Glanzmann's Thrombasthenia Mutation of the Genes ITGA2B and ITGB3.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2411-2411
Author(s):  
Giorgio Corinaldesi ◽  
Christian Corinaldesi
Keyword(s):  
Conflicts Of Interest ◽  
Stop Codon ◽  
Genetic Mutation ◽  
Severe Bleeding ◽  
Clot Retraction ◽  
Site Mutation ◽  
Gene Encoding ◽  
Protein Activation ◽  
Calcium Dependent ◽  
Exon 11

Abstract Abstract 2411 Poster Board II-389 Glanzmann Thrombasthenia (GT) is a rare autosomal recessive bleeding disorder characterized by a life-long mucocutaneous bleeding tenedency and absence or severely reduced platelet aggregation in response to ADP, epinephrine, and collagen, but relatively normal in response to ristocetin, where the glycoprotein (GP) IIb/IIIa a calcium dependent heterodimer complex is deficient or present but dysfunctional. GPIIb 172kbp is composed of 30 exons and GPIIIa 65Kbp is composed of 15 exons, have their own separate genes on the long arm of chomosome 17 (17q21-32), specific genetic abnormalities of each GP include missense, non sense, splite site mutation, deletions and point mutation. Mutation abrogates ligand binding to the activate integrin to the adhesive protein: fibrinogen, vWF, fibronectin, vitronectin, CD40L and the platelet are unable to mediate outside-inside signaling promoting actin plymerization and cytoskeletal reorganization such as clot retraction, talin and kindlin protein activation. We have studied four patients with mutation of the gene encoding platelet GPIIb (ITGAIIB) exon 17 mutation 1750 C (cystein)-T (threonin) phenotype non sense R584X,the proband showed a platelet with 3%-10% a fibrinogen binding and GPIIb/IIIa receptors; exon 23 mutation 2333 A (alanin)-C (cystein) phenotype missense Q778P, produced truncated protein, cystein residue is ipermethylated with a reduction of adhesion <8% cystein is postulated to be critical for post translational processing of GPIIb; and the gene encoding platelet GPIIIa (ITGB3) exon 11 mutation 1813 G (glycin)-A (alanin) phenotype missense H306P,ifluencing the Ca2+ dependent stabilty of the GPIIb/IIIa complex to divalent cation chelation; exon 3 mutation 355 C (cystein)- T (threonin) phenotype missense R119W escluding at codon 355 leader sequence, producing a frame-shift and protein termination and a stop codon with a great abnormalities of GPIIb/IIIa heterodimer inter subunit surface interaction, and intracellular trafficking. The patients have all severe bleeding included epistaxis, petechiae, gum bleeding, and a high grade of relapsing, refractory bleeding often requiring the transfusion with HLA compatible platelet concentrats and/or administration of recombinant FVIIa. This study confirmed that the genetic mutation can be significatly associated with the frequency and severity of bleeding and these approach may be the future of the management of GT. Disclosures: No relevant conflicts of interest to declare.

Regulation of Platelet Procoagulant Activity

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. SCI-33-SCI-33
Author(s):  
Johan Heemskerk
Keyword(s):  
Calcium Signaling ◽  
Conflicts Of Interest ◽  
Coagulation Factors ◽  
Genetic Mutation ◽  
Cytoskeletal Proteins ◽  
Fiber Formation ◽  
Clot Retraction ◽  
Platelet Surface ◽  
Anoctamin 6 ◽  
Calcium Dependent

Abstract Platelets play prominent and unique roles in the kinetics of the coagulation process. Modulated by the flow conditions, they control coagulation in various ways: (1) by integrin activation and ensuing clot retraction; (2) via exposure of the procoagulant phospholipid phosphatidylserine (PS), which causes binding of a specific set of coagulation factors at the platelet surface with as a result tenase activation and thrombin generation; (3) by initiating fibrin fiber formation at the platelet surface, a process specifically catalyzed by coated platelets. Recent evidence points to fibrin as an active structural network, which provides binding sides for plasma factors and platelets and, thereby, provides an important feedback mechanism for the stimulation of platelet activation. This overview will focus on novel insights into the signaling and activation processes in platelets that regulate these distinct procoagulant functions. One key mechanism is the activation and secondary closure of integrin alphaIIb-beta3. Another key mechanism concerns the calcium-dependent exposure of PS, which is accompanied by swelling of the platelets. Together, these processes control not only platelet adhesion, but also the accessibility for coagulation factors. Major distortions in these procoagulant functions are seen in platelets from a patient with the Scott syndrome, a rare bleeding disorder associated with mutations in the calcium-dependent ion channel protein anoctamin-6 (gene ANO6, previously TMEM16A). These platelets are deficient in calcium-induced PS exposure, swelling, integrin inactivation and in the formation of thrombin and fibrin at the platelet surface. These dysfunctions are precisely phenocopied in mice lacking anoctamin-6 expression. Advanced platelet proteomics analysis indicated that the deficiency in anoctamin-6 was accompanied by decreased calpain-dependent cleavage of a whole spectrum of intracellular proteins, and an increased phosphorylation state of many signaling and cytoskeletal proteins. However, calcium signaling in the Scott platelets was unchanged. In contrast, reports on patients with a gain in platelet procoagulant function, the Stormorken syndrome, indicate a link with genetic mutation in the calcium signaling protein STIM1. The possible consequences of these novel insights for our understanding of haemorrhagic and thrombotic deseases will be discussed. Disclosures No relevant conflicts of interest to declare.

Absence of Band 3 in Severe Dyserythropoietic/Hemolytic Anemia with Complete Distal Renal Acidosis and a Novel Homozygous Exon 12 C.1430C>a (p.Ser477X) SLC4A1 Gene Mutation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 945-945 ◽  
Author(s):  
Leo Kager ◽  
Lesley J Bruce ◽  
Joanna F Flatt ◽  
Petra Zeitlhofer ◽  
Gerhard Fritsch ◽  
...  
Keyword(s):  
Hemolytic Anemia ◽  
Conflicts Of Interest ◽  
Stop Codon ◽  
Disease Process ◽  
Failure To Thrive ◽  
Autosomal Recessive Inheritance ◽  
Band 3 ◽  
Southeast Asian ◽  
Heterozygous Mutation ◽  
Exon 11

Abstract The solute carrier 4A1 gene (SLC4A1) encodes theband 3 or bicarbonate anionic exchanger 1 (AE1). It is not only the major glycoprotein of the red blood cell (RBC) membrane but also expressed in acid secreting alpha-intercalated kidney cells. Functionally impairing SLC4A1 mutations reduce the expression and/or activity of AE1 thereby causing a unique combination of hemolytic anemia and distal renal tubular acidosis (dRTA). So far, only four such particular homozygote mutations have been documented in humans: an exon 11 p.400-408 deletion in Southeast Asian ovalocytosis (SAO) with transfusion-dependent dyserythropoietic anemia and dRTA (Picard et al, Blood 123:1963;2014), an exon 13 p.V488M mutation in transfusion-dependent hereditary spherocytosis (HS) and dRTA lacking band 3 (Ribeiro et al, Blood 96:1602;2000), an exon 16 p.S667F mutation in transfusion-dependent HS and incomplete dRTA (Toye et al, Blood 111:5380;2008), and finally an exon 19 p.Ala858Asp in a compensated hemolytic anemia with marked acanthocytosis, echinocytosis and dRTA (Fawaz et al, Europ J Haematol 88:350;2012). We report herein a novel homozygote variant in exon 12 in a patient with a transfusion-dependent dyserythropoietic/hemolytic anemia and complete dRTA. The now 4-years old Turkish boy was born after 32 weeks of gestation and presented with a severe hemolytic anemia (Hb 40 g/L) that required exchange transfusions and a complete dRTA that was treated with oral bicarbonate. He also suffered from delayed psychomotoric developmental with failure to thrive, trigonocephalus and strabismus convergens. Bone marrow smears showed marked dyserythropoiesis but normal myeloid and megakaryocytic lineages. Although necessary monthly transfusions impeded the patient's direct diagnostic work-up, a flow cytometric eosin-5-maleimide assay eventually revealed a reduced staining of his consanguine parents' and his two siblings' erythrocytes, who all had subclinical signs of spherocytosis despite normal RBC counts. Based on these findings, we analyzed the SLC4A1 gene and found two homozygous sequence variants in the patient, namely a novel disease-relevant exon 12 nonsense mutation c.1430C>A (p.Ser477X) and a disease-unrelated c.2312-48T>G (rs13306780). The ensuing stop codon of the former truncates the protein, prevents band 3 formation and reduces glycophorin A expression. Bright field imaging uncovered few phenotypic spherocytic band 3 null RBCs even in the peripheral blood. In accordance with the autosomal recessive inheritance pattern, both healthy parents as well as his healthy siblings were found to be heterozygous carriers. The band 3 protein was reduced to 50-60% in the parents' erythrocytes. An increased approximately 22 kDa-sized band was evident in Coomassie stained gels of the heterozygous mutation carriers' membrane preparations and classified by immunoblotting as peroxiredoxin 2 (PRDX2), which plays a major role in protecting RBCs from oxidative stress. Taken together, the provided data clearly confirm the relevance of this particular c.1430C>A (p.Ser477X) SLC4A1 mutation in the disease process. Of note, such a severe dyserythropoietic anemia and complete dRTA was also recently reported in a patient with Southeast Asian ovalocytosis and another form of homozygous SLC4A1 mutation (Picard et al, Blood 123:1963;2014). Disclosures No relevant conflicts of interest to declare.

Gene Analysis of 45 FXIII Deficient Patients in the US: An in Depth Whole Gene NGS Sequencing Analysis of FXIII a and B Subunit Mutations

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 757-757 ◽  
Author(s):  
Diane J. Nugent ◽  
Leiquian Tai ◽  
Shirley Williams ◽  
Suman Verma ◽  
Moore Mathew ◽  
...  
Keyword(s):  
Sanger Sequencing ◽  
Conflicts Of Interest ◽  
Stop Codon ◽  
Gene Sequencing ◽  
Severe Bleeding ◽  
Compound Heterozygous ◽  
Homozygous Mutation ◽  
Sequencing Analysis ◽  
B Subunit ◽  
The Us

Factor XIII deficiency is a rare clotting protein deficiency characterized by a very high risk of spontaneous intracranial hemorrhage (ICH), mucosal bleeding, miscarriage, and poor wound healing. The majority of FXIII deficient patients lack the A subunits which carry the catalytic site. Patients with B subunit deficiency have a less severe bleeding diathesis, but their FXIII survival is very short, reduced to 6-8 hours as compared to a normal FXIII half-life of 6-10 days. The striking finding for FXIII deficiency is that nearly every patient appears to have unique combinations of mutations resulting in a wide spectrum of bleeding severity, even within the same family. This is particularly true in the US where about a third of the families demonstrate a compound heterozygous pattern and only 50% are homozygous for the same mutation, usually associated with a history of consanguinity or geographic isolation. Sequencing of FXIII A and B subunit mutations is used clinically to initiate appropriate treatment and as a research tool to further our understanding of genotype-phenotype associations. While traditional Sanger sequencing of exons is currently the standard of care, this approach is time consuming, expensive, and 15-20% of FXIII deficient patients do not show any mutations in the exon coding regions. Therefore, we evaluated a whole gene sequencing approach to improve accuracy and turn-around time to diagnosis. Methods: Generation of Next Generation Sequencing panel for FXIII A and B subunits. Sequencing libraries were prepared using a bait capture approach, and sequencing was conducted on a MiSeq platform by Illumina using standard methodologies. The library panel was designed to cover all exons and over 500 nucleotides adjacent to each exon, thus including splice sites, and regulatory regions. Additionally, a total of 12 introns are completely covered by the sequencing design, as well as 1500 nucleotides both upstream and downstream from the A and B subunit genes. Results: We compared the results of 45 FXIII deficient patients previously sequenced in our laboratory using a Sanger approach to those results obtained using the NGS assay. The NGS assay confirmed all exonic mutations previously detected using Sanger sequencing. Additionally, the NGS assay was able to identify a series of mutations that were not picked up using Sanger technology, including mutations in intronic regions, and large entire exonic deletions which were previously suspected, but could not be confirmed using Sanger sequencing alone. Among the 45 patients, 21 had a homozygous mutation pattern, 19 were compound heterozygotes and there was no new exon coding mutations found in 5 patients. Of the 40 mutations identified, 21 were missense, 5 resulted in stop codon, 3 resulted in frameshift, 1 was a splice site mutation, and 4 had large deletions covering many exons. Of these mutations, only 12 had been previously reported in the literature. Conclusion: We report the results of the largest group of USA FXIII deficient patients to be sequenced thus far, and compare the genotypes obtained from both a Sanger Sequencing and NGS approach. Using NGS whole gene sequencing , we found multiple new variants in the intron and flanking sequences, including insertions and deletions in all patients including those without a mutation detected on Sanger sequencing. These are currently being analyzed as possible causative mutations in the 5 patients without exonic mutations and as potential modifying variants in patients with heterozygous mutations. NGS whole gene sequencing will give us more information than currently available on FXIII genome sequence and provide a rapid, cost effective assay to analyze future patients. Funded in part through an Investigator Initiated Award to Dr Diane Nugent from Novo Nordisk Disclosures No relevant conflicts of interest to declare.

scholarly journals Four New Cases of SLC35A2-CDG With Novel Mutations and Clinical Features

2021 ◽  
Vol 12 ◽  
Author(s):  
Kuerbanjiang Abuduxikuer ◽  
Jian-She Wang
Keyword(s):  
Clinical Features ◽  
De Novo ◽  
Stop Codon ◽  
Positive Family History ◽  
Premature Stop Codon ◽  
Splice Site Mutation ◽  
Genetic Mutation ◽  
Site Mutation ◽  
Rare Type ◽  
Han Ethnicity

SLC35A2-CDG is a rare type of X-linked CDG with more than 60 reported cases. We retrospectively analyzed clinical phenotypes and SLC35A2 genotypes of four cases of SLC35A2-CDG from four unrelated families of Han ethnicity in China. All patients had infantile onset epilepsies that were completely or partly resistant to multiple anti-epileptic medications or ketogenic diet. Three patients had severe developmental delay. All patients were female patients carrying de novo deleterious mutations in SLC35A2 (NM_001042498.2) gene, including one canonical splice-site mutation (c.426+1G &gt; A), one large deletion (c.-322_c.274+1del), and two frameshift mutations leading to premature stop codon (c.781delC/p.Arg289ValfsTer88 and c.601delG/p.Ala201GlnfsTer148). Novel clinical features in some of our patients include anemia, hypertriglyceridemia, hypertonia, small ears, extra folds on earlobes, and maternal oligohydramnios or hypothyroidism during pregnancy. In one patient, concomitant Marfan syndrome was confirmed for having positive family history, carrying a heterozygous known disease-causing mutation in FBN1 gene (c.7240C &gt; T/p.Arg2414Ter), and presence of typical features (rachnodactyly, ventrical septal defect, and mitral valve regurgitation). In conclusion, we expanded clinical phenotype and genetic mutation spectrum of SLC35A2-CDG by reporting four new cases with novel pathogenic variants and novel clinical features.

scholarly journals SAT-286 TSH Synthesis and Secretion Are Unperturbed in Male IRS4 Knockout Mice

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Emilie Brule ◽  
Anita Boelen ◽  
Daniel J Bernard
Keyword(s):  
Knockout Mice ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Whole Body ◽  
Gene Encoding ◽  
Central Hypothyroidism ◽  
Guide Rna ◽  
Downstream Effectors ◽  
Tsh Secretion ◽  
Hpt Axis

Abstract It was recently reported that mutations in the insulin receptor substrate 4 (IRS4) gene cause a novel form of X-linked congenital central hypothyroidism (OMIM 300904). To date, four different mutations, three frameshift and one nonsense, have been reported, with two affected male patients showing decreased basal, pulsatile, and total thyroid-stimulation hormone (TSH) secretion (PMID 30061370). Members of the IRS family canonically act as scaffold proteins between tyrosine kinase receptors and their downstream effectors. IRS4/Irs4 expression is enriched in the pituitary; however, its role in the hypothalamic-pituitary-thyroid (HPT) axis has not been studied in detail. We generated novel whole-body Irs4-knockout mouse lines using CRISPR-Cas9. A specific guide RNA was used to target the Cas9 enzyme to the 5’ end of the single exon Irs4 gene. A two-nucleotide deletion was introduced into Irs4, resulting in a frameshift and premature stop codon. We hypothesized that like IRS4 deficient patients, these mice would exhibit central hypothyroidism. Given that Irs4 is X-linked, we focused our initial characterization on males. Under normal laboratory conditions, Irs4 knockout mice do not exhibit differences in pituitary expression of Tshb, which encodes one of the subunits of the TSH heterodimer. Expression of the gene encoding the thyrotropin-releasing hormone (TRH) receptor, Trhr1, is also unperturbed in these knockout mice. Additionally, there are no differences in their serum thyroid hormones, T3 (triiodothyronine) and T4 (thyroxine). When Irs4 knockout males were placed on a low-iodine diet supplemented with propylthiouracil (PTU) for 3 weeks and rendered hypothyroid, their serum TSH increased similarly to wild-type males. Overall, Irs4 knockout males do not exhibit central hypothyroidism or phenocopy IRS4 deficient patients. Compensation by another IRS protein may explain euthyroidism in these mice.

scholarly journals Two Monogenetic Disorders, Activated PI3-Kinase-δ Syndrome 2 and Smith–Magenis Syndrome, in One Patient: Case Report and a Literature Review of Neurodevelopmental Impact in Primary Immunodeficiencies Associated With Disturbed PI3K Signaling

2021 ◽  
Vol 9 ◽  
Author(s):  
Nidia Moreno-Corona ◽  
Loïc Chentout ◽  
Lucie Poggi ◽  
Romane Thouenon ◽  
Cecile Masson ◽  
...  
Keyword(s):  
Viral Infections ◽  
Genetic Disorder ◽  
Pi3 Kinase ◽  
Pi3k Signaling ◽  
Gene Encoding ◽  
Regulatory Subunits ◽  
Neurodevelopmental Delay ◽  
Exon 11 ◽  
Complex Genetic Disorder ◽  
Splice Product

Activated PI3-kinase-δ syndrome 2 (APDS2) is caused by autosomal dominant mutations in the PIK3R1 gene encoding the p85α, p55α, and p50α regulatory subunits. Most diagnosed APDS2 patients carry mutations affecting either the splice donor or splice acceptor sites of exon 11 of the PIK3R1 gene responsible for an alternative splice product and a shortened protein. The clinical presentation of APDS2 patients is highly variable, ranging from mild to profound combined immunodeficiency features as massive lymphoproliferation, increased susceptibility to bacterial and viral infections, bronchiectasis, autoimmune manifestations, and occurrence of cancer. Non-immunological features such as growth retardation and neurodevelopmental delay have been reported for APDS2 patients. Here, we describe a patient suffering from an APDS2 associated with a Smith–Magenis syndrome (SMS), a complex genetic disorder affecting, among others, neurological manifestations and review the literature describing neurodevelopmental impacts in APDS2 and other PIDs/monogenetic disorders associated with dysregulated PI3K signaling.

scholarly journals A Novel Nonsense Mutation in FGB (c.1421G>A; p.Trp474Ter) in the Beta Chain of Fibrinogen Causing Hypofibrinogenemia with Bleeding Phenotype

Biomedicines ◽  
2020 ◽  
Vol 8 (12) ◽  
pp. 605
Author(s):  
Tomas Simurda ◽  
Rui Vilar ◽  
Jana Zolkova ◽  
Eliska Ceznerova ◽  
Zuzana Kolkova ◽  
...  
Keyword(s):  
Structural Changes ◽  
Phenotypic Expression ◽  
Clinical Manifestations ◽  
Severe Bleeding ◽  
Loss Of Function ◽  
Protein Modelling ◽  
Gene Encoding ◽  
Heterozygous Variant ◽  
Thrombotic Complications ◽  
Congenital Hypofibrinogenemia

Congenital hypofibrinogenemia is a rare bleeding disorder characterized by a proportional decrease of functional and antigenic fibrinogen levels. Hypofibrinogenemia can be considered the phenotypic expression of heterozygous loss of function mutations occurring within one of the three fibrinogen genes (FGA, FGB, and FGG). Clinical manifestations are highly variable; most patients are usually asymptomatic, but may appear with mild to severe bleeding or thrombotic complications. We have sequenced all exons of the FGA, FGB, and FGG genes using the DNA isolated from the peripheral blood in two unrelated probands with mild hypofibrinogenemia. Coagulation screening, global hemostasis, and functional analysis tests were performed. Molecular modeling was used to predict the defect of synthesis and structural changes of the identified mutation. DNA sequencing revealed a novel heterozygous variant c.1421G>A in exon 8 of the FGB gene encoding a Bβ chain (p.Trp474Ter) in both patients. Clinical data from patients showed bleeding episodes. Protein modelling confirmed changes in the secondary structure of the molecule, with the loss of three β sheet arrangements. As expected by the low fibrinogen levels, turbidity analyses showed a reduced fibrin polymerisation and imaging difference in thickness fibrin fibers. We have to emphasize that our patients have a quantitative fibrinogen disorder; therefore, the reduced function is due to the reduced concentration of fibrinogen, since the Bβ chains carrying the mutation predicted to be retained inside the cell. The study of fibrinogen molecules using protein modelling may help us to understand causality and effect of novel genetic mutations.

scholarly journals Viability of clathrin heavy-chain-deficient Saccharomyces cerevisiae is compromised by mutations at numerous loci: implications for the suppression hypothesis.

1991 ◽  
Vol 11 (8) ◽  
pp. 3868-3878 ◽  
Author(s):  
A L Munn ◽  
L Silveira ◽  
M Elgort ◽  
G S Payne
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Cell Growth ◽  
Heavy Chain ◽  
Secretory Pathway ◽  
Genetic Locus ◽  
Wild Type ◽  
Site Mutation ◽  
Gene Encoding ◽  
Clathrin Heavy Chain ◽  
Lethal Allele

The gene encoding clathrin heavy chain in Saccharomyces cerevisiae (CHC1) is not essential for growth in most laboratory strains tested. However, in certain genetic backgrounds, a deletion of CHC1 (chc1) results in cell death. Lethality in these chc1 strains is determined by a locus designated SCD1 (suppressor of clathrin deficiency) which is unlinked to CHC1 (S. K. Lemmon and E. W. Jones, Science 238:504-509, 1987). The lethal allele of SCD1 has no effect on cell growth when the wild-type version of CHC1 is present. This result led to the proposal that most yeast strains are viable in the absence of clathrin heavy chain because they possess the SCD1 suppressor. Discovery of another yeast strain that cannot grow without clathrin heavy chain has allowed us to perform a genetic test of the suppressor hypothesis. Genetic crosses show that clathrin-deficient lethality in the latter strain is conferred by a single genetic locus (termed CDL1, for clathrin-deficient lethality). By constructing strains in which CHC1 expression is regulated by the GAL10 promoter, we demonstrate that the lethal alleles of SCD1 and CDL1 are recessive. In both cases, very low expression of CHC1 can allow cells to escape from lethality. Genetic complementation and segregation analyses indicate that CDL1 and SCD1 are distinct genes. The lethal CDL1 allele does not cause a defect in the secretory pathway of either wild-type or clathrin heavy-chain-deficient yeast. A systematic screen to identify mutants unable to grow in the absence of clathrin heavy chain uncovered numerous genes similar to SCD1 and CDL1. These findings argue against the idea that viability of chc1 cells is due to genetic suppression, since this hypothesis would require the existence of a large number of unlinked genes, all of which are required for suppression. Instead, lethality appears to be a common, nonspecific occurrence when a second-site mutation arises in a strain whose cell growth is already severely compromised by the lack of clathrin heavy chain.

scholarly journals Homozygous Splice Site Mutation in ZP1 Causes Familial Oocyte Maturation Defect

Genes ◽  
2020 ◽  
Vol 11 (4) ◽  
pp. 382 ◽  
Author(s):  
Özlem Okutman ◽  
Cem Demirel ◽  
Firat Tülek ◽  
Veronique Pfister ◽  
Umut Büyük ◽  
...  
Keyword(s):  
Oocyte Maturation ◽  
Splice Site ◽  
Splice Site Mutation ◽  
Controlled Ovarian Hyperstimulation ◽  
Sequencing Analysis ◽  
Site Mutation ◽  
Vitro Fertilization ◽  
Maturation Defect ◽  
Exon 11

In vitro fertilization (IVF) involves controlled ovarian hyperstimulation using hormones to produce large numbers of oocytes. The success of IVF is tightly linked to the availability of mature oocytes. In most cases, about 70% to 80% of the oocytes are mature at the time of retrieval, however, in rare instances, all of them may be immature, implying that they were not able to reach the metaphase II (MII) stage. The failure to obtain any mature oocytes, despite a well conducted ovarian stimulation in repeated cycles is a very rare cause of primary female infertility, for which the underlying suspected genetic factors are still largely unknown. In this study, we present the whole exome sequencing analysis of a consanguineous Turkish family comprising three sisters with a recurrent oocyte maturation defect. Analysis of the data reveals a homozygous splice site mutation (c.1775-3C>A) in the zona pellucida glycoprotein 1 (ZP1) gene. Minigene experiments show that the mutation causes the retention of the intron 11 sequence between exon 11 and exon 12, resulting in a frameshift and the likely production of a truncated protein.

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