Ran/TC4 is a small nuclear G protein that forms a complex with the chromatin-bound guanine nucleotide release factor RCC1 (ref. 2). Loss of RCC1 causes defects in cell cycle progression, RNA export and nuclear protein import. Some of these can be suppressed by overexpression of Ran/TC4 (ref. 1), suggesting that Ran/TC4 functions downstream of RCC1. We have searched for proteins that bind Ran/TC4 by using a two-hybrid screen, and here we report the identification of RanBP2, a novel protein of 3,224 residues. This giant protein comprises an amino-terminal 700-residue leucine-rich region, four RanBP1-homologous (refs 9, 10) domains, eight zinc-finger motifs similar to those of NUP153 (refs 11, 12), and a carboxy terminus with high homology to cyclophilin. The molecule contains the XFXFG pentapeptide motif characteristic of nuclear pore complex (NPC) proteins, and immunolocalization suggests that RanBP2 is a constituent of the NPC. The fact that NLS-mediated nuclear import can be inhibited by an antibody directed against RanBP2 supports a functional role in protein import through the NPC.

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Moyamoya disease is a specific chronic cerebrovascular occlusive disease first reported by Japanese surgeons in 1957. The disease is characterized by stenosis or occlusion of the terminal portions of the bilateral internal carotid arteries and abnormal vascular network in the vicinity of the arterial occlusion. It may cause ischemic attacks or cerebral infarction, which is more frequent in children than in adults. In adults, cerebral hemorrhage may occur. The disease is distributed in all age groups, but the highest peak is in childhood at less than 10 years of age. The characteristic histopathologic features of the steno-occlusive arteries are fibrocellular thickening of the intima containing proliferated smooth muscle cells and prominently tortuous and often duplicated internal elastic lamina. There is usually no atheromatous plaque in the arterial wall. Etiology of the disease is still unknown; however, multifactorial inheritance is considered possible because of a higher incidence of the disease in Japanese and Koreans and approximately 10% of familial occurrence among the Japanese. Recent genetic studies suggest some responsible genetic foci in chromosomes 3, 6 and 17.

These data suggest that hMSCs together with bFGF in a skin defect model accelerate cutaneous wound healing as the hMSCs transdifferentiate into the epithelium.

Background and Purpose-Moyamoya disease is a cerebrovascular disease of unknown cause that mainly affects Japanese children. The incidence of familial occurrence accounts for 9% of cases. The characteristic lesions of moyamoya disease are occasionally seen in neurofibromatosis type 1, of which the causative gene (NF1) has been assigned to chromosome 17q11.2. Methods-To determine whether a gene related to moyamoya disease is located on chromosome 17, we conducted microsatellite linkage analyses on 24 families containing 56 patients with moyamoya disease. Leukocyte DNA extracted from the family members was subjected to polymerase chain reaction for a total of 22 microsatellite markers on chromosome 17. The amplified polymerase chain reaction fragments were analyzed with GeneScan on an automated sequencer. Results-Two-point linkage analysis gave a maximum log 10 odds (LOD) score of 3.11 at the recombination fraction of 0.00for the marker at locus D17S939. The affected pedigree member method also showed a significantly low P value (Ͻ1.0ϫ10 Ϫ5 ) for the 5 adjacent markers at 17q25. Multipoint linkage analysis also indicated that the disease gene is contained within the 9-cM region of D17S785 to D17S836, with a maximum LOD score of 4.58. Key Words: child Ⅲ genetics Ⅲ moyamoya disease S pontaneous occlusion of the circle of Willis (moyamoya disease) is a clinical entity of unknown cause that is characterized primarily by angiographic findings of bilateral occlusion at the terminal portion of the internal carotid artery with a characteristic telangiectasic vascular network ("moyamoya" vessels) at the base of the brain. Although the disease is extremely uncommon in non-Asian populations, 1 its estimated prevalence in the entire Japanese population is Ն3 per 100 000 persons. 2 Together with the elevated incidence in the Japanese population, there are several lines of evidence that indicate moyamoya disease is related to genetic factors 3-5 : (1) familial occurrence is seen in Ϸ9% of cases, (2) the incidence of the disease in both monozygotic twins is 80%, and (3) the sib recurrence rate and relative incidence rate in offspring are 42 and 34 times higher than the incidence rate in the general population. On the basis of the statistical data, Osawa et al 4 concluded that moyamoya disease is inherited most probably in a polygenic mode or an autosomal dominant fashion with a low penetrance. Conclusions-In this regard, it is quite interesting that the characteristic lesions of moyamoya disease are occasionally associated with neurofibromatosis type 1 (NF1; von Recklinghausen's disease), of which the responsible gene, NF1, is located on chromosome 17q11.2. 6 More than 50 cases of such an association have been reported so far. 4,[7][8][9] In the present study, we conducted linkage analyses on pedigrees of familial moyamoya disease to test the hypothesis that moyamoya disease is linked to a particular chromosomal region. Subjects and Methods AscertainmentEach member of 24 families who agreed to participate in the present study wa...

Moyamoya disease is characterized by bilateral stenosis and/or occlusion of the terminal portion of the internal carotid artery. Moyamoya disease is prevalent among patients <10 years of age. Although most cases appear to be sporadic, approximately 10% occur as familial cases. The incidence of familial cases has been increasing because noninvasive diagnostic equipment, such as magnetic-resonance imaging and magnetic-resonance angiography, can detect the disease in almost all affected patients, including asymptomatic patients, during screening studies. In this study, we performed a total genome search to identify the location of a familial moyamoya disease gene in 16 families, assuming an unknown mode of inheritance. A linkage was found between the disease and markers located at 3p24.2-26. A maximum NPL score of 3.46 was obtained with marker D3S3050. This is the first genetic locus found to be involved in the molecular pathogenesis of familial moyamoya disease.

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Either encephaloduroarteriosynangiosis (EDAS) or superficial temporal artery to middle cerebral artery (STA-MCA) anastomosis combined with encephalomyosynangiosis (EMS) has been performed on most of the children with moyamoya disease in our department. EDAS alone was done in the parietal region of 13 sides in 10 patients, and STA-MCA anastomosis with EMS in the parietal region was done on 7 sides in 6 patients. The surgical results of these two different procedures were then compared. Postoperative collateral formation was observed on external carotid angiograms, and the improvement of clinical symptoms was monitored for 1 year after the bypass procedure. STA-MCA anastomosis with EMS was found to be superior to EDAS in both the development of collateral circulation (P less than 0.05) and postoperative clinical improvement (P less than 0.01). EDAS can be done easily and safely on small children with moyamoya disease, but STA-MCA anastomosis with EMS is considered to be more appropriate, whenever possible.