China
Africa
Explore chapters and articles related to this topic
Severe male factor infertility: Genetic consequences and recommendations for genetic testing
Published in David K. Gardner, Ariel Weissman, Colin M. Howles, Zeev Shoham, Textbook of Assisted Reproductive Techniques, 2017
Katrien Stouffs, Willy Lissens, Sara Seneca
Very rarely, patients with other mostly syndrome- associated genetic defects may consult at a male infertility clinic. Up to 80% of patients with Noonan syndrome present with oligozoospermia or azoospermia as a result of cryptorchidism (67). The diagnosis is so far based on other symptoms, including small stature, chest deformity, a rather typical facial dysmorphism, and congenital heart disease. Defects in a gene on chromosome 12q24.1, PTPN11, are responsible for approximately 40% of patients with Noonan syndrome (68). Another six genes involved in Noonan syndrome have been identified; all seven known genes account for around 60% of cases. Consequently, more (currently unknown) genes are involved in Noonan syndrome. The autosomal dominant inheritance asks for genetic counseling. Other possible patients may be affected by Aarskog-Scott syndrome with acrosomal sperm defects (69, 70) or Beckwith-Wiedemann syndrome with cryptorchidism (71). Syndromes such as Bardet-Biedl syndrome and Prader-Willi syndrome, both presenting with hypogonadism, are associated with other major symptoms, including (severe) mental retardation, which limit procreation (72–74). Prader-Willi syndrome is an imprinting syndrome resulting from the absence of expression of the paternal alleles in the 15q11-q13 imprinted region (75–77). Other causes of male infertility include deficiencies in enzymes involved in the synthesis of testosterone (64, 66), luteinizing hormone, and luteinizing hormone receptor (78, 79).
Screening and diagnosis of inherited platelet disorders
Published in Critical Reviews in Clinical Laboratory Sciences, 2022
Alex Bourguignon, Subia Tasneem, Catherine P. Hayward
Some PFDs cause unique impairments in hemostasis. Scott syndrome is a rare, recessive PFD caused by mutations in ANO6, which encodes the calcium-dependent phospholipid scramblase anoctamin 6 [74]. Scott syndrome severely impairs the activation-induced expression of procoagulant phospholipids on the outer surface of platelets and other cells [74]. Quebec platelet disorder (QPD) is a unique α-granule disorder caused by a duplication mutation of PLAU that repositions a downstream, megakaryocyte-specific gene enhancer element that “rewires” PLAU; the consequence is a unique, platelet-dependent, gain-of-function defect in fibrinolysis, due to >100 increased levels of urokinase plasminogen activator (uPA) in platelets and megakaryocytes [113]. QPD results in intraplatelet plasmin generation, which proteolyzes diverse α-granule proteins, and accelerates clot lysis when QPD platelets release uPA [114].
Why do platelets express K+ channels?
Published in Platelets, 2021
Joy R Wright, Martyn P. Mahaut-Smith
Full platelet activation requires a sustained elevation of intracellular calcium, resulting in the externalization of the negatively charged membrane phospholipid component phosphatidylserine (PS) from the inner leaflet of the platelet membrane. Scott syndrome patients have a mild bleeding phenotype and have been noted to be deficient in the scramblase mechanism that facilitates PS exposure in erythrocytes and platelets, and also in the ability to produce platelet microparticles from the platelet surface membrane [28]. This defect in platelet procoagulant response may be due in part to reduced Gardos channel function, since the impaired procoagulant response in Scott patients following platelet activation with combined collagen and thrombin application was almost completely restored to normal levels by the K+ ionophore valinomycin [13]. Interestingly, valinomycin will insert into both intracellular and surface membranes [29] and could exert its observed effect at least in part by affecting mitochondrial membrane potential which has a key influence on procoagulant activity. Whether KCa3.1 is also present in platelet organellar membranes is unknown. Experiments in SK4-/- transgenic mice suggest that the Gardos channel also plays a role in stromal cell-derived factor 1 (SDF-1)-dependent platelet migration [30]. A further potential role for KCa3.1 in platelets and megakaryocytes is the regulation of cell volume, as proposed in the human megakaryocytic cell line DAMI [31].
Detecting post-translational modification signatures as potential biomarkers in clinical mass spectrometry
Published in Expert Review of Proteomics, 2018
Ruzanna Mnatsakanyan, Gerta Shema, Mark Basik, Gerald Batist, Christoph H. Borchers, Albert Sickmann, René P. Zahedi
Solari et al. applied quantitative iTRAQ-8plex-based ChaFRADIC and (phospho)proteomics to platelets isolated from the only Scott syndrome patient available worldwide. The Scott syndrome is a rare but likely underdiagnosed bleeding disorder associated with mutations in ANO6 that lead to an impaired procoagulant response [179]. From only 20 µg of protein per sample, they quantified 1596 N-terminal peptides between activated patient and control platelets, 180 of which were confirmed as calpain-regulated (corresponding to 106 proteins) and 23 (corresponding to 23 proteins) were confirmed as caspase-regulated. The authors detected reduced calpain-dependent cleavage of cytoskeleton-linked and signaling proteins in the Scott patient, in agreement with increased phosphorylation states. While in this study, the high sensitivity was achieved using a rather elaborate HPLC-based ChaFRADIC workflow, the authors have recently developed a tip-based improvement of the procedure that allows quantitative N-terminomics with high sensitivity [180].