title: A large homozygous deletion in the SAMHD1 gene causes atypical Aicardi-Goutiéres syndrome associated with mtDNA deletions.
abstract: Aicardi-Goutiéres syndrome (AGS) is a genetic neurodegenerative disorder with clinical symptoms mimicking a congenital viral infection. Five causative genes have been described: three prime repair exonuclease1 (TREX1), ribonucleases H2A, B and C, and most recently SAM domain and HD domain 1 (SAMHD1). We performed a detailed clinical and molecular characterization of a family with autosomal recessive neurodegenerative disorder showing white matter destruction and calcifications, presenting in utero and associated with multiple mtDNA deletions. A muscle biopsy was normal and did not show any evidence of respiratory chain dysfunction. Southern blot analysis of tissue from a living child and affected fetuses demonstrated multiple mtDNA deletions. Molecular analysis of genes involved in mtDNA synthesis and maintenance (POLGα, POLGβ, Twinkle, ANT1, TK2, SUCLA1 and DGOUK) revealed normal sequences. Sequencing of TREX1 and ribonucleases H2A, B and C failed to reveal any mutations. Whole-genome homozygosity mapping revealed a candidate region containing the SAMHD1 gene. Sequencing of the gene in the affected child and two affected fetuses revealed a large deletion (9 kb), spanning the promoter, exon1 and intron 1. The parents were found to be heterozygous for this deletion. The identification of a homozygous large deletion in the SAMHD1 gene causing atypical AGS with multiple mtDNA deletions may add information regarding the involvement of mitochondria in self-activation of innate immunity by cell intrinsic components.
authors.affiliation: Molecular Genetics Laboratory, Wolfson Medical Center, Holon, Israel. leshinsky@wolfson.health.gov.il
authors.forename: Esther
authors.initials: E
authors.lastname: Leshinsky-Silver
authors.forename: Gustavo
authors.initials: G
authors.lastname: Malinger
authors.forename: Liat
authors.initials: L
authors.lastname: Ben-Sira
authors.forename: Dvora
authors.initials: D
authors.lastname: Kidron
authors.forename: Sarit
authors.initials: S
authors.lastname: Cohen
authors.forename: Shani
authors.initials: S
authors.lastname: Inbar
authors.forename: Tali
authors.initials: T
authors.lastname: Bezaleli
authors.forename: Arie
authors.initials: A
authors.lastname: Levine
authors.forename: Chana
authors.initials: C
authors.lastname: Vinkler
authors.forename: Dorit
authors.initials: D
authors.lastname: Lev
authors.forename: Tally
authors.initials: T
authors.lastname: Lerman-Sagie
mesh_terms: D020274:Autoimmune Diseases of the Nervous System / Q000235:genetics; D015139:Blotting, Southern; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007223:Infant; D008297:Male; D008928:Mitochondria / Q000737:chemistry / Q000235:genetics; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics*; D009421:Nervous System Malformations / Q000235:genetics; D010375:Pedigree; D011247:Pregnancy; D000076106:SAM Domain and HD Domain-Containing Protein 1
chemical_list: D004272:DNA, Mitochondrial; D000076106:SAM Domain and HD Domain-Containing Protein 1; C484280:SAMHD1 protein, human; D020559:Monomeric GTP-Binding Proteins