Human Molecular Genetics, 2000, Vol. 9, No. 9 1351-1355
© 2000 Oxford University Press
KRIT1 is mutated in hyperkeratotic cutaneous capillary–venous malformation associated with cerebral capillary malformation
Laboratory of Human Molecular Genetics, Institute of Cellular Pathology (ICP) and Université Catholique de Louvain (UCL), Avenue Hippocrate 75+4, B-1200 Brussels, Belgium, 1Department of Neuropathology, University of Erlangen-Nürnberg, D-91054, Erlangen, Germany, 2Institute of Human Genetics, Genetica AG, CH-8001, Zurich, Switzerland, 3Centre for Vascular Anomalies, Division of Plastic Surgery, Université Catholique de Louvain, B-1200, Brussels, Belgium and 4Vascular Anomalies Center, Division of Plastic Surgery, Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Hyperkeratotic capillary–venous malformations (HCCVMs) are rare cutaneous lesions that occur in a small subgroup of patients with cerebral capillary malformation (CCM). CCMs cause neurological problems that range from headaches to life-threatening intracranial bleeding. CCMs and HCCVMs have a similar histopathological appearance of dilated capillary–venous channels. Genetic linkage of inherited CCMs has been established to three chromosomal loci, 3q25.2–27, 7p13–15 and 7q21–22. The first mutations were identified in the CCM1 gene (located on 7q21–22), which encodes KRIT1 protein (KREV1 interaction trapped 1), presumably a membrane-bound protein with signalling activity. Although KRIT1 is known to interact with KREV1/RAP1A, a Ras-family GTPase, the exact function of KRIT1 in the formation of cerebral capillaries and veins is poorly understood. In this study, we screened five families with CCM for mutations in the KRIT1 gene. In one of the families, CCMs co-segregated with HCCVMs. We identified a KRIT1
G103 mutation in this family, suggesting that this rare form of the condition is also caused by mutations in the CCM1 gene and that KRIT1 is probably important for cutaneous vasculature. Interestingly, this deletion introduces the earliest stop codon among identified mutations, suggesting a possible correlation between the molecular alteration and the cutaneous phenotype. Another novel mutation, KRIT1IVS2+2(T
C), was found in a family with only cerebral capillary–venous malformations.
+ To whom correspondence should be addressed. Tel: +32 2 764 6530; Fax: +32 2 764 7548; Email: vikkula@bchm.ucl.ac.be
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