A large homozygous deletion in the SAMHD1 gene causes atypical Aicardi–Goutiéres syndrome associated with mtDNA deletions

Abstract

Aicardi-Goutié res 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 (POLGa, POLGb, 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.

SAMHD1 restricts the replication of human immunodeficiency virus type 1 by depleting the intracellular pool of deoxynucleoside triphosphates

“…The role of Vpx in counteracting APOBEC3A is unclear, but it is possible that under conditions of low dNTP caused by SAMHD1, in which reverse transcription is slowed, APOBEC3A more effectively deaminates nascent reverse transcripts. It is noteworthy that a large homozygous deletion in the SAMHD1 gene has been associated with mitochondrial DNA deletions, as mitochondrial diseases are often the result of mutations in the genes encoding enzymes that are involved in dNTP metabolism 30-32 .…”

Intracellular nucleotide levels and the control of retroviral infections

“…Collectively, these findings support that the extremely low cellular dNTP pool serves as a myeloid cell specific biochemical anti-lentiviral restriction factor, which is maintained by SAMHD1 dNTP triphosphohydrolase activity. Interestingly, genetic alterations in SAMDH1 result in a rare human genetic developmental disorder, Aicardi-Goutières syndrome (AGS), which mimics viral infection and immune activation (39, 53, 66). A recent study reported that the CD14 + monocytes from AGS patients are highly susceptible to HIV-1 infection, which is consistent with the idea that SAMHD1 restricts HIV replication in myeloid cell types (5).…”

Aicardi–Goutieres syndrome: from patients to genes and beyond

“…Others are advocating the use of chilblain as another diagnostic sign for AGS (38), especially that AGS-associated chilblain lesions has been observed in all five complementation groups. A homozygous large deletion in the SAMHD1 gene was shown to cause multiple mtDNA deletions (43). Compellingly, another de novo dominant negative mutation in TREX1 at the same amino acid residue (D200H) and mutations in SAMHD1 has led to a combination of both AGS and SLE in patients (33,40).…”