The novel acceptor splice site mutation 11396(G-&gt;A) in the factor XII gene causes a truncated transcript in cross-reacting material negative patients

Schloesser, Manfred; Hofferbert, Sigrun; U, Bartz; Lutze, Gerd; Lämmle, Bernhard; Engel, Wolfgang

doi:10.1093/hmg/4.7.1235

Cited by 25 publications

(15 citation statements)

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“…33 Another variant, c.1681-1 G.A in F12, alters a canonical splice acceptor, leading to a truncated transcript, reduced protein expression, increased partial thromboplastin time, and recurrent superficial venous thrombosis. 30 The role of coagulation activity in aHUS patients has been evaluated at the mRNA level in one study, in which gene expression was quantitated in glomeruli from archival paraffinembedded renal biopsies. 34 Expression of antifibrinolytic, prothrombotic plasminogen activator inhibitor-1 and antithrombotic thrombomodulin were increased, and expression of profibrinolytic, antithrombotic tissue plasminogen activator was decreased compared with controls, suggesting that reduction of fibrinolysis is important in aHUS.…”

Section: Discussionmentioning

confidence: 99%

“…Other interesting ultrarare DRVs included a G-to-A transition that alters a canonical splice site in F12 (c.1681-1G.A) and leads to factor XII deficiency. 30 Novel nsRV Identification Among 18 novel variants that we identified, there were 15 missense, 2 frame-shift, and 1 splice site change variants (Supplemental Table 1). These variants included a G-to-C transversion in VWF, c.4165G.C (p.Glu1389Gln), that alters the same nucleotide as a DRV (c.4165G.A, p.Glu1389Lys), which is reported to cause type 2 von Willebrand disease by reducing amounts of high-molecular weight VWF and VWF-platelet binding.…”

Section: Sequencing Quality Metrics and Variant Callingmentioning

confidence: 99%

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Comprehensive Genetic Analysis of Complement and Coagulation Genes in Atypical Hemolytic Uremic Syndrome

Maga

Meyer

et al. 2014

Journal of the American Society of Nephrology

207

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Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy caused by uncontrolled activation of the alternative pathway of complement at the cell surface level that leads to microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney failure. In approximately one half of affected patients, pathogenic loss-of-function variants in regulators of complement or gain-of-function variants in effectors of complement are identified, clearly implicating complement in aHUS. However, there are strong lines of evidence supporting the presence of additional genetic contributions to this disease. To identify novel aHUS-associated genes, we completed a comprehensive screen of the complement and coagulation pathways in 36 patients with sporadic aHUS using targeted genomic enrichment and massively parallel sequencing. After variant calling, quality control, and hard filtering, we identified 84 reported or novel nonsynonymous variants, 22 of which have been previously associated with disease. Using computational prediction methods, 20 of the remaining 62 variants were predicted to be deleterious. Consistent with published data, nearly one half of these 42 variants (19; 45%) were found in genes implicated in the pathogenesis of aHUS. Several genes in the coagulation pathway were also identified as important in the pathogenesis of aHUS. PLG, in particular, carried more pathogenic variants than any other coagulation gene, including three known plasminogen deficiency mutations and a predicted pathogenic variant. These data suggest that mutation screening in patients with aHUS should be broadened to include genes in the coagulation pathway.

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Section: Discussionmentioning

confidence: 99%

Section: Sequencing Quality Metrics and Variant Callingmentioning

confidence: 99%

Comprehensive Genetic Analysis of Complement and Coagulation Genes in Atypical Hemolytic Uremic Syndrome

Maga

Meyer

et al. 2014

Journal of the American Society of Nephrology

207

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“…Factor XII deficiency can be caused by variants in F12; a heterozygous variant can lead to an intermediated level of factor XII activity, whereas homozygous or compound heterozygous variants lead to almost no activity (o1%). 38,39 The current individual had a factor XII activity o1%, and a paternal inherited loss of function variant in F12, c.827G4A (p.(Trp276*)), but his father had a normal factor XII activity. The mother had an intermediate factor XII activity, but no variant could be identified in her exome results.…”

Section: Pi-plc Treatment and Facs Analysismentioning

confidence: 89%

Cerebral visual impairment and intellectual disability caused by PGAP1 variants

et al. 2015

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Homozygous variants in PGAP1 (post-GPI attachment to proteins 1) have recently been identified in two families with developmental delay, seizures and/or spasticity. PGAP1 is a member of the glycosylphosphatidylinositol anchor biosynthesis and remodeling pathway and defects in this pathway are a subclass of congenital disorders of glycosylation. Here we performed whole-exome sequencing in an individual with cerebral visual impairment (CVI), intellectual disability (ID), and factor XII deficiency and revealed compound heterozygous variants in PGAP1, c.274_276del (p.(Pro92del)) and c.921_925del (p.(Lys308Asnfs*25)). Subsequently, PGAP1-deficient Chinese hamster ovary (CHO)-cell lines were transfected with either mutant or wild-type constructs and their sensitivity to phosphatidylinositol-specific phospholipase C (PI-PLC) treatment was measured. The mutant constructs could not rescue the PGAP1-deficient CHO cell lines resistance to PI-PLC treatment. In addition, lymphoblastoid cell lines (LCLs) of the affected individual showed no sensitivity to PI-PLC treatment, whereas the LCLs of the heterozygous carrier parents were partially resistant. In conclusion, we report novel PGAP1 variants in a boy with CVI and ID and a proven functional loss of PGAP1 and show, to our knowledge, for the first time this genetic association with CVI. INTRODUCTIONCerebral visual impairment (CVI) accounts for 27% of the visual impairment in children, and is due to a disorder in projection and/or interpretation of the visual input in the brain. 1-3 Acquired damages, for example, due to preterm birth, are well known causes of CVI, whereas genetic factors are largely unidentified. 4 Several chromosomal aberrations have been associated with CVI, such as Phelan-McDermid syndrome (22q13.3 deletion) and 1p36 microdeletion syndrome. 5 Moreover, single-gene disorders can be implicated in CVI, and, recently, we identified de novo variants in NR2F1 as a cause of CVI. 6 In addition, in several congenital disorders of glycosylation (CDG type 1a, type 1q and type 1v) CVI has been reported. 4,[7][8][9] Glycosylation disorders are caused by a defect in the glycosylation of glycoproteins and glycolipids, and one subclass is the defect in glycosylphosphatidylinositol (GPI) anchor glycosylation. 10 GPI anchor many cell-surface proteins with various functions, so called GPI-anchored proteins (GPI-APs), to the membrane of eukaryotic cells. 11-13 GPI is synthesized in the endoplasmic reticulum, transferred to the proteins, and remodeled. During the biosynthesis of GPI anchors, an acyl chain is linked to the inositol. This acyl chain is a transient structure and is necessary for efficient completion of later steps in GPI biosynthesis. After the attachment of GPI to the protein, this acyl chain is removed by PGAP1 (post-GPI attachment to proteins 1), the first step of the remodeling phase. 14 Subsequently, the GPI anchor is transported from the endoplasmic reticulum to the plasma membrane through the Golgi apparatus and further remodeled. When the inositol-linked...

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“…5 Soluble CD26 and sCD30 are age dependent, with serum levels of sCD26 increasing until adolescence and sCD30 decreasing throughout childhood. 7 These factors should be taken into account when evaluating the potential clinical utility of these markers.…”

Section: Iis Hospital La Fementioning

confidence: 99%