Mutations in a gene encoding a novel protein containing a phosphotyrosine-binding domain cause type 2 cerebral cavernous malformations

Abstract

Cerebral cavernous malformations (CCMs) are congenital vascular anomalies of the central nervous system that can result in hemorrhagic stroke, seizures, recurrent headaches, and focal neurologic deficits. Mutations in the gene KRIT1 are responsible for type 1 CCM (CCM1). We report that a novel gene, MGC4607, exhibits eight different mutations in nine families with type 2 CCM (CCM2). MGC4607, similar to the KRIT1 binding partner ICAP1alpha, encodes a protein with a phosphotyrosine-binding domain. This protein may be part of the complex pathway of integrin signaling that, when perturbed, causes abnormal vascular morphogenesis in the brain, leading to CCM formation.

Figure 1

Sequence traces of the eight CCM2 mutations. Each mutation is indicated by a black arrow. The extent of a 4-bp deletion is shown with conjoined arrows.

Figure 2

Northern blot analysis of MGC4607 expression. The 12 human tissues are indicated at the top, and size (in kb) is indicated on the left.

Figure 3

Schematic diagram of malcavernin. Each exon is shown as a box with the corresponding exon number. The PTB domain is shown in gray. The location and description of the eight CCM2 mutations are shown. Mutations affecting splice junctions are shown above, with the introns indicated by lines.