Ring finger protein 213 is a protein that in humans is encoded by the RNF213 gene.
RNF213 is a 591kDa cytosolic E3 Ubiquitin-ligase with RING finger and AAA+ ATPase domains.
A genome-wide association study identified RNF213 as the first gene associated to Moyamoya disease.
Given that oxygen and glucose consumption scales with total neuron number, RNF213 may have played a role in facilitating the evolution of larger brains in primates.
A variant in the Ring Finger 213 gene (RNF213), altering arginine at position 4810 (p.R4810K), is associated with Moyamoya disease MMD in Asian populations.
However, there are a lack of data on the role of RNF213 in patients with MMD of additional ethnicities and diasporic Asian populations.
Cecchi et al., investigate the contribution of RNF213 alterations to MMD in an ethnically diverse population based in the United States.
Results confirm that alterations in RNF213 predispose patients of diverse ethnicities to MMD, and that the p.R4810K variant predisposes individuals of Asian descent in the United States to MMD 1).
The exact mechanism by which the RNF213 abnormality leads to MMD remains unknown. Ito et al. sought to clarify the role of RNF213 in angiogenesis under ischemic conditions using conventional RNF213 knockout mice and assessed the infarction volume, cerebral edema, and vascular density in the ischemic brain after transient middle cerebral artery occlusion (tMCAO). To further evaluate systemic angiogenesis following chronic ischemia, they investigated blood flow recovery using laser speckle flowmetry, the severity of ambulatory impairments, and vascular density in the hind-limb after permanent femoral artery ligation. Results were compared between homozygous RNF213 knockout mice (RNF213 -/-) and wild-type littermates (Wt). No significant differences were observed in infarction volume or the formation of edema following tMCAO, or in vascular density 28 days after tMCAO between RNF213 -/- and Wt. Blood flow recovery was significantly improved in RNF213 -/- from 3 to 28 days after femoral artery ligation, and angiogenesis as shown by vascular density in the hind-limb was significantly enhanced in RNF213 -/- at 28 days. The amelioration of ambulatory impairments was also evident in RNF213 -/-. Angiogenesis was enhanced in mice lacking RNF213 after chronic hind-limb ischemia, which suggested the potential role of the RNF213 abnormality in the development of pathological vascular networks in chronic ischemia 2).
The p.R4810K (rs112735431) variant is a founder polymorphism that is strongly associated with moyamoya disease in East Asia. Many non-p.R4810K rare variants of RNF213 have been identified in white moyamoya disease patients, although the ethnic mutations have not been investigated in this population. In the present study, we screened for RNF213 variants in 19 Slovakian and Czech moyamoya disease patients. A total of 69 RNF213 coding exons were directly sequenced in 18 probands and one relative who suffered from moyamoya disease in Slovakia and the Czech Republic. We previously reported one proband harboring RNF213 p.D4013N. Results from the present study identified four rare variants other than p.D4013N (p.R4019C, p.E4042K, p.V4146A, and p.W4677L) in four of the patients. P.V4146A was determined to be a novel de novo mutation, and p.R4019C and p.E4042K were identified as double mutations inherited on the same allele. P.W4677L, found in two moyamoya disease patients and an unaffected subject in the same pedigree, was a rare single nucleotide polymorphism. Functional analysis showed that RNF213 p.D4013N, p.R4019C and p.V4146A-transfected human umbilical vein endothelial cells displayed significant lowered migration, and RNF213 p.V4146A significantly reduced tube formation, indicating that these are disease-causing mutations. Results from the present study identified RNF213 rare variants in 22.2% (4/18 probands) of Slovakian and Czech moyamoya disease patients, confirming that RNF213 may also be a major causative gene in a relative large population of white patients 3).
Although RNF213 is a risk factor for moyamoya disease in East Asians, Zhou et al., demonstrated that it might also be a risk factor for IA in the FC population. It therefore appears that the function of RNF213 can be differently altered to predispose distinct populations to dissimilar neurovascular conditions, highlighting the importance of a population's background in genetic studies of heterogeneous disease 4).
Moyamoya Disease Explored Through RNF213: Genetics, Molecular Pathology, and Clinical Sciences (Current Topics in Environmental Health and Preventive Medicine) Moyamoya Disease Explored Through RNF213: Genetics, Molecular Pathology, and Clinical Sciences (Current Topics in Environmental Health and Preventive Medicine)
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This book presents the latest findings on biological, epidemiological, and clinical investigations of RNF213, which is thought to be involved in many biological processes and plays a key role in cerebro- and cardiovascular disease . By discussing the epidemiology and genetic epidemiology of the disease with a particular focus on the molecular function of RNF213, research using animal models, diagnosis, therapy and clinical management around the world, this work makes a valuable contribution to the study of the disease. Moyamoya Disease Explored Through RNF213 is an indispensable resource for both beginning and experienced researchers, pediatricians, neurologists, and neurosurgeons who are seeking comprehensive information on adult and childhood stroke.
Published on: 2017-03-22 Original language: English Number of items: 1 Dimensions: 9.30" h x .0" w x 6.10" l, Binding: Hardcover 185 pages
About the Author Akio Koizumi, Department of Health and Environmental Sciences, Graduate School of Medicine, Kyoto University
Kazuhiro Nagata, Laboratory of Molecular and Cellular biology, Faculty of Life Sciences, Kyoto Sangyo University
Kiyohiro Houkin, Department of Neurosurgery, Graduate School of Medicine, Hokkaido University
Teiji Tominaga, Department of Neurosurgery, Tohoku University School of Medicine
Susumu Miyamoto, Department of Neurosurgery, Graduate School of Medicine, Kyoto University
Shigeo Kure, Department of Pediatrics, Tohoku University School of Medicine
Elizabeth Tournier‐Lasserve, CHU Paris‐GH St‐Louis Lariboisière F‐Widal ‐ Hôpital Lariboisière