<i>USP27X</i>variants underlying X-linked intellectual disability disrupt protein function via distinct mechanisms

Koch, Intisar; Slovik, Maya; Zhang, Yuling; Liu, Bingyu; Rennie, Martin; Konz, Emily; Cogne, Benjamin; Daana, Muhannad; Davids, Laura; Diets, Illja J; Gold, Nina B; Holtz, Alexander M; Isidor, Bertrand; Mor-Shaked, Hagar; Neira Fresneda, Juanita; Niederhoffer, Karen Y; Nizon, Mathilde; Pfundt, Rolph; Simon, MEH; Stegmann, APA; Guillen Sacoto, Maria J; Wevers, Marijke; Barakat, Tahsin Stefan; Yanovsky-Dagan, Shira; Atanassov, Boyko S; Toth, Rachel; Gao, Chengjiang; Bustos, Francisco; Harel, Tamar

doi:10.26508/lsa.202302258

Cited by 3 publications

(1 citation statement)

References 59 publications

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“…However, the terminology varies globally, with "learning disability" commonly used in Europe. Idiopathic Intellectual Disability (IID) represents unexplained cases of ID, accounting for almost half of all instances, where genetic and clinical examinations do not reveal a cause [3] . Learning disabilities, distinct from ID, encompass a broad range of disorders affecting specific cognitive functions such as reading, writing, and numerical understanding, often linked to central nervous system dysfunction [4] .…”

Section: Introductionmentioning

confidence: 99%

Karyotype and molecular cytogenetic analysis among sample of Iraqi children with idiopathic intellectual disability

Nasif,

Shareef

2024

Int. J. Paediatrics Geriatrics

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Background: Most children with uncertain etiology have moderate ID, which accounts for 48.8% of all intellectual impairments. Genetic testing allows early etiologic diagnosis, medical comorbidity monitoring, and genetic counselling for families. Aim of the study:To study the clinical features of Intellectual disabilities, determine the yield of karyotyping in children with idiopathic intellectual disability. Patients and Methods: A retrospective and prospective observational study were conducted on seventy-two Pediatric patients with intellectual disabilities who visited child welfare teaching hospital outpatient clinic for Pediatric neurological diseases. The data records were collected from the beginning of January 2018 to the end of July 2022, children aged 5 up to 14 years who were diagnosed clinically to have intellectual disability were included. Raven's IQ test, Brain MRI were performed in all patients with intellectual disability. GTG banding karyotype, florescence in situ hybridization and PCR were the materials used. Results:The male-to-female ratio was ≈ (4:1). Speech difficulty and Behavioral abnormalities were significantly higher among males (P=0.042), (P=0.017) respectively. The majority of children were with normal MRI 45 (62.5%), while the highest proportion of abnormal MRI findings was brain atrophy reported in 16 (22.2%) of cases. Epilepsy was among only 22 (30.6%). Conclusion:In this study, Individuals with intellectual disabilities including speech delays and/or learning disabilities, with or without behavior problems, are more likely to have chromosome abnormalities, in form of deletion, duplication, and fragile X, and particularly del (22) (22q 11.2)], [del (5) (p15.1-p 15.2)..Most of the cases with duplication had mild levels of intellectual disability and positive history of parental consanguinity.

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Section: Introductionmentioning

confidence: 99%

Karyotype and molecular cytogenetic analysis among sample of Iraqi children with idiopathic intellectual disability

Nasif,

Shareef

2024

Int. J. Paediatrics Geriatrics

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De novo variants in ATXN7L3 lead to developmental delay, hypotonia and distinctive facial features

Harel,

Spicher,

Scheer

et al. 2024

Brain

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Deubiquitination is critical for the proper functioning of numerous biological pathways such as DNA repair, cell cycle progression, transcription, signal transduction, and autophagy. Accordingly, pathogenic variants in deubiquitinating enzymes (DUBs) have been implicated in neurodevelopmental disorders (ND) and congenital abnormalities. ATXN7L3 is a component of the DUB module of the SAGA complex, and two other related DUB modules, and serves as an obligate adaptor protein of 3 ubiquitin-specific proteases (USP22, USP27X or USP51). Through exome sequencing and GeneMatching, we identified nine individuals with heterozygous variants in ATXN7L3. The core phenotype included global motor and language developmental delay, hypotonia, and distinctive facial characteristics including hypertelorism, epicanthal folds, blepharoptosis, a small nose and mouth, and low-set posteriorly rotated ears. In order to assess pathogenicity, we investigated the effects of a recurrent nonsense variant [c.340C>T; p.(Arg114Ter)] in fibroblasts of an affected individual. ATXN7L3 protein levels were reduced, and deubiquitylation was impaired, as indicated by an increase in histone H2Bub1 levels. This is consistent with the previous observation of increased H2Bub1 levels in Atxn7l3-null mouse embryos, which have developmental delay and embryonic lethality. In conclusion, we present clinical information and biochemical characterization supporting ATXN7L3 variants in the pathogenesis of a rare syndromic ND.

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X-chromosome linked genes associated with myeloid cell CNS trafficking contributes to female–male differences in the disease outcome for neuroinflammatory diseases

Darchiashvili,

Kulkarni,

Tandon

et al. 2024

NeuroImmune Pharmacology and Therapeutics

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Certain diseases such as Multiple Sclerosis (MS), a chronic demyelinating disease, affect more women than men, despite males appearing to be predisposed to infections and malignancies. X-linked genes contribute to increased MS susceptibility. Currently, an immense body of research exists that explores the complexity surrounding underlying risk factors for MS development including X-chromosome-linked inflammatory processes. Female–male disparities in disease susceptibility have been found at both the gene and chromosomal level. Genes such as CXORF21 and DDX3X can escape X-chromosome inactivation (XCI) and contribute to various disease pathogenesis. Additionally, blocking immune cell entry to the central nervous system (CNS) can have a major impact on MS. Prior research on MS has shown that immune cells such as T cells and dendritic cells (DCs) infiltrate the CNS. Due to persistent tissue stress, these cells may induce local inflammation and autoimmunity, subsequent neurodegeneration, and both the onset and progression of MS. Chemokines are signaling proteins which regulate leukocyte trafficking to the site of injury, contributing to cell recruitment, CNS inflammation, and disease severity. Some chemokine receptors (CXCR3) are X-linked and may escape XCI. This review provides an account of the contribution of x-linked genes in MS in relation to the chemotaxis of myeloid cells into CNS and subsequent neuroinflammation. The impact of the X-chromosome on autoimmunity, including XCI and the expression of X-linked genes is evaluated. Collectively, the analyses from this review seek to advance both our understanding of MS and advocate for more patient-specific therapies.

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USP27Xvariants underlying X-linked intellectual disability disrupt protein function via distinct mechanisms

Cited by 3 publications

References 59 publications

Karyotype and molecular cytogenetic analysis among sample of Iraqi children with idiopathic intellectual disability

Karyotype and molecular cytogenetic analysis among sample of Iraqi children with idiopathic intellectual disability

De novo variants in ATXN7L3 lead to developmental delay, hypotonia and distinctive facial features

X-chromosome linked genes associated with myeloid cell CNS trafficking contributes to female–male differences in the disease outcome for neuroinflammatory diseases

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