title: Atypical Aicardi-Goutieres syndrome: is the WRN locus a modifier?
abstract: We describe a 28-year-old Turkish man with consanguineous parents who presented with an aged appearance with prematurely gray hair and scleroderma-like skin, spastic paraplegia, and apparent disability. The proband and each of his parents were heterozygous for a mutation in WRN, which could not explain his symptoms. Exome sequencing of the proband's blood DNA showed a homozygous c.626-1G > C mutation in intron 5 of the SAMHD1 gene, which encodes a triphosphohydrolase involved in the regulation of intracellular dNTP pools and which is mutated in Aicardi-Goutieres syndrome. The RNA studies confirmed aberrant splicing of exon 6, and family studies showed that both parents are heterozygous for this mutation. We conclude that mutations in SAMHD1 - in addition to causing an early-onset form of encephalopathy in Aicardi-Goutieres syndrome - may present with modest signs of accelerated aging similar to Werner syndrome. The extent to which heterozygosity at the WRN locus may modify the effect of biallelic SAMHD1 mutations is unknown. It is conceivable that synergistic effects of these two mutations might be responsible for the unusual phenotype.
authors.affiliation: Institute of Human Genetics, University of Ulm, Ulm, Germany.
authors.forename: Davor
authors.initials: D
authors.lastname: Lessel
authors.forename: Bidisha
authors.initials: B
authors.lastname: Saha
authors.forename: Fuki
authors.initials: F
authors.lastname: Hisama
authors.forename: Bahar
authors.initials: B
authors.lastname: Kaymakamzade
authors.forename: Gulay
authors.initials: G
authors.lastname: Nurlu
authors.forename: Yasemin
authors.initials: Y
authors.lastname: Gursoy-Özdemir
authors.forename: Holger
authors.initials: H
authors.lastname: Thiele
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: George M
authors.initials: GM
authors.lastname: Martin
authors.forename: Christian
authors.initials: C
authors.lastname: Kubisch
authors.forename: Junko
authors.initials: J
authors.lastname: Oshima
mesh_terms: D000328:Adult; D020274:Autoimmune Diseases of the Nervous System / Q000235:genetics*; D005090:Exodeoxyribonucleases / Q000235:genetics*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009421:Nervous System Malformations / Q000235:genetics*; D053484:RecQ Helicases / Q000235:genetics*; D000076106:SAM Domain and HD Domain-Containing Protein 1; D014898:Werner Syndrome / Q000235:genetics; D000071657:Werner Syndrome Helicase
chemical_list: D005090:Exodeoxyribonucleases; D000076106:SAM Domain and HD Domain-Containing Protein 1; C484280:SAMHD1 protein, human; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase; D020559:Monomeric GTP-Binding Proteins
keywords: Aicardi-Goutieres syndrome; Mendelian disease; SAMHD1; WRN; Werner syndrome; molecular genetics; neurology