) in the PH domain. Both mutations conferred aberrant JAK-STAT signaling in cell lines and primary patient samples, indicating that loss of LNK negative feedback regulation contributes to MPN pathogenesis. We now report the results of a comprehensive screen of a large cohort of MPN, overlap myelodysplastic syndrome (MDS)/MPN, and post-MDS/MPN acute myeloid leukemia (AML) patients for LNK mutations. Methods: A total of 341 samples were sequenced (Table 1; polycythemia vera (PV)=34, erythrocytosis=7, ET=61, PMF=75, post-PV/ET MF=25, MPN-U=7, chronic myelomonocytic leukemia (CMML)=71, juvenile myelomonocytic leukemia=20, MDS/MPN=8, MDS with fibrosis=2, refractory anemia with ring sideroblasts and thrombocytosis=4, idiopathic hypereosinophilic syndrome/chronic eosinophilic leukemia=4, systemic mastocytosis=4, and post MDS/MPN AML=19). A deep sequencing approach (Illumina multiplexing system) was used to evaluate 84 samples, in which all exons of LNK were sequenced. For the remainder of the samples, direct sequencing was performed on exon 2, the region containing the previously reported DEL and E208Q mutations. Results: After excluding variants previously reported in SNP databases, a total of 11/341 (3.2%) patients were found to have non-synonymous mutations, including 3/61 (4.9%) ET, 3/75 (4.0%) PMF, and 5/71 (7.0%) CMML patients (Table 1). Each of the mutations localized to exon 2 of LNK, implicating this region as a possible mutational hotspot. This included the aforementioned patients with the DEL and E208Q mutations, which were confirmed by deep sequencing. In two other patients, sequencing of DNA from cultured skin fibroblasts DNA indicated that the mutations were germline. For the remaining seven patients, germline analysis is currently ongoing. In one patient with CMML, a 1 bp deletion leading to a frameshift and premature stop codon was identified (Q72fs). This mutation localized to the Pro/DD, likely resulting in a complete loss of LNK function. Interestingly, this patient who is wild type for the JAK2 and RAS genes, also carries a heterozygous CBL mutation (C396Y), suggesting that LNK and CBL mutations may have cooperative effects. Four patients (one with PMF, three with CMML) were found to have a missense mutation (S186I) at a highly conserved residue in the Pro/DD. The previously reported E208Q mutation was also found in one patient with ET and one patient with CMML. None of the 81 patients known to be JAK2 V617F-positive exhibited somatic LNK mutations, suggesting that LNK mutations may provide an alternative basis for JAK-STAT activation in the absence of JAK2 V617F. Conclusion: Missense and deletion mutations of the LNK gene occur at a low frequency in MPNs and MDS/MPNs and segregate predominantly in exon 2. Further analysis of post-MPN AML samples (represented at a low frequency in the current cohort) and other subtypes of acute and chronic myeloid malignancies is warranted to better characterize the disease spectrum of LNK mutations and whether they are mutually exclusive of JAK2 V617F. We are currently investigating whether loss of negative feedback regulation of JAK-STAT signaling is related to haploinsufficiency of LNK or dominant negative effects of the mutant protein. Disclosures: No relevant conflicts of interest to declare.

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A Novel Mutation in the CLDN16 Gene in a Palestinian Family with Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis

Journal of Child Science ◽

10.1055/s-0037-1604294 ◽

2017 ◽

Vol 07 (01) ◽

pp. e32-e35

Author(s):

Abdulsalam Abu-Libdeh ◽

Bassam Abu-Libdeh ◽

Ulla Abdulhag

Keyword(s):

Renal Failure ◽

Missense Mutation ◽

Novel Mutation ◽

Positive Family History ◽

Male Infant ◽

Molecular Testing ◽

Loss Of Function ◽

Renal Disorder ◽

Exon 2 ◽

Familial Hypomagnesemia

AbstractFamilial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive renal disorder characterized by excessive renal magnesium and calcium loss, bilateral nephrocalcinosis, and progressive renal failure, due to impaired tubular reabsorption in the thick ascending loop of Henle. FHHNC is caused by loss of function mutations in the claudin-16 gene (CLDN16) and claudin-19 gene (CLDN19). A 2-month-old male infant presented with convulsions during hypomagnesemia, hypocalcemia, and hypophosphatemia, biochemical findings were consistent with FHHNC. There is a positive family history of the death of a 12 years old sibling due to renal failure. Gene sequencing of the CLDN16 revealed a novel missense mutation with the replacement of T by C in codon 120 located in exon 2, predicting cysteine to arginine substitution p.Cys120Arg. This is the first description of this missense mutation and the first confirmation of FHHNC by molecular testing in a Palestinian family which enables genetic counseling and future prenatal diagnosis.

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Missense mutation Ala34Val in exon 2 of the Lipoprotein Lipase gene in a young man with chylomicronemia

Nutrition Metabolism and Cardiovascular Diseases ◽

10.1016/s0939-4753(04)80179-0 ◽

2004 ◽

Vol 14 (5) ◽

pp. 312

Keyword(s):

Missense Mutation ◽

Lipoprotein Lipase ◽

Lipase Gene ◽

Exon 2 ◽

Lipoprotein Lipase Gene

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

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.1347 ◽

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.

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Molecular analysis of 9 new families with chronic granulomatous disease caused by mutations in CYBA, the gene encoding p22phox

Blood ◽

10.1182/blood.v96.3.1106.015k44_1106_1112 ◽

2000 ◽

Vol 96 (3) ◽

pp. 1106-1112 ◽

Cited By ~ 1

Author(s):

Julie Rae ◽

Deborah Noack ◽

Paul G. Heyworth ◽

Beverly A. Ellis ◽

John T. Curnutte ◽

...

Keyword(s):

Nadph Oxidase ◽

Chronic Granulomatous Disease ◽

Missense Mutation ◽

Nonsense Mutation ◽

Granulomatous Disease ◽

Microbial Infection ◽

Gene Encoding ◽

Catalytic Core ◽

Exon 2 ◽

Cyba Gene

Chronic granulomatous disease is a rare inherited disorder caused by nonexistent or severely decreased phagocyte superoxide production that results in a severe defect in host defense and consequent predisposition to microbial infection. The enzyme responsible for generating the superoxide, NADPH oxidase, involves at least 5 protein components. The absence of, or a defect in, any 1 of 4 of these proteins (p22phox, p47phox, p67phox, or gp91phox) gives rise to the known types of chronic granulomatous disease. One of the rarest forms of the disease is due to defects in the CYBA gene encoding p22phox, which together with gp91phox forms flavocytochromeb558, the catalytic core of NADPH oxidase. To date, only 9 kindreds with p22phoxdeficiency have been described in the literature comprising 10 mutant alleles. Four polymorphisms in the CYBA gene have also been reported. Here we describe 9 new, unrelated kindreds containing 12 mutations, 9 of which are novel. In addition, we report 3 new polymorphisms. The novel mutations are (a) deletion of exons 2 and 3, (b) a missense mutation in exon 3 (T155→C), (c) a splice site mutation at the 5′ end of intron 3, (d) a missense mutation in exon 2 (G74→T), (e) a nonsense mutation in exon 1 (G26→A), (f) a missense mutation in exon 4 (C268→T), (g) a frameshift in exon 3 due to the insertion of C at C162, (h) a nonsense mutation in exon 2 (G107→A), and (i) a missense mutation in exon 2 (G70→A).

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