title: Cerebral arterial stenoses and stroke: novel features of Aicardi-Goutières syndrome caused by the Arg164X mutation in SAMHD1 are associated with altered cytokine expression.
abstract: Aicardi-Goutières syndrome (AGS) is a rare inborn multisystemic disease, resembling intrauterine viral infection and resulting in psychomotor retardation, spasticity and chilblain-likeskin lesions. Diagnostic criteria include intracerebral calcifications and elevated interferon-alpha and pterin levels in cerebrospinal fluid (CSF). We report on four adult siblings with unknown neurodegenerative disease presenting with cerebrovascular stenoses, stroke and glaucoma in childhood, two of whom died at the age of 40 and 29 years. Genome-wide homozygosity mapping identified 170 candidate genes embedded in a common haplotype of 8Mb on chromosome 20q11-13. Next generation sequencing of the entire region identified the c.490C>T (p.Arg164X) mutationin SAMHD1, a gene most recently described in AGS, on both alleles in all affected siblings.Clinical diagnosis of AGS was then confirmed by demonstrating intracerebral calcifications on cranial computed tomography in all siblings and elevated pterin levels in CSF in three of them. Inpatient fibroblasts, lack of SAMHD1 protein expression was associated with increased basal expression of IL8, while stimulated expression of IFNB1 was reduced. We conclude that cerebrovascular stenoses and stroke associated with the Arg164X mutation in SAMHD1 extend the phenotypic spectrum of AGS. The observed vascular changes most likely reflect a vasculitis caused by dysregulated inflammatory stress response.
authors.affiliation: Cologne Center for Genomics, University of Cologne, 50931 Cologne, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Thiele
authors.forename: Marcel
authors.initials: M
authors.lastname: du Moulin
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Barczyk
authors.forename: Christel
authors.initials: C
authors.lastname: George
authors.forename: Wolfram
authors.initials: W
authors.lastname: Schwindt
authors.forename: Gudrun
authors.initials: G
authors.lastname: Nürnberg
authors.forename: Michael
authors.initials: M
authors.lastname: Frosch
authors.forename: Gerhard
authors.initials: G
authors.lastname: Kurlemann
authors.forename: Johannes
authors.initials: J
authors.lastname: Roth
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Frank
authors.initials: F
authors.lastname: Rutsch
mesh_terms: D000328:Adult; D020274:Autoimmune Diseases of the Nervous System / Q000235:genetics; D001483:Base Sequence; D002539:Cerebral Arterial Diseases / Q000235:genetics*; D018389:Codon, Nonsense; D003241:Consanguinity; D003251:Constriction, Pathologic; D016207:Cytokines / Q000235:genetics; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000235:genetics; D005260:Female; D015870:Gene Expression; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D008297:Male; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics* / Q000276:immunology; D009421:Nervous System Malformations / Q000235:genetics; D010375:Pedigree; D000076106:SAM Domain and HD Domain-Containing Protein 1; D035781:Siblings; D020521:Stroke / Q000235:genetics*; D055815:Young Adult
chemical_list: D018389:Codon, Nonsense; D016207:Cytokines; D017931:DNA Primers; D000076106:SAM Domain and HD Domain-Containing Protein 1; C484280:SAMHD1 protein, human; D020559:Monomeric GTP-Binding Proteins