RÉSUMÉ
Inherited deficiency of the RNA lariat-debranching enzyme 1 (DBR1) is a rare etiology of brainstem viral encephalitis. The cellular basis of disease and the range of viral predisposition are unclear. We report inherited DBR1 deficiency in a 14-year-old boy who suffered from isolated SARS-CoV-2 brainstem encephalitis. The patient is homozygous for a previously reported hypomorphic and pathogenic DBR1 variant (I120T). Consistently, DBR1 I120T/I120T fibroblasts from affected individuals from this and another unrelated kindred have similarly low levels of DBR1 protein and high levels of RNA lariats. DBR1 I120T/I120T human pluripotent stem cell (hPSC)-derived hindbrain neurons are highly susceptible to SARS-CoV-2 infection. Exogenous WT DBR1 expression in DBR1 I120T/I120T fibroblasts and hindbrain neurons rescued the RNA lariat accumulation phenotype. Moreover, expression of exogenous RNA lariats, mimicking DBR1 deficiency, increased the susceptibility of WT hindbrain neurons to SARS-CoV-2 infection. Inborn errors of DBR1 impair hindbrain neuron-intrinsic antiviral immunity, predisposing to viral infections of the brainstem, including that by SARS-CoV-2.
Sujet(s)
Tronc cérébral , COVID-19 , Neurones , SARS-CoV-2 , Humains , Mâle , SARS-CoV-2/génétique , COVID-19/génétique , COVID-19/virologie , Tronc cérébral/anatomopathologie , Tronc cérébral/virologie , Tronc cérébral/métabolisme , Adolescent , Neurones/métabolisme , Neurones/anatomopathologie , Encéphalite virale/génétique , Encéphalite virale/anatomopathologie , Encéphalite virale/virologie , Fibroblastes/métabolisme , Rhombencéphale/métabolismeRÉSUMÉ
We found that 19 (10.4%) of 183 unvaccinated children hospitalized for COVID-19 pneumonia had autoantibodies (auto-Abs) neutralizing type I IFNs (IFN-α2 in 10 patients: IFN-α2 only in three, IFN-α2 plus IFN-ω in five, and IFN-α2, IFN-ω plus IFN-ß in two; IFN-ω only in nine patients). Seven children (3.8%) had Abs neutralizing at least 10 ng/ml of one IFN, whereas the other 12 (6.6%) had Abs neutralizing only 100 pg/ml. The auto-Abs neutralized both unglycosylated and glycosylated IFNs. We also detected auto-Abs neutralizing 100 pg/ml IFN-α2 in 4 of 2,267 uninfected children (0.2%) and auto-Abs neutralizing IFN-ω in 45 children (2%). The odds ratios (ORs) for life-threatening COVID-19 pneumonia were, therefore, higher for auto-Abs neutralizing IFN-α2 only (OR [95% CI] = 67.6 [5.7-9,196.6]) than for auto-Abs neutralizing IFN-ω only (OR [95% CI] = 2.6 [1.2-5.3]). ORs were also higher for auto-Abs neutralizing high concentrations (OR [95% CI] = 12.9 [4.6-35.9]) than for those neutralizing low concentrations (OR [95% CI] = 5.5 [3.1-9.6]) of IFN-ω and/or IFN-α2.
Sujet(s)
COVID-19 , Interféron de type I , Enfant , Humains , Interféron alpha , AutoanticorpsRÉSUMÉ
Recessive or dominant inborn errors of type I interferon (IFN) immunity can underlie critical COVID-19 pneumonia in unvaccinated adults. The risk of COVID-19 pneumonia in unvaccinated children, which is much lower than in unvaccinated adults, remains unexplained. In an international cohort of 112 children (<16 yr old) hospitalized for COVID-19 pneumonia, we report 12 children (10.7%) aged 1.5-13 yr with critical (7 children), severe (3), and moderate (2) pneumonia and 4 of the 15 known clinically recessive and biochemically complete inborn errors of type I IFN immunity: X-linked recessive TLR7 deficiency (7 children) and autosomal recessive IFNAR1 (1), STAT2 (1), or TYK2 (3) deficiencies. Fibroblasts deficient for IFNAR1, STAT2, or TYK2 are highly vulnerable to SARS-CoV-2. These 15 deficiencies were not found in 1,224 children and adults with benign SARS-CoV-2 infection without pneumonia (P = 1.2 × 10-11) and with overlapping age, sex, consanguinity, and ethnicity characteristics. Recessive complete deficiencies of type I IFN immunity may underlie â¼10% of hospitalizations for COVID-19 pneumonia in children.
Sujet(s)
COVID-19 , Interféron de type I , Pneumopathie infectieuse , Adulte , COVID-19/génétique , Enfant , Humains , Modes de transmission héréditaire , SARS-CoV-2RÉSUMÉ
Autosomal recessive IRF7 deficiency was previously reported in three patients with single critical influenza or COVID-19 pneumonia episodes. The patients' fibroblasts and plasmacytoid dendritic cells produced no detectable type I and III IFNs, except IFN-ß. Having discovered four new patients, we describe the genetic, immunological, and clinical features of seven IRF7-deficient patients from six families and five ancestries. Five were homozygous and two were compound heterozygous for IRF7 variants. Patients typically had one episode of pulmonary viral disease. Age at onset was surprisingly broad, from 6 mo to 50 yr (mean age 29 yr). The respiratory viruses implicated included SARS-CoV-2, influenza virus, respiratory syncytial virus, and adenovirus. Serological analyses indicated previous infections with many common viruses. Cellular analyses revealed strong antiviral immunity and expanded populations of influenza- and SARS-CoV-2-specific memory CD4+ and CD8+ T cells. IRF7-deficient individuals are prone to viral infections of the respiratory tract but are otherwise healthy, potentially due to residual IFN-ß and compensatory adaptive immunity.
Sujet(s)
COVID-19 , Grippe humaine , Maladies virales , Virus , Adulte , COVID-19/génétique , Humains , Grippe humaine/génétique , SARS-CoV-2RÉSUMÉ
We conducted an observational research study to collect information on sleep-wake patterns from participants with a confirmed status of the cryptochrome circadian clock 1 (CRY1) splicing variant, CRY1Δ11 c.1657 + 3A > C, and their controls, defined as wild-type (WT) family members. Altogether, 67 participants were enrolled and completed this study in Turkey, recruited from a list of families with at least one CRY1-confirmed member. We measured sleep-wake patterns and metabolic output, specifically time and frequency of bowel movements, for all participants by daily post-sleep diaries over 28 days. The sleep diary measured self-reported bed time, wake time, midpoint of sleep, and latency to persistent sleep (LPS), and accounted for naps and awakenings for religious purposes. Wake time and midpoint of sleep were significantly later in the CRY1Δ11 variant group versus WT, and LPS was significantly greater in participants in the CRY1Δ11 variant group. The mean bed time on all nights of sleep was later in participants with a CRY1Δ11 variant versus WT. Additionally, participants with a CRY1Δ11 variant had significantly affected metabolic outputs, measured by later bowel movements than WT participants. These results demonstrate that, on average, individuals with the studied splicing variant experience pronounced delays in sleep period and circadian-related metabolic processes.
Sujet(s)
Rythme circadien , Cryptochromes/génétique , Mutation , Troubles de la veille et du sommeil/anatomopathologie , Adulte , Études cas-témoins , Femelle , Humains , Mâle , Troubles de la veille et du sommeil/épidémiologie , Troubles de la veille et du sommeil/génétique , Troubles de la veille et du sommeil/métabolismeRÉSUMÉ
Autosomal inborn errors of type I IFN immunity and autoantibodies against these cytokines underlie at least 10% of critical COVID-19 pneumonia cases. We report very rare, biochemically deleterious X-linked TLR7 variants in 16 unrelated male individuals aged 7 to 71 years (mean: 36.7 years) from a cohort of 1,202 male patients aged 0.5 to 99 years (mean: 52.9 years) with unexplained critical COVID-19 pneumonia. None of the 331 asymptomatically or mildly infected male individuals aged 1.3 to 102 years (mean: 38.7 years) tested carry such TLR7 variants (p = 3.5 × 10-5). The phenotypes of five hemizygous relatives of index cases infected with SARS-CoV-2 include asymptomatic or mild infection (n=2, 5 and 38 years), or moderate (n=1, 5 years), severe (n=1, 27 years), or critical (n=1, 29 years) pneumonia. Two boys (aged 7 and 12 years) from a cohort of 262 male patients with severe COVID-19 pneumonia (mean: 51.0 years) are hemizygous for a deleterious TLR7 variant. The cumulative allele frequency for deleterious TLR7 variants in the male general population is < 6.5x10-4 We also show that blood B cell lines and myeloid cell subsets from the patients do not respond to TLR7 stimulation, a phenotype rescued by wild-type TLR7 The patients' blood plasmacytoid dendritic cells (pDCs) produce low levels of type I IFNs in response to SARS-CoV-2. Overall, X-linked recessive TLR7 deficiency is a highly penetrant genetic etiology of critical COVID-19 pneumonia, in about 1.8% of male patients below the age of 60 years. Human TLR7 and pDCs are essential for protective type I IFN immunity against SARS-CoV-2 in the respiratory tract.
Sujet(s)
COVID-19/complications , Maladies génétiques liées au chromosome X/complications , Maladies du système immunitaire/complications , Récepteur de type Toll-7/déficit , Adolescent , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Allèles , Enfant , Enfant d'âge préscolaire , Humains , Nourrisson , Mâle , Adulte d'âge moyen , Pedigree , Pénétrance , Récepteur de type Toll-7/génétique , Jeune adulteRÉSUMÉ
The construction of population-based variomes has contributed substantially to our understanding of the genetic basis of human inherited disease. Here, we investigated the genetic structure of Turkey from 3,362 unrelated subjects whose whole exomes (n = 2,589) or whole genomes (n = 773) were sequenced to generate a Turkish (TR) Variome that should serve to facilitate disease gene discovery in Turkey. Consistent with the history of present-day Turkey as a crossroads between Europe and Asia, we found extensive admixture between Balkan, Caucasus, Middle Eastern, and European populations with a closer genetic relationship of the TR population to Europeans than hitherto appreciated. We determined that 50% of TR individuals had high inbreeding coefficients (≥0.0156) with runs of homozygosity longer than 4 Mb being found exclusively in the TR population when compared to 1000 Genomes Project populations. We also found that 28% of exome and 49% of genome variants in the very rare range (allele frequency < 0.005) are unique to the modern TR population. We annotated these variants based on their functional consequences to establish a TR Variome containing alleles of potential medical relevance, a repository of homozygous loss-of-function variants and a TR reference panel for genotype imputation using high-quality haplotypes, to facilitate genome-wide association studies. In addition to providing information on the genetic structure of the modern TR population, these data provide an invaluable resource for future studies to identify variants that are associated with specific phenotypes as well as establishing the phenotypic consequences of mutations in specific genes.
Sujet(s)
Variation génétique/génétique , Génome humain/génétique , Allèles , Consanguinité , Exome , Fréquence d'allèle/génétique , Dérive génétique , Génétique des populations/méthodes , Étude d'association pangénomique/méthodes , Génotype , Haplotypes/génétique , Migration humaine/tendances , Humains , Turquie/ethnologie , /méthodesRÉSUMÉ
The homozygous LAMC3 gene mutation is associated with severe bilateral smoothening and thickening of the lateral occipital cortex . Despite this and further significant changes in gray matter structure, a patient harboring this mutation exhibited a range of remarkably intact perceptual abilities . One possible explanation of this perceptual sparing could be that the white matter structural integrity and functional connectivity in relevant pathways remained intact. To test this idea, we used diffusion tensor and functional magnetic resonance imaging to investigate functional connectivity in resting-state networks in major structural pathways involved in object perception and visual attention and corresponding microstructural integrity in a patient with homozygous LAMC3 mutation and sex, age, education, and socioeconomically matched healthy control group. White matter microstructural integrity results indicated widespread disruptions in both intra- and interhemispheric structural connections except inferior longitudinal fasciculus. With a few exceptions, the functional connectivity between the patient's adjacent gray matter regions of major white matter tracts of interest was conserved. In addition, functional localizers for face, object, and place areas showed similar results with a representative control, providing an explanation for the patient's intact face, place, and object recognition abilities. To generalize this finding, we also compared functional connectivity between early visual areas and face, place, and object category-selective areas, and we found that the functional connectivity of the patient was not different from the control group. Overall, our results provided complementary information about the effects of LAMC3 gene mutation on the human brain including intact temporo-occipital structural and functional connectivity that are compatible with preserved perceptual abilities.
Sujet(s)
Substance blanche , Cartographie cérébrale , Substance grise/imagerie diagnostique , Humains , Laminine , Imagerie par résonance magnétique , Mutation , Réseau nerveux , Voies nerveuses/imagerie diagnostique , Substance blanche/imagerie diagnostiqueRÉSUMÉ
Most patients with autosomal dominant hyper-IgE syndrome (AD-HIES) carry rare heterozygous STAT3 variants. Only six of the 135 in-frame variants reported have been experimentally shown to be dominant negative (DN), and it has been recently suggested that eight out-of-frame variants operate by haploinsufficiency. We experimentally tested these 143 variants, 7 novel out-of-frame variants found in HIES patients, and other STAT3 variants from the general population. Strikingly, all 15 out-of-frame variants were DN via their encoded (1) truncated proteins, (2) neoproteins generated from a translation reinitiation codon, and (3) isoforms from alternative transcripts or a combination thereof. Moreover, 128 of the 135 in-frame variants (95%) were also DN. The patients carrying the seven non-DN STAT3 in-frame variants have not been studied for other genetic etiologies. Finally, none of the variants from the general population tested, including an out-of-frame variant, were DN. Overall, our findings show that heterozygous STAT3 variants, whether in or out of frame, underlie AD-HIES through negative dominance rather than haploinsufficiency.
Sujet(s)
Gènes dominants , Syndrome de Job/génétique , Mutation/génétique , Facteur de transcription STAT-3/génétique , Adolescent , Adulte , Allèles , Épissage alternatif/génétique , Enfant , Enfant d'âge préscolaire , Codon non-sens/génétique , Évolution moléculaire , Famille , Femelle , Mutation avec décalage du cadre de lecture/génétique , Génétique des populations , Cellules HEK293 , Humains , Nourrisson , Nouveau-né , Mâle , Adulte d'âge moyen , Pedigree , Biosynthèse des protéines , ARN messager/génétique , ARN messager/métabolismeRÉSUMÉ
46,XX testicular disorder of sex development (46,XX TDSD) is a relatively rare condition characterised by the presence of testicular tissue with 46,XX karyotype. The present study aims to reveal the phenotype to genotype correlation in a series of sex-determining region Y (SRY)-positive 46,XX TDSD cases. We present the clinical findings, hormone profiles and genetic test results of six patients with SRY-positive 46,XX TDSD and give the details and follow-up findings of our three of previously published patients. All patients presented common characteristics such as azoospermia, hypergonadotropic hypogonadism and an SRY gene translocated on the terminal part of the short arm of one of the X chromosomes. Mean ± standard deviation (SD) height of the patients was 164.78 ± 8.0 cm. Five patients had decreased secondary sexual characteristics, and three patients had gynaecomastia with varying degrees. Five of the seven patients revealed a translocation between protein kinase X (PRKX) and inverted protein kinase Y (PRKY) genes, and the remaining two patients showed a translocation between the pseudoautosomal region 1 (PAR1) of X chromosome and the differential region of Y chromosome. X chromosome inactivation (XCI) analysis results demonstrated random and skewed XCI in 5 cases and 1 case, respectively. In brief, we delineate the phenotypic spectrum of patients with SRY-positive 46,XX TDSD and the underlying mechanisms of Xp;Yp translocations.
Sujet(s)
Gène sry , Maladies testiculaires , Gène sry/génétique , Humains , Caryotypage , Mâle , Phénotype , Translocation génétiqueRÉSUMÉ
Attention deficit/hyperactivity disorder (ADHD) is a common and heritable phenotype frequently accompanied by insomnia, anxiety, and depression. Here, using a reverse phenotyping approach, we report heterozygous coding variations in the core circadian clock gene cryptochrome 1 in 15 unrelated multigenerational families with combined ADHD and insomnia. The variants led to functional alterations in the circadian molecular rhythms, providing a mechanistic link to the behavioral symptoms. One variant, CRY1Δ11 c.1657+3A>C, is present in approximately 1% of Europeans, therefore standing out as a diagnostic and therapeutic marker. We showed by exome sequencing in an independent cohort of patients with combined ADHD and insomnia that 8 of 62 patients and 0 of 369 controls carried CRY1Δ11. Also, we identified a variant, CRY1Δ6 c.825+1G>A, that shows reduced affinity for BMAL1/CLOCK and causes an arrhythmic phenotype. Genotype-phenotype correlation analysis revealed that this variant segregated with ADHD and delayed sleep phase disorder (DSPD) in the affected family. Finally, we found in a phenome-wide association study involving 9438 unrelated adult Europeans that CRY1Δ11 was associated with major depressive disorder, insomnia, and anxiety. These results defined a distinctive group of circadian psychiatric phenotypes that we propose to designate as "circiatric" disorders.
Sujet(s)
Trouble déficitaire de l'attention avec hyperactivité/génétique , Cryptochromes/génétique , Mutation , Troubles du rythme circadien du sommeil/génétique , Facteurs de transcription ARNTL/génétique , Facteurs de transcription ARNTL/métabolisme , Adulte , Trouble déficitaire de l'attention avec hyperactivité/métabolisme , Trouble déficitaire de l'attention avec hyperactivité/anatomopathologie , Protéines CLOCK/génétique , Protéines CLOCK/métabolisme , Cryptochromes/métabolisme , Femelle , Études d'associations génétiques , Cellules HEK293 , Humains , Mâle , Troubles du rythme circadien du sommeil/métabolismeRÉSUMÉ
The occipital lobe contains a substantial part of the neural machinery involved in visual perception. Mutations in the LAMC3 gene have recently been shown to cause complex bilateral occipital cortical gyration abnormalities. However, to what extent these structural changes impact visual behavior is not known. We recorded responses for two screening test batteries targeting visual function (Leuven - Perceptual Organization Screening Test, Cortical Vision Screening Test) and measured eye fixation performance in a visual attention experiment from a patient with homozygous LAMC3 gene mutation. Using voxel-based morphometry (VBM) we quantitatively assessed the extent of structural changes brought on by the genetic mutation by comparing mean cortical curvature, cortical thickness, and gray matter volume in 34 cortical areas between patient and an age-, sex-, and education-matched control group. Anatomical connectivity between these cortical areas was investigated by a structural covariance analysis. Visual screening-, and behavioral results revealed that the patient's impairments were predominantly in visuo-spatial attention. Consistent with this, VBM and structural connectivity results revealed significant structural changes in cortical regions subserving attentional functions. We conclude that the LAMC3 gene mutation affects cortical areas beyond the occipital lobe and primarily those visual functions that involve heavily distributed networks - such as visuo-spatial attention.
Sujet(s)
Attention/physiologie , Cortex cérébral/malformations , Mouvements oculaires/physiologie , Laminine/génétique , Réseau nerveux/malformations , Troubles de la perception/anatomopathologie , Troubles de la perception/physiopathologie , Perception visuelle/physiologie , Adulte , Cortex cérébral/imagerie diagnostique , Femelle , Humains , Imagerie par résonance magnétique , Mutation , Réseau nerveux/imagerie diagnostique , Neuroimagerie , Lobe occipital/malformations , Lobe occipital/imagerie diagnostique , Troubles de la perception/imagerie diagnostique , Troubles de la perception/génétiqueRÉSUMÉ
Inherited IL-12Rß1 and TYK2 deficiencies impair both IL-12- and IL-23-dependent IFN-γ immunity and are rare monogenic causes of tuberculosis, each found in less than 1/600,000 individuals. We show that homozygosity for the common TYK2 P1104A allele, which is found in about 1/600 Europeans and between 1/1000 and 1/10,000 individuals in regions other than East Asia, is more frequent in a cohort of patients with tuberculosis from endemic areas than in ethnicity-adjusted controls (P = 8.37 × 10-8; odds ratio, 89.31; 95% CI, 14.7 to 1725). Moreover, the frequency of P1104A in Europeans has decreased, from about 9% to 4.2%, over the past 4000 years, consistent with purging of this variant by endemic tuberculosis. Surprisingly, we also show that TYK2 P1104A impairs cellular responses to IL-23, but not to IFN-α, IL-10, or even IL-12, which, like IL-23, induces IFN-γ via activation of TYK2 and JAK2. Moreover, TYK2 P1104A is properly docked on cytokine receptors and can be phosphorylated by the proximal JAK, but lacks catalytic activity. Last, we show that the catalytic activity of TYK2 is essential for IL-23, but not IL-12, responses in cells expressing wild-type JAK2. In contrast, the catalytic activity of JAK2 is redundant for both IL-12 and IL-23 responses, because the catalytically inactive P1057A JAK2, which is also docked and phosphorylated, rescues signaling in cells expressing wild-type TYK2. In conclusion, homozygosity for the catalytically inactive P1104A missense variant of TYK2 selectively disrupts the induction of IFN-γ by IL-23 and is a common monogenic etiology of tuberculosis.
Sujet(s)
Interféron gamma/immunologie , Interleukine-23/immunologie , Mutation faux-sens/génétique , TYK2 Kinase/génétique , Tuberculose/immunologie , Cellules cultivées , Homozygote , Humains , Interleukine-23/déficit , TYK2 Kinase/immunologieRÉSUMÉ
PURPOSE: Congenital mirror movement disorder (CMMD) is characterized by unintended, nonsuppressible, homologous mirroring activity contralateral to the movement on the intended side of the body. In healthy controls, unilateral movements are accompanied with predominantly contralateral cortical activity, whereas in CMMD, in line with the abnormal behavior, bilateral cortical activity is observed for unilateral motor tasks. However, task-related activities in subcortical structures, which are known to play critical roles in motor actions, have not been investigated in CMMD previously. METHODS: We investigated the functional activation patterns of the motor components in CMMD patients. By using linkage analysis and exome sequencing, common mutations were revealed in seven affected individuals from the same family. Next, using functional magnetic resonance imaging (fMRI) we investigated cortical and subcortical activity during manual motor actions in two right-handed affected brothers and sex, age, education, and socioeconomically matched healthy individuals. RESULTS: Genetic analyses revealed heterozygous RAD51 c.401C>T mutation which cosegregated with the phenotype in two affected members of the family. Consistent with previous literature, our fMRI results on these two affected individuals showed that mirror movements were closely related to abnormal cortical activity in M1 and SMA during unimanual movements. Furthermore, we have found previously unknown abnormal task-related activity in subcortical structures. Specifically, we have found increased and bilateral activity during unimanual movements in thalamus, striatum, and globus pallidus in CMMD patients. CONCLUSION: These findings reveal further neural correlates of CMMD, and may guide our understanding of the critical roles of subcortical structures for unimanual movements in healthy individuals.
Sujet(s)
Encéphale/imagerie diagnostique , Encéphale/physiopathologie , Imagerie par résonance magnétique/méthodes , Troubles de la motricité/génétique , Troubles de la motricité/physiopathologie , Rad51 Recombinase/génétique , Adulte , Humains , Mâle , Mutation/génétiqueRÉSUMÉ
Medical genetics and genomic medicine in Turkey: a bright future at a new era in life sciences.
RÉSUMÉ
Patterns of daily human activity are controlled by an intrinsic circadian clock that promotes â¼24 hr rhythms in many behavioral and physiological processes. This system is altered in delayed sleep phase disorder (DSPD), a common form of insomnia in which sleep episodes are shifted to later times misaligned with the societal norm. Here, we report a hereditary form of DSPD associated with a dominant coding variation in the core circadian clock gene CRY1, which creates a transcriptional inhibitor with enhanced affinity for circadian activator proteins Clock and Bmal1. This gain-of-function CRY1 variant causes reduced expression of key transcriptional targets and lengthens the period of circadian molecular rhythms, providing a mechanistic link to DSPD symptoms. The allele has a frequency of up to 0.6%, and reverse phenotyping of unrelated families corroborates late and/or fragmented sleep patterns in carriers, suggesting that it affects sleep behavior in a sizeable portion of the human population.
Sujet(s)
Cryptochromes/métabolisme , Troubles du rythme circadien du sommeil/génétique , Rythme circadien , Cryptochromes/génétique , Exons , Femelle , Délétion de gène , Humains , Mâle , Adulte d'âge moyen , Pedigree , Troubles du rythme circadien du sommeil/physiopathologieRÉSUMÉ
Study of the Greater Middle East (GME), home to approximately 10% of the world's population, has made invaluable contributions to the characterization of rare genetic disease, especially recessive conditions arising from the tradition of consanguinity and large families with multiple children. A new study now reports 1,111 unrelated exomes from the GME and provides a comprehensive view of genetic variation for enhanced discovery of disease-associated genes.
Sujet(s)
Consanguinité , Variation génétique , Gènes récessifs , Génomique , Humains , Moyen OrientRÉSUMÉ
BACKGROUND: Autoimmune diseases, including rheumatoid arthritis (RA) and systemic sclerosis (SSc) are characterized by a strong genetic susceptibility from the Human Leucocyte Antigen (HLA) locus. Additionally, disorders of epigenetic processes, in particular non-random X chromosome inactivation (XCI), have been reported in many female-predominant autoimmune diseases. Here we test the hypothesis that women with RA or SSc who are strongly genetically predisposed are less susceptible to XCI bias. METHODS: Using methylation sensitive genotyping of the androgen receptor (AR) gene, XCI profiles were performed in peripheral blood mononuclear cells from 161 women with RA, 96 women with SSc and 100 healthy women. HLA-DRB1 and DQB1 were genotyped. Presence of specific autoantibodies was documented for patients. XCI skewing was defined as having a ratio ≥ 80:20 of cells inactivating the same X chromosome. RESULTS: 110 women with RA, 68 women with SSc, and 69 controls were informative for the AR polymorphism. Among them 40.9% of RA patients and 36.8% of SSc patients had skewed XCI compared to 17.4% of healthy women (P = 0.002 and 0.018, respectively). Presence of RA-susceptibility alleles coding for the "shared epitope" correlated with higher skewing among RA patients (P = 0.002) and such correlation was not observed in other women, healthy or with SSc. Presence of SSc-susceptibility alleles did not correlate with XCI patterns among SSc patients. CONCLUSION: Data demonstrate XCI skewing in both RA and SSc compared to healthy women. Unexpectedly, skewed XCI occurs more often in women with RA carrying the shared epitope, which usually reflects severe disease. This reinforces the view that loss of mosaicism in peripheral blood may be a consequence of chronic autoimmunity.