Browse
Submit Data
Databases
API
Help

Dataset Information

28 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Case Report: Novel Compound Heterozygous RNASEH2B Mutations Cause Aicardi-Goutieres Syndrome.

ABSTRACT: Aicardi-Goutières Syndrome (AGS) is a rare disorder characterized by neurological and immunological signs. In this study we have described a child with a phenotype consistent with AGS carrying a novel compound heterozygous mutation in RNASEH2B gene. Next Generation Sequencing revealed two heterozygous variants in RNASEH2B gene. We also highlighted a reduction of RNase H2B transcript and protein levels in all the family members. Lower protein levels of RNase H2A have been observed in all the members of the family as well, whereas a deep depletion of RNase H2C has only been identified in the affected child. The structural analysis showed that both mutations remove many intramolecular contacts, possibly introducing conformational rearrangements with a decrease of the stability of RNase H2B and strongly destabilizing the RNase H2 complex. Taken together, these results highlight the importance of an integrated diagnostic approach which takes into consideration clinical, genetic, and molecular analyses.

SUBMITTER: Garau J

PROVIDER: S-EPMC8107470 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Heterozygous mutations in TREX1 cause familial chilblain lupus and dominant Aicardi-Goutieres syndrome.

Project description:TREX1 constitutes the major 3'-->5' DNA exonuclease activity measured in mammalian cells. Recently, biallelic mutations in TREX1 have been shown to cause Aicardi-Goutieres syndrome at the AGS1 locus. Interestingly, Aicardi-Goutieres syndrome shows overlap with systemic lupus erythematosus at both clinical and pathological levels. Here, we report a heterozygous TREX1 mutation causing familial chilblain lupus. Additionally, we describe a de novo heterozygous mutation, affecting a critical catalytic residue in TREX1, that results in typical Aicardi-Goutieres syndrome.

| S-EPMC1852703 | biostudies-literature

Compound heterozygous mutations in PMFBP1 cause acephalic spermatozoa syndrome: A case report.

Project description:BackgroundAcephalic spermatozoa syndrome (ASS) is an extremely rare form of severe teratozoospermia, where in most of the sperm either appear to lack heads or have disconnected or poorly connected heads and tails.Case summaryWe reported the case of a male patient with secondary infertility whose sperm showed typical ASS upon morphological analysis. Whole-exome sequencing was performed on the patient's peripheral blood, which revealed two heterozygous variants of the PMFBP1 gene: PMFBP1c.414+1G>T (p.?) and PMFBP1c.393del (p.C132Afs*3).ConclusionIt is speculated that the compound homozygous mutation of PMFBP1 may be the cause of ASS. We conducted a literature review in order to provide the basis for genetic counseling and clinical diagnosis of patients with ASS.

| S-EPMC9791525 | biostudies-literature

Case Report: Aicardi-Goutieres Syndrome Caused by Novel TREX1 Variants.

Project description:TREX1 (three prime repair exonuclease 1) gene encodes DNA 3' end repair exonuclease that plays an important role in DNA repair. Mutations in TREX1 gene have been identified as the cause of a rare autoimmune neurological disease, Aicardi-Goutières syndrome (AGS). Here, we report an AGS case of a 6-month-old Chinese girl with novel TREX1 variants. The patient had mild rashes on the face and legs, increased muscle tensions in the limbs, and positive cervical correction reflex. Cranial magnetic resonance imaging showed that there were patches of slightly longer T1 and T2 signals in the bilateral cerebral hemisphere and brainstem white matter, mainly in the frontotemporal lobe, together with decreased white matter volume, enlarged ventricles, and widened sulcus fissure. Total exon sequencing showed that the TREX1 gene of the child had mutations of c.137_138insC and c.292_293insA, which had not been reported before. In addition, elevated type I interferons were detected by using enzyme-linked immunosorbent assay in the patient's serum. Together, our study demonstrated that novel TREX1 variants (c.137_138insC and c.292_293insA) cause AGS for the first time.

| S-EPMC8113616 | biostudies-literature

Functional consequences of the RNase H2A subunit mutations that cause Aicardi-Goutieres syndrome.

Project description:Mutations in the three genes encoding the heterotrimeric RNase H2 complex cause Aicardi-Goutières Syndrome (AGS). Our mouse RNase H2 structure revealed that the catalytic RNase H2A subunit interfaces mostly with the RNase H2C subunit that is intricately interwoven with the RNase H2B subunit. We mapped the positions of AGS-causing RNase H2A mutations using the mouse RNase H2 structure and proposed that these mutations cause varied effects on catalytic potential. To determine the functional consequences of these mutations, heterotrimeric human RNase H2 complexes containing the RNase H2A subunit mutations were prepared, and catalytic efficiencies and nucleic acid binding properties were compared with the wild-type (WT) complex. These analyses reveal a dramatic range of effects with mutations at conserved positions G37S, R186W, and R235Q, reducing enzymatic activities and substrate binding affinities by as much as a 1000-fold, whereas mutations at non-conserved positions R108W, N212I, F230L, T240M, and R291H reduced activities and binding modestly or not at all. All mutants purify as three-subunit complexes, further supporting the required heterotrimeric structure in eukaryotic RNase H2. These kinetic properties reveal varied functional consequences of AGS-causing mutations in the catalytic RNase H2A subunit and reflect the complex mechanisms of nuclease dysfunction that include catalytic deficiencies and altered protein-nucleic acid interactions relevant in AGS.

| S-EPMC3089542 | biostudies-literature

Aicardi-Goutieres syndrome type 7 in a Chinese child: A case report.

Project description:BackgroundIFIH1 is a protein-coding gene. Disorders associated with IFIH1 include Aicardi-Goutières syndrome (AGS) type 7 and Singleton-Merten syndrome type 1. Related pathways include RIG-I/MDA5-mediated induction of the interferon (IFN)-α/β pathway and the innate immune system. AGS type 7 is an autosomal dominant inflammatory disorder characterized by severe neurological impairment. In infancy, most patients present with psychomotor retardation, axial hypotonia, spasticity, and brain imaging changes Laboratory assessments showed increased IFN-α activity with upregulation of IFN signaling and IFN-stimulated gene expression. Some patients develop normally in the early stage, and then have episodic neurological deficits.Case summaryThe 5-year-old girl presented with postpartum height and weight growth retardation, language retardation, brain atrophy, convulsions, and growth hormone deficiency. DNA samples were obtained from peripheral blood from the child and her parents for whole-exome sequencing and test of genome-wide copy number variation. Heterozygous mutations in the IFIH1 gene were found. Physical examination at admission found that language development was delayed, the reaction to name calling was average, there was no communication with people, but there was eye contact, no social smile, and no autonomous language. However, the child had rich gesture language and body language, could understand instructions, had bad temper. When she wants to achieve something, she starts crying or shouting. Cardiopulmonary examination showed no obvious abnormality, and abdominal examination was normal. Bilateral muscle strength and muscle tone were symmetrical and slightly decreased. Physiological reflexes exist, but pathological reflexes were not elicited.ConclusionWe reported the clinical characteristics of a Chinese child with a clinical diagnosis of AGS type 7, which expanded the mutational spectrum of the IFIH1 gene.

| S-EPMC10130998 | biostudies-literature

Aicardi-Goutieres syndrome is caused by IFIH1 mutations.

Project description:Aicardi-Goutières syndrome (AGS) is a rare, genetically determined early-onset progressive encephalopathy. To date, mutations in six genes have been identified as etiologic for AGS. Our Japanese nationwide AGS survey identified six AGS-affected individuals without a molecular diagnosis; we performed whole-exome sequencing on three of these individuals. After removal of the common polymorphisms found in SNP databases, we were able to identify IFIH1 heterozygous missense mutations in all three. In vitro functional analysis revealed that IFIH1 mutations increased type I interferon production, and the transcription of interferon-stimulated genes were elevated. IFIH1 encodes MDA5, and mutant MDA5 lacked ligand-specific responsiveness, similarly to the dominant Ifih1 mutation responsible for the SLE mouse model that results in type I interferon overproduction. This study suggests that the IFIH1 mutations are responsible for the AGS phenotype due to an excessive production of type I interferon.

| S-EPMC4085581 | biostudies-literature

Mutations in ADAR1 cause Aicardi-Goutieres syndrome associated with a type I interferon signature.

Project description:Adenosine deaminases acting on RNA (ADARs) catalyze the hydrolytic deamination of adenosine to inosine in double-stranded RNA (dsRNA) and thereby potentially alter the information content and structure of cellular RNAs. Notably, although the overwhelming majority of such editing events occur in transcripts derived from Alu repeat elements, the biological function of non-coding RNA editing remains uncertain. Here, we show that mutations in ADAR1 (also known as ADAR) cause the autoimmune disorder Aicardi-Goutières syndrome (AGS). As in Adar1-null mice, the human disease state is associated with upregulation of interferon-stimulated genes, indicating a possible role for ADAR1 as a suppressor of type I interferon signaling. Considering recent insights derived from the study of other AGS-related proteins, we speculate that ADAR1 may limit the cytoplasmic accumulation of the dsRNA generated from genomic repetitive elements.

| S-EPMC4154508 | biostudies-literature

Novel compound heterozygous mutations in AMN cause Imerslund-Grasbeck syndrome in two half-sisters: a case report.

Project description:BackgroundImerslund-Gräsbeck Syndrome (IGS) is a rare autosomal recessive disease characterized by intestinal vitamin B12 malabsorption. Clinical features include megaloblastic anemia, recurrent infections, failure to thrive, and proteinuria. Recessive mutations in cubilin (CUBN) and in amnionless (AMN) have been shown to cause IGS. To date, there are only about 300 cases described worldwide with only 37 different mutations found in CUBN and 30 different in the AMN gene.Case presentationWe collected pedigree structure, clinical data, and DNA samples from 2 Caucasian English half-sisters with IGS. Molecular diagnostics was performed by direct Sanger sequencing of all 62 exons of the CUBN gene and 12 exons of the AMN gene. Because of lack of parental DNA, cloning, and sequencing of multiple plasmid clones was performed to assess the allele of identified mutations. Genetic characterization revealed 2 novel compound heterozygous AMN mutations in both half-sisters with IGS. Trans-configuration of the mutations was confirmed.ConclusionWe have identified novel compound heterozygous mutations in AMN in a family from the United Kingdom with clinical features of Imerslund-Gräsbeck Syndrome.

| S-EPMC4630879 | biostudies-literature

CHRNE compound heterozygous mutations in congenital myasthenic syndrome: A case report.

Project description:Congenital myasthenic syndrome (CMSs) are a group of rare genetic disorders of the neurological junction, which can result in structural or functional weakness. Here, we characterized a case of CMS in order to clarify the diagnosis and expand the understanding of it. The molecular diagnosis had implications for choice of treatment and genetic counseling.A 3-year-old male patient with CMS had ptosis and limb weakness for 2 months after birth. Clinical course and electrophysiological, imaging, and genetic findings were assessed. Protein structure/function was predicted. A novel mutation of c.295C>T (exon 4) and another known mutation of c.442T>A (exon 5) were found in CHRNE. Both mutations localized in conserved sequences. The c.442T>A (p.C148S) missense mutation in CHRNE was predicted to be damaging/deleterious. The iterative threading assembly refinement (I-TASSER) server generated vastly different 3-dimensional (3D) atomic models based on protein sequences from wide-type and novel nonsense mutation of c.295C>T (p.R99X) in CHRNE.The diagnosis of CMS with CHRNE mutations in Han Chinese was confirmed.The patient was given prednisone (10?mg, once daily, taken orally) and pyridostigmine (15?mg, three times a day, taken orally).The patient had a moderate response to prednisone and pyridostigmine.We expanded the genotype and phenotype of CMS with CHRNE mutations in Han Chinese and provided new insights into the molecular mechanism of CMS and help to the diagnosis and treatment of CMS.

| S-EPMC5944527 | biostudies-literature

Case Report: Novel compound heterozygous <i>TPRKB</i> variants cause Galloway-Mowat syndrome.

Project description:BackgroundGalloway-Mowat syndrome (GAMOS) is a rare genetic disease characterized by early-onset nephrotic syndrome and microcephaly with central nervous system abnormalities. Pathogenic variants in genes encoding kinase, endopeptidase, and other proteins of small size (KEOPS) complex subunits cause GAMOS. The subunit TPRKB (TP53RK binding protein) has been reported in only two patients with GAMOS with homozygous missense variants.Clinical reportHerein, we described a three-year-old male with GAMOS. He exhibited developmental delay, developmental regression, microcephaly, distinctive facial features, skeletal abnormalities, and epilepsy. Brain magnetic resonance imaging revealed progressive brain atrophy, delayed myelination, T2-hypointense signals in the thalamus, and multiple intracranial abnormal signals on diffusion-weighted imaging. He presented with relapsing nephrotic proteinuria exacerbated by upper respiratory tract infections and progressive renal function decline. Exome sequencing identified compound heterozygous missense and frameshift variants in TPRKB: c.224dup, p.(Ser76IlefsTer3) and c.247C>T, p.(Leu83Phe).ConclusionsOur study supports that pathogenic TPRKB variants cause KEOPS complex-related GAMOS.

| S-EPMC11018998 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data