Association of a polymorphism of the ACVRL1 gene with sporadic arteriovenous malformations of the central nervous system.
OBJECTIVE
Important central nervous system (CNS) manifestations in patients with hereditary hemorrhagic telangiectasia (HHT) include arteriovenous malformations (AVMs) and dural arteriovenous fistulas (DAVFs). Hereditary hemorrhagic telangiectasia is caused by germline mutations of two genes: ENG (HHT Type 1) and ACVRL1 (HHT Type 2). The ENG gene variations have been associated with the formation of intracranial aneurysms. The authors studied whether sequence variations in ACVRL1 or ENG are associated with the development of clinically sporadic arteriovenous dysplasias and aneurysms of the CNS.


METHODS
The coding sequence (in 44 patients with AVMs and 27 with aneurysms) and the 5' end and the polyA site (in 53 patients with AVMs) of the ACVRL1 gene were analyzed for sequence variations using direct sequencing and single-strand conformational polymorphism analysis. One ENG and three ACVRL1 gene polymorphisms were genotyped using restriction enzyme-based analysis in 101 patients with sporadic AVMs and DAVFs of the CNS, 79 patients treated for intracranial aneurysms, and 202 control volunteers. The authors identified a statistically significant association between the IVS3 -35A/T polymorphism in intron 3 of the ACVRL1 gene and the development of AVMs and DAVFs (p = 0.004; odds ratio [OR] 1.73; 95% confidence interval [CI] 1.19-2.51; after adjustments for age and sex), but not aneurysms (crude OR 0.82; 95% CI 0.55-1.18).


CONCLUSIONS
The results of this study link ACVRL1 (HHT Type 2 gene) to the formation of the clinically sporadic variants of vascular malformations of the CNS most commonly seen in patients with HHT, that is, AVMs and DAVFs.
Simon
Matthias
M
Neurochirurgische Klinik and Institut für Klinische Biochemie, Universitatskliniken Bonn, Germany. Matthias.Simon@ukb.uni-bonn.de
Franke
Daniel
D
Ludwig
Michael
M
Aliashkevich
Ales F
AF
Köster
Gertraud
G
Oldenburg
Johannes
J
Boström
Azize
A
Ziegler
Andreas
A
Schramm
Johannes
J
D030301:Activin Receptors, Type II / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000235:genetics*; D001165:Arteriovenous Malformations / Q000235:genetics*; D016022:Case-Control Studies; D020785:Central Nervous System Vascular Malformations / Q000235:genetics*; D002648:Child; D000071063:Endoglin; D005260:Female; D006801:Humans; D002532:Intracranial Aneurysm / Q000235:genetics*; D007438:Introns / Q000235:genetics; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000235:genetics*
D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; D011956:Receptors, Cell Surface; C425364:ACVRL1 protein, human; D030301:Activin Receptors, Type II