title: Genetic predisposition of white matter infarction with protein S deficiency and R355C mutation.
abstract: BACKGROUND
  The association between protein S deficiency (PSD) and ischemic stroke is controversial and warrants further investigation.
  
  
  METHODS
  We conducted a genotype and MRI correlation study in a Chinese family in which hereditary PSD cosegregated with premature ischemic strokes. Six out of 11 family members inherited PSD type III in an autosomal dominant manner.
  
  
  RESULTS
  Among all PSD members, a novel missense mutation 1063C→T in exon 10 of protein S alpha (PROS1) was identified, which encoded a substitution of arginine to cysteine at position 355 (R355C) in the first globular domain of laminin A of protein S. Wild-type PROS1 sequences were retained in non-PSD members. MRI detected deep white matter infarctions predominantly distributed in the borderzone regions. The infarct topography was homogeneous in all adult mutant carriers. By contrast, cerebral infarction was absent in nonmutant carriers. Extensive investigation in the family did not reveal any confounding stroke risk. Haplotype analysis with high-density single nucleotide polymorphism markers revealed a 6.1-Mb minimally rearranged region (rs12494685 to rs1598240) in 3q11.2, lod = 3.0. Among the 7 annotated genes in this region, PROS1 is known to be associated with thrombotic disorders. MRI screening in an additional 10 PSD families without R355C showed no cerebral infarction.
  
  
  CONCLUSIONS
  PROS1 R355C mutation cosegregated with PSD type III and premature white matter infarctions in the index family. The findings substantiate an association between PSD and stroke. Study of the mechanism underlying this association may improve our understanding of premature cryptogenic white matter infarction.
authors.affiliation: Division of Neurology, Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong. drtleung@cuhk.edu.hk
authors.forename: T W
authors.initials: TW
authors.lastname: Leung
authors.forename: S-F
authors.initials: SF
authors.lastname: Yip
authors.forename: C-W
authors.initials: CW
authors.lastname: Lam
authors.forename: T L
authors.initials: TL
authors.lastname: Chan
authors.forename: W W M
authors.initials: WW
authors.lastname: Lam
authors.forename: D Y W
authors.initials: DY
authors.lastname: Siu
authors.forename: Y H
authors.initials: YH
authors.lastname: Fan
authors.forename: N P H
authors.initials: NP
authors.lastname: Chan
authors.forename: H S Y
authors.initials: HS
authors.lastname: Liu
authors.forename: L-C
authors.initials: LC
authors.lastname: Chan
authors.forename: K-S
authors.initials: KS
authors.lastname: Wong
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001120:Arginine; D001921:Brain / Q000098:blood supply / Q000473:pathology*; D002544:Cerebral Infarction / Q000235:genetics* / Q000473:pathology*; D002648:Child; D003545:Cysteine; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006723:Hong Kong; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D058977:Molecular Sequence Annotation; D020125:Mutation, Missense; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D017293:Protein S / Q000235:genetics*; D018455:Protein S Deficiency / Q000150:complications*; D012307:Risk Factors; D055815:Young Adult
chemical_list: D017293:Protein S; D001120:Arginine; D003545:Cysteine