title: FAM222B Is Not a Likely Novel Candidate Gene for Cerebral Cavernous Malformations.
abstract: Cerebral cavernous malformations (CCMs) are prevalent slow-flow vascular lesions which harbour the risk to develop intracranial haemorrhages, focal neurological deficits, and epileptic seizures. Autosomal dominantly inherited CCMs were found to be associated with heterozygous inactivating mutations in 3 genes, CCM1 (KRIT1), CCM2 (MGC4607), and CCM3 (PDCD10) in 1999, 2003 and 2005, respectively. Despite the availability of high-throughput sequencing techniques, no further CCM gene has been published since. Here, we report on the identification of an autosomal dominantly inherited frameshift mutation in a gene of thus far unknown function, FAM222B (C17orf63), through exome sequencing of CCM patients mutation-negative for CCM1-3. A yeast 2-hybrid screen revealed interactions of FAM222B with the tubulin cytoskeleton and STAMBP which is known to be associated with microcephaly-capillary malformation syndrome. However, a phenotype similar to existing models was not found, neither in fam222bb/fam222ba double mutant zebrafish generated by transcription activator-like effector nucleases nor in an in vitro sprouting assay using human umbilical vein endothelial cells transfected with siRNA against FAM222B. These observations led to the assumption that aberrant FAM222B is not involved in the formation of CCMs.
authors: Department of Human Genetics, University Medicine Greifswald and Interfaculty Institute of Genetics and Functional Genomics, University of Greifswald, Greifswald, Germany.
authors: Stefanie
authors: S
authors: Spiegler
authors: Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt, Frankfurt am Main, Germany; Hubrecht Institute - KNAW & UMC Utrecht, Utrecht, The Netherlands.
authors: Bettina
authors: B
authors: Kirchmaier
authors: Department of Human Genetics, University Medicine Greifswald and Interfaculty Institute of Genetics and Functional Genomics, University of Greifswald, Greifswald, Germany.
authors: Matthias
authors: M
authors: Rath
authors: Department of Neuropaediatrics, Children's Hospital, Oldenburg, Germany.
authors: G Christoph
authors: GC
authors: Korenke
authors: Vascular Signaling and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Fabian
authors: F
authors: Tetzlaff
authors: Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors: Maartje
authors: M
authors: van de Vorst
authors: Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors: Kornelia
authors: K
authors: Neveling
authors: Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt, Frankfurt am Main, Germany.
authors: Amparo
authors: A
authors: Acker-Palmer
authors: Department of Human Genetics, University Medicine Greifswald and Interfaculty Institute of Genetics and Functional Genomics, University of Greifswald, Greifswald, Germany.
authors: Andreas W
authors: AW
authors: Kuss
authors: Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors: Christian
authors: C
authors: Gilissen
authors: Vascular Signaling and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Andreas
authors: A
authors: Fischer
authors: Institute for Cardiovascular Organogenesis and Regeneration, Cells-in-Motion Cluster of Excellence, Faculty of Medicine, University of Münster, Münster, Germany; Hubrecht Institute - KNAW & UMC Utrecht, Utrecht, The Netherlands.
authors: Stefan
authors: S
authors: Schulte-Merker
authors: Department of Human Genetics, University Medicine Greifswald and Interfaculty Institute of Genetics and Functional Genomics, University of Greifswald, Greifswald, Germany.
authors: Ute
authors: U
authors: Felbor
keywords: Angiogenesis; Animal models; Cerebral cavernous malformations; Cerebrovascular disease; Intracerebral haemorrhage