A Progressive familial encephalopathy in infancy with calcifications of the basal ganglia and chronic cerebrospinal fluid lymphocytosis

Aicardi, Jean; Goutières, Françoise

doi:10.1002/ana.410150109

Cited by 417 publications

(294 citation statements)

References 15 publications

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“…An absence in our patients of specific clinical and biochemical features allows for the exclusion of well characterized disorders in which ICC occurs in combination with PMG [Chitayat et al, 1992;Samson et al, 1994;Sakai et al, 1997] or separately as a major diagnostic sign [Aicardi and Goutières, 1984;Coskun et al, 1990;Aalfs and Hennekam 1995;al-Mane et al, 1998;Rapin et al, 2006;Thomas-Sohl et al, 2004;Renella et al, 2006;Saillour et al, 2007;Briggs et al, 2008].…”

Section: Discussionmentioning

confidence: 93%

Band‐like intracranial calcification with simplified gyration and polymicrogyria: A distinct “pseudo‐TORCH” phenotype

Briggs

Wolf

D’Arrigo

et al. 2008

American J of Med Genetics Pt A

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The combination of intracranial calcification and polymicrogyria is usually seen in the context of intrauterine infection, most frequently due to cytomegalovirus. Rare familial occurrences have been reported. We describe five patients—two male–female sibling pairs, one pair born to consanguineous parents, and an unrelated female—with a distinct pattern of band‐like intracranial calcification associated with simplified gyration and polymicrogyria. Clinical features include severe post‐natal microcephaly, seizures and profound developmental arrest. Testing for infectious agents was negative. We consider that these children have the same recognizable “pseudo‐TORCH” phenotype inherited as an autosomal recessive trait. © 2008 Wiley‐Liss, Inc.

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Section: Discussionmentioning

confidence: 93%

Band‐like intracranial calcification with simplified gyration and polymicrogyria: A distinct “pseudo‐TORCH” phenotype

Briggs

Wolf

D’Arrigo

et al. 2008

American J of Med Genetics Pt A

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“…Five distinct mutations within the TREX1 gene were identified as the underlying cause of AGS (22), and a form of systemic lupus erythematosus, familial chilblain lupus, is also known to map to the same genetic locus (23). AGS is a severe neurological brain disease that shares many symptoms with Cree encephalopathy, microcephaly, intracranial calcification syndrome, and systemic lupus erythematosus (42). AGS symptoms also closely mimic those of in utero viral infections (43).…”

Section: Resultsmentioning

confidence: 99%

The Crystal Structure of TREX1 Explains the 3′ Nucleotide Specificity and Reveals a Polyproline II Helix for Protein Partnering

Silva

Choudhury

Bailey

et al. 2007

Journal of Biological Chemistry

102

160

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The TREX1 enzyme processes DNA ends as the major 3 3 5 exonuclease activity in human cells. Mutations in the TREX1 gene are an underlying cause of the neurological brain disease Aicardi-Goutières syndrome implicating TREX1 dysfunction in an aberrant immune response. TREX1 action during apoptosis likely prevents autoimmune reaction to DNA that would otherwise persist. To understand the impact of TREX1 mutations identified in patients with Aicardi-Goutières syndrome on structure and activity we determined the x-ray crystal structure of the dimeric mouse TREX1 protein in substrate and product complexes containing single-stranded DNA and deoxyadenosine monophosphate, respectively. The structures show the specific interactions between the bound nucleotides and the residues lining the binding pocket of the 3 terminal nucleotide within the enzyme active site that account for specificity, and provide the molecular basis for understanding mutations that lead to disease. Three mutant forms of TREX1 protein identified in patients with AicardiGoutières syndrome were prepared and the measured activities show that these specific mutations reduce enzyme activity by 4 -35,000-fold. The structure also reveals an 8-amino acid polyproline II helix within the TREX1 enzyme that suggests a mechanism for interactions of this exonuclease with other protein complexes.Processing of DNA ends is an important step in many DNA metabolic pathways such as replication, repair, and recombination. The 3Ј 3 5Ј exonucleases play a critical role in correcting fragmented, modified, mispaired, or even normal nucleotides to generate 3Ј termini suitable for downstream events. The drastic consequences that result from impaired 3Ј exonuclease activities underscore the importance of these enzymes for cell survival. Proofreading of DNA synthesis by 3Ј exonucleases is one of the major determinants of mutagenesis and genome stability and cells lacking this ability show a high incidence of cancers (1-3) (for review, see Ref. 4). Cells with defects in proteins containing 3Ј exonuclease activity, such as the Werner syndrome protein, MRE11, APE1, and p53 proteins display chromosomal instability, cell cycle checkpoint defects, and sensitivity to ionizing radiation (5-9).The major 3Ј 3 5Ј exonuclease activity detected in human cell extracts is catalyzed by the TREX1 enzyme. The genes encoding the TREX1 and closely related TREX2 proteins have been identified and cloned (10, 11), and the recombinant proteins confirm the robust catalytic nature of these enzymes (12, 13). Amino acid sequence analysis reveals the TREX proteins belong to the DnaQ family of 3Ј 3 5Ј exonucleases; a structurally conserved group of exonucleases that span Archaea and bacteria to humans and includes such proteins as the exonuclease domains of Werner syndrome protein, the bacterial ⑀ subunit of DNA polymerase III (⑀ subunit), and exonuclease I (Exo I) 2 (14 -17). A hallmark of the DnaQ family exonucleases is three conserved sequence motifs known as Exo I, II, and III. These motifs contain four ...

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“…Goutieres, described an unusual condition in a Portuguese family characterised by chronic lymphocyte infiltration into the cerebrospinal fluid (CSF), calcification of the basal ganglia and early onset progressive severe encephalopathy (brain degeneration) [1]. Since the clinical sequelae of this condition closely mimicked intra-uterine infection, cytomegalovirus was originally suspected as the causative agent.…”

Section: In 1984 Two French Paediatric Neurologists Jean Aicardi Andmentioning

confidence: 99%

TREX1 DNA exonuclease deficiency, accumulation of single stranded DNA and complex human genetic disorders

O’Driscoll

2008

DNA Repair

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A Progressive familial encephalopathy in infancy with calcifications of the basal ganglia and chronic cerebrospinal fluid lymphocytosis

Cited by 417 publications

References 15 publications

Band‐like intracranial calcification with simplified gyration and polymicrogyria: A distinct “pseudo‐TORCH” phenotype

Band‐like intracranial calcification with simplified gyration and polymicrogyria: A distinct “pseudo‐TORCH” phenotype

The Crystal Structure of TREX1 Explains the 3′ Nucleotide Specificity and Reveals a Polyproline II Helix for Protein Partnering

TREX1 DNA exonuclease deficiency, accumulation of single stranded DNA and complex human genetic disorders

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