Siebers-Renelt U.,Institute for Neuropathology |
Hans V.,Institute for Neuropathology |
Wesseling P.,VU University Amsterdam |
Wesseling P.,Radboud University Nijmegen |
Flucke U.,University Hospital Muenster
American Journal of Surgical Pathology
Germline SMARCB1 mutations predispose in schwannomatosis patients to the development of multiple benign schwannomas and, in some cases, meningiomas. Here, we report on a 34-year-old female patient who developed multiple schwannomas at various locations and in addition a leiomyoma of the cervix uteri. She carried a c.362+1G>A mutation that inactivates the donor splice site of exon 3. This mutation caused the schwannomatosis phenotype in this patient and was also demonstrated to be present in her affected mother. The leiomyoma displayed the genetic features that are characteristic for germline SMARCB1 mutation-associated tumors. The mutant allele retained in the tumor, whereas the wild-type allele was lost by loss of heterozygosity. Furthermore, the loss of heterozygosity involved net loss of chromosome 22. An NF2 mutation was not found. However, quantitative polymerase chain reaction suggested that both NF2 copies were lost in the tumor. Immunostaining with a SMARCB1 antibody revealed the mosaic expression pattern that is typical for schwannomatosis- associated tumors. To our knowledge, this is the first reported case of leiomyoma associated with a germline SMARCB1 mutation. As such, it widens the spectrum of benign tumors associated with a germline SMARCB1 mutation. Copyright © 2014 by Lippincott Williams & Wilkins. Source
Czabanka M.,Charite - Medical University of Berlin |
Pena-Tapia P.,University of Heidelberg |
Schubert G.A.,University of Heidelberg |
Heppner F.L.,Institute for Neuropathology |
And 4 more authors.
Background: Moyamoya disease (MMD) is graded based on digital subtraction angiography (DSA) with limited clinical applications. The aim was to identify clinically relevant parameters that may be used to develop a novel MMD grading system. Methods: In 40 MMD patients bilateral revascularization surgery was performed. Clinical data including DSA, MRI and regional cerebral blood flow studies were assessed. χ 2 test corrected for dependency of measurements at the same subject and analysis of receiver operating characteristics were used to identify key parameters. Grading system included: DSA (stenosis/occlusion = 1 point; stenosis/occlusion + intracranial compensation = 2 points; stenosis/occlusion + intracranial compensation + extra-intracranial compensation = 3 points), MRI (no sign of ischemia = 0 points; signs of ischemia = 1 point) and cerebrovascular reserve capacity (CVRC > -5% = 0 points; CVRC < -5% = 2 points). MMD grade I referred to 1-2 points, grade II to 3-4 and grade III to 5-6 points. Results: DSA, MRI and CVRC were dependent factors associated with the occurrence of clinical symptoms. Receiver operating characteristics analysis indentified the grading system as superior to each single parameter in predicting clinical symptoms. Fourteen hemispheres were graded as mild (grade I), 35 as moderate (grade II) and 31 as severe (grade III); 21% of grade I, 63% of grade II and 93% of grade III hemispheres were clinically symptomatic. Conclusions: The proposed grading system allows to stratify for clinical symptomatology in MMD patients. Future studies will have to investigate its value for assessing clinical symptoms and treatment risks. © 2011 S. Karger AG, Basel. Source
Leipold E.,Friedrich - Schiller University of Jena |
Liebmann L.,Jena University Hospital |
Korenke G.C.,Pediatric Center |
Heinrich T.,Jena University Hospital |
And 19 more authors.
The sensation of pain protects the body from serious injury. Using exome sequencing, we identified a specific de novo missense mutation in SCN11A in individuals with the congenital inability to experience pain who suffer from recurrent tissue damage and severe mutilations. Heterozygous knock-in mice carrying the orthologous mutation showed reduced sensitivity to pain and self-inflicted tissue lesions, recapitulating aspects of the human phenotype. SCN11A encodes Na v 1.9, a voltage-gated sodium ion channel that is primarily expressed in nociceptors, which function as key relay stations for the electrical transmission of pain signals from the periphery to the central nervous system. Mutant Na v 1.9 channels displayed excessive activity at resting voltages, causing sustained depolarization of nociceptors, impaired generation of action potentials and aberrant synaptic transmission. The gain-of-function mechanism that underlies this channelopathy suggests an alternative way to modulate pain perception. © 2013 Nature America, Inc. All rights reserved. Source
Kvarnung M.,Karolinska Institutet |
Kvarnung M.,Karolinska University Hospital |
Nilsson D.,Karolinska Institutet |
Nilsson D.,Karolinska University Hospital |
And 18 more authors.
Journal of Medical Genetics
Purpose: To delineate the molecular basis for a novel autosomal recessive syndrome, characterised by distinct facial features, intellectual disability, hypotonia and seizures, in combination with abnormal skeletal, endocrine, and ophthalmologic findings. Methods: We examined four patients from a consanguineous kindred with a strikingly similar phenotype, by using whole exome sequencing (WES). Functional validation of the initial results were performed by flow cytometry determining surface expression of glycosylphosphatidylinositol (GPI) and GPI anchored proteins and, in addition, by in vivo assays on zebrafish embryos. Results: The results from WES identified a homozygous mutation, c.547A>C ( p.Thr183Pro), in PIGT; Sanger sequencing of additional family members confirmed segregation with the disease. PIGT encodes phosphatidylinositol-glycan biosynthesis class T (PIG-T) protein, which is a subunit of the transamidase complex that catalyses the attachment of proteins to GPI. By flow cytometry, we found that granulocytes from the patients had reduced levels of the GPI anchored protein CD16b, supporting pathogenicity of the mutation. Further functional in vivo validation via morpholino mediated knockdown of the PIGT ortholog in zebrafish ( pigt) showed that, unlike human wild-type PIGT mRNA, the p.Thr183Pro encoding mRNA failed to rescue gastrulation defects induced by the suppression of pigt. Conclusions: We identified mutations in PIGT as the cause of a novel autosomal recessive intellectual disability syndrome. Our results demonstrate a new pathogenic mechanism in the GPI anchor pathway and expand the clinical spectrum of disorders belonging to the group of GPI anchor deficiencies. Source
Rausch T.,European Molecular Biology Laboratory EMBL |
Jones D.T.W.,Im Neuenheimer Feld |
Zapatka M.,Im Neuenheimer Feld |
Stutz A.M.,European Molecular Biology Laboratory EMBL |
And 55 more authors.
Genomic rearrangements are thought to occur progressively during tumor development. Recent findings, however, suggest an alternative mechanism, involving massive chromosome rearrangements in a one-step catastrophic event termed chromothripsis. We report the whole-genome sequencing-based analysis of a Sonic-Hedgehog medulloblastoma (SHH-MB) brain tumor from a patient with a germline TP53 mutation (Li-Fraumeni syndrome), uncovering massive, complex chromosome rearrangements. Integrating TP53 status with microarray and deep sequencing-based DNA rearrangement data in additional patients reveals a striking association between TP53 mutation and chromothripsis in SHH-MBs. Analysis of additional tumor entities substantiates a link between TP53 mutation and chromothripsis, and indicates a context-specific role for p53 in catastrophic DNA rearrangements. Among these, we observed a strong association between somatic TP53 mutations and chromothripsis in acute myeloid leukemia. These findings connect p53 status and chromothripsis in specific tumor types, providing a genetic basis for understanding particularly aggressive subtypes of cancer. © 2012 Elsevier Inc. Source