Aicardi-Goutieres Syndrome (AGS) is an autosomal recessive encephalopathy characterized by basal ganglia and white matter calcification in the presence of chronic cerebrospinal fluid lymphocytosis, and a raised level of cerebrospinal fluid IFNalpha. There is progressive neurological dysfunction resulting in a failure of development of expected physical and social skills. AGS presents in infancy and is lethal in ~40% of cases. It can be caused by mutations in the following genes, TREX1, RNaseH2 and SAMHD1 that lead to excessive intracellular accumulation of DNA and abnormal type I IFN metabolism.
Category
Immune system disease
Brite
Human diseases in ICD-11 classification [BR:br08403]
05 Endocrine, nutritional or metabolic diseases
Metabolic disorders
Inborn errors of metabolism
5C55 Inborn errors of purine, pyrimidine or nucleotide metabolism
H00290 Aicardi-Goutieres syndrome
08 Diseases of the nervous system
Disorders with neurocognitive impairment as a major feature
8A2Y Other specified disorders with neurocognitive impairment as a major feature
H00290 Aicardi-Goutieres syndrome
Pathway-based classification of diseases [BR:br08402]
Replication and repair
nt06509 DNA replication
H00290 Aicardi-Goutieres syndrome
Immune system
nt06519 RLR signaling
H00290 Aicardi-Goutieres syndrome
nt06520 CGAS-STING signaling
H00290 Aicardi-Goutieres syndrome
Rice GI, Bond J, Asipu A, Brunette RL, Manfield IW, Carr IM, Fuller JC, Jackson RM, Lamb T, Briggs TA, Ali M, Gornall H, Couthard LR, Aeby A, Attard-Montalto SP, Bertini E, Bodemer C, Brockmann K, Brueton LA, Corry PC, Desguerre I, Fazzi E, Cazorla AG, Gener B, Hamel BC, Heiberg A, Hunter M, van der Knaap MS, Kumar R, Lagae L, Landrieu PG, Lourenco CM, Marom D, McDermott MF, van der Merwe W, Orcesi S, Prendiville JS, Rasmussen M, Shalev SA, Soler DM, Shinawi M, Spiegel R, Tan TY, Vanderver A, Wakeling EL, Wassmer E, Whittaker E, Lebon P, Stetson DB, Bonthron DT, Crow YJ
Title
Mutations involved in Aicardi-Goutieres syndrome implicate SAMHD1 as regulator of the innate immune response.
Uggenti C, Lepelley A, Depp M, Badrock AP, Rodero MP, El-Daher MT, Rice GI, Dhir S, Wheeler AP, Dhir A, Albawardi W, Fremond ML, Seabra L, Doig J, Blair N, Martin-Niclos MJ, Della Mina E, Rubio-Roldan A, Garcia-Perez JL, Sproul D, Rehwinkel J, Hertzog J, Boland-Auge A, Olaso R, Deleuze JF, Baruteau J, Brochard K, Buckley J, Cavallera V, Cereda C, De Waele LMH, Dobbie A, Doummar D, Elmslie F, Koch-Hogrebe M, Kumar R, Lamb K, Livingston JH, Majumdar A, Lorenco CM, Orcesi S, Peudenier S, Rostasy K, Salmon CA, Scott C, Tonduti D, Touati G, Valente M, van der Linden H Jr, Van Esch H, Vermelle M, Webb K, Jackson AP, Reijns MAM, Gilbert N, Crow YJ
Title
cGAS-mediated induction of type I interferon due to inborn errors of histone pre-mRNA processing.
Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterised by the production of IgG autoantibodies that are specific for self-antigens, such as DNA, nuclear proteins and certain cytoplasmic components, in association with a diverse array of clinical manifestations. The primary pathological findings in patients with SLE are those of inflammation, vasculitis, immune complex deposition, and vasculopathy. Immune complexes comprising autoantibody and self-antigen is deposited particularly in the renal glomeruli and mediate a systemic inflammatory response by activating complement or via Fc{gamma}R-mediated neutrophil and macrophage activation. Activation of complement (C5) leads to injury both through formation of the membrane attack complex (C5b-9) or by generation of the anaphylatoxin and cell activator C5a. Neutrophils and macrophages cause tissue injury by the release of oxidants and proteases. It has been reported that there is a relatively high genetic component behind SLE. The data of family-based studies point toward an oligogenic background, with several susceptibility genes (SLEB) acting on disease expression along with environmental factors.
Category
Immune system disease
Brite
Human diseases in ICD-11 classification [BR:br08403]
04 Diseases of the immune system
Nonorgan specific systemic autoimmune disorders
4A40 Lupus erythematosus
H00080 Systemic lupus erythematosus
Pathway-based classification of diseases [BR:br08402]
Immune system
nt06517 TLR signaling
H00080 Systemic lupus erythematosus
nt06520 CGAS-STING signaling
H00080 Systemic lupus erythematosus
nt06537 TCR/BCR signaling
H00080 Systemic lupus erythematosus
Kyogoku C, Langefeld CD, Ortmann WA, Lee A, Selby S, Carlton VE, Chang M, Ramos P, Baechler EC, Batliwalla FM, Novitzke J, Williams AH, Gillett C, Rodine P, Graham RR, Ardlie KG, Gaffney PM, Moser KL, Petri M, Begovich AB, Gregersen PK, Behrens TW
Title
Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE.
Melki I, Allaeys I, Tessandier N, Mailhot B, Cloutier N, Campbell RA, Rowley JW, Salem D, Zufferey A, Laroche A, Levesque T, Patey N, Rauch J, Lood C, Droit A, McKenzie SE, Machlus KR, Rondina MT, Lacroix S, Fortin PR, Boilard E
Title
FcgammaRIIA expression accelerates nephritis and increases platelet activation in systemic lupus erythematosus.
Lee-Kirsch MA, Gong M, Chowdhury D, Senenko L, Engel K, Lee YA, de Silva U, Bailey SL, Witte T, Vyse TJ, Kere J, Pfeiffer C, Harvey S, Wong A, Koskenmies S, Hummel O, Rohde K, Schmidt RE, Dominiczak AF, Gahr M, Hollis T, Perrino FW, Lieberman J, Hubner N
Title
Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 are associated with systemic lupus erythematosus.
Graham RR, Kozyrev SV, Baechler EC, Reddy MV, Plenge RM, Bauer JW, Ortmann WA, Koeuth T, Gonzalez Escribano MF, Pons-Estel B, Petri M, Daly M, Gregersen PK, Martin J, Altshuler D, Behrens TW, Alarcon-Riquelme ME
Title
A common haplotype of interferon regulatory factor 5 (IRF5) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus.
Zervou MI, Andreou A, Matalliotakis M, Spandidos DA, Goulielmos GN, Eliopoulos EE
Title
Association of the DNASE1L3 rs35677470 polymorphism with systemic lupus erythematosus, rheumatoid arthritis and systemic sclerosis: Structural biological insights.
Brown GJ, Canete PF, Wang H, Medhavy A, Bones J, Roco JA, He Y, Qin Y, Cappello J, Ellyard JI, Bassett K, Shen Q, Burgio G, Zhang Y, Turnbull C, Meng X, Wu P, Cho E, Miosge LA, Andrews TD, Field MA, Tvorogov D, Lopez AF, Babon JJ, Lopez CA, Gonzalez-Murillo A, Garulo DC, Pascual V, Levy T, Mallack EJ, Calame DG, Lotze T, Lupski JR, Ding H, Ullah TR, Walters GD, Koina ME, Cook MC, Shen N, de Lucas Collantes C, Corry B, Gantier MP, Athanasopoulos V, Vinuesa CG
Title
TLR7 gain-of-function genetic variation causes human lupus.
Familial chilblain lupus (FCL) is a rare, inherited form of cutaneous lupus with prominent skin manifestations in acral parts of the body. Two families with autosomal dominant-inherited chilblain lupus have been reported. First symptoms manifest in early childhood, developing hypergammaglobulinemia and rheumatoid factor antibody production. In FCL, missense mutations in TREX1 that decrease its exonuclease activity were described. The failure of DNA degradation can result in aberrant immune response.
Category
Immune system disease
Brite
Pathway-based classification of diseases [BR:br08402]
Immune system
nt06520 CGAS-STING signaling
H00291 Familial chilblain lupus (FCL)
DISEASE: Retinal vasculopathy with cerebral leukodystrophy
Entry
H01000 Disease
Name
Retinal vasculopathy with cerebral leukodystrophy
Description
Retinal vasculopathy with cerebral leukodystrophy (RVCL) is a rare autosomal dominant microvascular endotheliopathy with middle-age onset. At around the age of 45, affected individuals may develop retinal and cerebral dysfunction. Death occurs in most cases within 10 years of the first symptoms appearing. The disease-causing mutations of TREX1 lead to truncation and abnormal localization of the 3'-5' exonuclease.
Category
Nervous system disease
Brite
Human diseases in ICD-11 classification [BR:br08403]
09 Diseases of the visual system
Disorders of the eyeball posterior segment
Disorders of the retina
9B78 Certain specified retinal disorders
H01000 Retinal vasculopathy with cerebral leukodystrophy
Pathway-based classification of diseases [BR:br08402]
Immune system
nt06520 CGAS-STING signaling
H01000 Retinal vasculopathy with cerebral leukodystrophy
Richards A, van den Maagdenberg AM, Jen JC, Kavanagh D, Bertram P, Spitzer D, Liszewski MK, Barilla-Labarca ML, Terwindt GM, Kasai Y, McLellan M, Grand MG, Vanmolkot KR, de Vries B, Wan J, Kane MJ, Mamsa H, Schafer R, Stam AH, Haan J, de Jong PT, Storimans CW, van Schooneveld MJ, Oosterhuis JA, Gschwendter A, Dichgans M, Kotschet KE, Hodgkinson S, Hardy TA, Delatycki MB, Hajj-Ali RA, Kothari PH, Nelson SF, Frants RR, Baloh RW, Ferrari MD, Atkinson JP
Title
C-terminal truncations in human 3'-5' DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy.
