The addition of O-linked β-N-acetylglucosamine (O-GlcNAc) to proteins (referred to as O-GlcNAcylation) is a modification that is crucial for vertebrate development. O-GlcNAcylation is catalyzed by O-GlcNAc transferase (OGT) and reversed by O-GlcNAcase (OGA). Missense variants of OGT have recently been shown to segregate with an X-linked syndromic form of intellectual disability, OGT-linked congenital disorder of glycosylation (OGT-CDG). Although the existence of OGT-CDG suggests that O-GlcNAcylation is crucial for neurodevelopment and/or cognitive function, the underlying pathophysiologic mechanisms remain unknown. Here we report a mouse line that carries a catalytically impaired OGT-CDG variant. These mice show altered O-GlcNAc homeostasis with decreased global O-GlcNAcylation and reduced levels of OGT and OGA in the brain. Phenotypic characterization of the mice revealed lower body weight associated with reduced body fat mass, short stature and microcephaly. This mouse model will serve as an important tool to study genotype-phenotype correlations in OGT-CDG in vivo and for the development of possible treatment avenues for this disorder.

• Klíčová slova
• O-GlcNAcylation, Intellectual disability, Vertebrate development,
• MeSH
• beta-N-acetylhexosaminidasy metabolismus   MeSH
• fenotyp MeSH
• glykosylace MeSH
• mentální retardace * genetika   MeSH
• modely nemocí na zvířatech * MeSH
• mozek patologie   metabolismus   MeSH
• myši MeSH
• N-acetylglukosaminyltransferasy * metabolismus   genetika   nedostatek   MeSH
• neurovývojové poruchy patologie   genetika   enzymologie   MeSH
• tělesná hmotnost MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• beta-N-acetylhexosaminidasy MeSH
• hexosaminidase C MeSH Prohlížeč
• N-acetylglukosaminyltransferasy * MeSH
• O-GlcNAc transferase MeSH Prohlížeč

Fragile X syndrome (FXS) is the most frequently inherited form of intellectual disability and prevalent single-gene cause of autism. A priority of FXS research is to determine the molecular mechanisms underlying the cognitive and social functioning impairments in humans and the FXS mouse model. Glutamate ionotropic alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPARs) mediate a majority of fast excitatory neurotransmission in the central nervous system and are critically important for nearly all aspects of brain function, including neuronal development, synaptic plasticity, and learning and memory. Both preclinical and clinical studies have indicated that expression, trafficking, and functions of AMPARs are altered and result in altered synapse development and plasticity, cognitive impairment, and poor mental health in FXS. In this review, we discuss the contribution of AMPARs to disorders of FXS by highlighting recent research advances with a specific focus on change in AMPARs expression, trafficking, and dependent synaptic plasticity. Since changes in synaptic strength underlie the basis of learning, development, and disease, we suggest that the current knowledge base of AMPARs has reached a unique point to permit a comprehensive re-evaluation of their roles in FXS.

• MeSH
• AMPA receptory genetika   metabolismus   MeSH
• lidé MeSH
• mentální retardace genetika   metabolismus   MeSH
• mutace fyziologie   MeSH
• neuroplasticita fyziologie   MeSH
• syndrom fragilního X genetika   metabolismus   MeSH
• transport proteinů fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• AMPA receptory MeSH

The ALF transcription factor paralogs, AFF1, AFF2, AFF3, and AFF4, are components of the transcriptional super elongation complex that regulates expression of genes involved in neurogenesis and development. We describe an autosomal dominant disorder associated with de novo missense variants in the degron of AFF3, a nine amino acid sequence important for its binding to ubiquitin ligase, or with de novo deletions of this region. The sixteen affected individuals we identified, along with two previously reported individuals, present with a recognizable pattern of anomalies, which we named KINSSHIP syndrome (KI for horseshoe kidney, NS for Nievergelt/Savarirayan type of mesomelic dysplasia, S for seizures, H for hypertrichosis, I for intellectual disability, and P for pulmonary involvement), partially overlapping the AFF4-associated CHOPS syndrome. Whereas homozygous Aff3 knockout mice display skeletal anomalies, kidney defects, brain malformations, and neurological anomalies, knockin animals modeling one of the microdeletions and the most common of the missense variants identified in affected individuals presented with lower mesomelic limb deformities like KINSSHIP-affected individuals and early lethality, respectively. Overexpression of AFF3 in zebrafish resulted in body axis anomalies, providing some support for the pathological effect of increased amount of AFF3. The only partial phenotypic overlap of AFF3- and AFF4-associated syndromes and the previously published transcriptome analyses of ALF transcription factors suggest that these factors are not redundant and each contributes uniquely to proper development.

• Klíčová slova
• AFF3, AFF4, horseshoe kidney, intellectual disability, mesomelic dysplasia,
• MeSH
• dánio pruhované genetika   MeSH
• dítě MeSH
• epilepsie komplikace   genetika   MeSH
• fenotyp MeSH
• frekvence genu MeSH
• fúze ledvin genetika   MeSH
• jaderné proteiny chemie   nedostatek   genetika   MeSH
• kojenec MeSH
• lidé MeSH
• mentální retardace genetika   MeSH
• missense mutace * MeSH
• mladiství MeSH
• mladý dospělý MeSH
• molekulární evoluce MeSH
• molekulární modely MeSH
• myši MeSH
• nemoci mozku etiologie   genetika   MeSH
• osteochondrodysplazie genetika   MeSH
• předškolní dítě MeSH
• sekvence aminokyselin MeSH
• stabilita proteinů MeSH
• syndrom MeSH
• transkripční elongační faktory chemie   genetika   MeSH
• zvířata MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• myši MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• AFF3 protein, human MeSH Prohlížeč
• AFF4 protein, human MeSH Prohlížeč
• jaderné proteiny MeSH
• transkripční elongační faktory MeSH

Intellectual disability affects 2-3% of the population; mutations of the X-chromosome are a major cause of moderate to severe cases. The link between the molecular consequences of the mutation and impaired cognitive function remains unclear. Loss of function mutations of oligophrenin-1 (OPHN1) disrupt Rho-GTPase signalling. Here we demonstrate abnormal neurotransmission at CA3 synapses in hippocampal slices from Ophn1-/y mice, resulting from a substantial decrease in the readily releasable pool of vesicles. As a result, synaptic transmission fails at high frequencies required for oscillations associated with cognitive functions. Both spontaneous and KA-induced gamma oscillations were reduced in Ophn1-/y hippocampal slices. Spontaneous oscillations were rapidly rescued by inhibition of the downstream signalling pathway of oligophrenin-1. These findings suggest that the intellectual disability due to mutations of oligophrenin-1 results from a synaptopathy and consequent network malfunction, providing a plausible mechanism for the learning disabilities. Furthermore, they raise the prospect of drug treatments for affected individuals.

• MeSH
• cytoskeletální proteiny genetika   MeSH
• gama rytmus EEG * MeSH
• hipokampální oblast CA3 metabolismus   patofyziologie   MeSH
• jaderné proteiny genetika   MeSH
• mentální retardace genetika   patofyziologie   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nervový přenos * MeSH
• proteiny aktivující GTPasu genetika   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cytoskeletální proteiny MeSH
• jaderné proteiny MeSH
• Ophn1 protein, mouse MeSH Prohlížeč
• proteiny aktivující GTPasu MeSH

Christianson syndrome (CS) is an X-linked neurodevelopmental and neurological disorder characterized in males by core symptoms that include non-verbal status, intellectual disability, epilepsy, truncal ataxia, postnatal microcephaly and hyperkinesis. CS is caused by mutations in the SLC9A6 gene, which encodes a multipass transmembrane sodium (potassium)-hydrogen exchanger 6 (NHE6) protein, functional in early recycling endosomes. The extent and variability of the CS phenotype in female heterozygotes, who presumably express the wild-type and mutant SLC9A6 alleles mosaically as a result of X-chromosome inactivation (XCI), have not yet been systematically characterized. Slc9a6 knockout mice (Slc9a6 KO) were generated by insertion of the bacterial lacZ/β-galactosidase (β-Gal) reporter into exon 6 of the X-linked gene. Mutant Slc9a6 KO male mice have been shown to develop late endosomal/lysosomal dysfunction associated with glycolipid accumulation in selected neuronal populations and patterned degeneration of Purkinje cells (PCs). In heterozygous female Slc9a6 KO mice, β-Gal serves as a transcriptional/XCI reporter and thus facilitates testing of effects of mosaic expression of the mutant allele on penetrance of the abnormal phenotype. Using β-Gal, we demonstrated mosaic expression of the mutant Slc9a6 allele and mosaically distributed lysosomal glycolipid accumulation and PC pathology in the brains of heterozygous Slc9a6 KO female mice. At the behavioral level, we showed that heterozygous female mice suffer from visuospatial memory and motor coordination deficits similar to but less severe than those observed in X-chromosome hemizygous mutant males. Our studies in heterozygous Slc9a6 KO female mice provide important clues for understanding the likely phenotypic range of Christianson syndrome among females heterozygous for SLC9A6 mutations and might improve diagnostic practice and genetic counseling by helping to characterize this presumably underappreciated patient/carrier group.

• Klíčová slova
• Christianson syndrome, Female heterozygotes, Mosaicism, NHE6 protein, Slc9a6, X-chromosome inactivation,
• MeSH
• alely MeSH
• ataxie genetika   MeSH
• chování zvířat MeSH
• epilepsie genetika   MeSH
• fenotyp MeSH
• G(M2) gangliosid imunologie   MeSH
• genetické nemoci vázané na chromozom X genetika   MeSH
• genotyp MeSH
• heterozygot MeSH
• kognitivní poruchy genetika   MeSH
• mentální retardace genetika   MeSH
• mikrocefalie genetika   MeSH
• modely nemocí na zvířatech MeSH
• mozaicismus * MeSH
• mutace MeSH
• myši knockoutované MeSH
• myši MeSH
• Na(+)-H(+) antiport genetika   fyziologie   MeSH
• poruchy hybnosti oka genetika   MeSH
• Purkyňovy buňky cytologie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• G(M2) gangliosid MeSH
• Na(+)-H(+) antiport MeSH
• NHE6 protein, mouse MeSH Prohlížeč

We describe a male and his sister's son with microcephaly, microphthalmia, microcornea, congenital cataract, hypogenitalism, severe mental deficiency, progressive spasticity and growth retardation. Both affected males have brachycephaly, upslanting palpebral fissures, epicanthal folds, highly arched palate, small mouth, and retrognathia. Two maternal cousins of the propositus's mother may also have been affected. Chromosomal and metabolic findings in the propositus were normal. To our knowledge, this disorder has not been reported before as an X-linked syndrome.

• MeSH
• abnormality očí genetika   MeSH
• chromozom X * MeSH
• dítě MeSH
• hypogonadismus genetika   MeSH
• katarakta genetika   MeSH
• lidé MeSH
• mentální retardace genetika   MeSH
• mikrocefalie genetika   MeSH
• poruchy růstu genetika   MeSH
• rodokmen MeSH
• svalová spasticita genetika   MeSH
• syndrom MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH

BACKGROUND: Organic acidurias (OADs) and urea cycle disorders (UCDs) are inborn metabolic disorders with a risk for acute and chronic metabolic decompensation resulting in impairments of the central nervous system and other organ systems. So far, there is no systematic study of intellectual functioning, behavioural/emotional problems and health-related quality of life (HRQoL), and how these domains are connected. METHODS: Data of 152 patients with OADs (n = 100) and UCDs (n = 52) from the European Registry and Network of intoxication type Metabolic Diseases (E-IMD) using standardized instruments were compared with normative data. RESULTS: Behavioural/emotional problems are increased in OADs or UCDs patients by a factor of 2.5 (3.0), in female asymptomatic carriers of X-linked inherited UCD ornithine transcarbamylase deficiency (fasOTCD) by a factor of 1.5. All groups show similar patterns of behavioural/emotional problems, not different from epidemiological data. Mental disability (IQ ≤ 70) was found in 31% of OAD, 43% of UCD, but not in fasOTCD subjects. HRQoL was decreased in the physical domain, but in the normal range. Behavioural/emotional problems were significantly associated with intellectual functioning (OR = 6.24, 95%CI: 1.39-27.99), but HRQoL was independent from both variables. CONCLUSIONS: Patients with OADs and UCDs show increased frequencies of mental disability and behavioural/emotional problems. Profiles of behavioural/emotional problems were similar to epidemiological data. Intellectual disability and behavioural/emotional problems were strongly associated. Patients' HRQoL was in the normal range, possibly compensated by coping strategies of their families. Diagnostics and clinical care of OAD/UCD patients should be improved regarding behavioural/emotional, intellectual and quality of life aspects.

• MeSH
• duševní poruchy etiologie   metabolismus   MeSH
• emoce MeSH
• kvalita života MeSH
• lidé MeSH
• mentální retardace etiologie   metabolismus   MeSH
• metabolické nemoci komplikace   metabolismus   MeSH
• nemoc z nedostatku ornithinkarbamoyltransferázy komplikace   metabolismus   MeSH
• předškolní dítě MeSH
• vrozené poruchy cyklu močoviny komplikace   metabolismus   MeSH
• vrozené poruchy metabolismu komplikace   metabolismus   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

PURPOSE: Variants in IQSEC2, escaping X inactivation, cause X-linked intellectual disability with frequent epilepsy in males and females. We aimed to investigate sex-specific differences. METHODS: We collected the data of 37 unpublished patients (18 males and 19 females) with IQSEC2 pathogenic variants and 5 individuals with variants of unknown significance and reviewed published variants. We compared variant types and phenotypes in males and females and performed an analysis of IQSEC2 isoforms. RESULTS: IQSEC2 pathogenic variants mainly led to premature truncation and were scattered throughout the longest brain-specific isoform, encoding the synaptic IQSEC2/BRAG1 protein. Variants occurred de novo in females but were either de novo (2/3) or inherited (1/3) in males, with missense variants being predominantly inherited. Developmental delay and intellectual disability were overall more severe in males than in females. Likewise, seizures were more frequently observed and intractable, and started earlier in males than in females. No correlation was observed between the age at seizure onset and severity of intellectual disability or resistance to antiepileptic treatments. CONCLUSION: This study provides a comprehensive overview of IQSEC2-related encephalopathy in males and females, and suggests that an accurate dosage of IQSEC2 at the synapse is crucial during normal brain development.

• Klíčová slova
• IQSEC2, X-linked inheritance, epilepsy, intellectual disability, isoforms,
• MeSH
• fenotyp MeSH
• kojenec MeSH
• lidé MeSH
• mentální retardace epidemiologie   genetika   patofyziologie   MeSH
• mozek růst a vývoj   metabolismus   MeSH
• mutace MeSH
• nemoci mozku epidemiologie   genetika   patofyziologie   MeSH
• novorozenec MeSH
• pohlavní dimorfismus MeSH
• protein - isoformy genetika   MeSH
• rodokmen MeSH
• výměnné faktory guaninnukleotidů genetika   MeSH
• záchvaty epidemiologie   genetika   patofyziologie   MeSH
• Check Tag
• kojenec MeSH
• lidé MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• IQSEC2 protein, human MeSH Prohlížeč
• protein - isoformy MeSH
• výměnné faktory guaninnukleotidů MeSH

Overgrowth syndromes are rare genetic disorders characterized by excessive pre- and postnatal growth accompanied by dysmorphic features and developmental disorders. In addition to other health hazards, the life expectancy of affected children may be compromised due to an increased risk of developing tumors. To demonstrate the need for early recognition, correct diagnostic evaluation and adequate follow-up, we present a family with recurrent Simpson-Golabi-Behmel syndrome (SGBS). SGBS is a X-linked neonatal overgrowth syndrome caused by mutations in the GPC3 or GPC4 genes. All three affected males manifested with congenital diaphragmatic hernia. When fetal overgrowth and congenital diaphragmatic hernia co-occur, the choice for a possible cause is limited among SGBS, Marfan syndrome and Pallister-Killian syndrome. Their different phenotypes allow clinical assessment and correct diagnosis in most cases and should be followed by genetic testing. Regular oncologic screening aimed towards early recognition of malignant tumors may improve long-term outcomes in SGBS as well as in all other overgrowth syndromes.

• Klíčová slova
• Congenital diaphragmatic hernia, GPC3, Hepatoblastoma, Overgrowth syndromes, Simpson-Golabi-Behmel syndrome,
• MeSH
• genetické nemoci vázané na chromozom X * MeSH
• gigantismus * MeSH
• glypikany MeSH
• lidé MeSH
• mentální retardace MeSH
• novorozenec MeSH
• srdeční arytmie MeSH
• vrozené srdeční vady MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• Publikační typ
• úvodníky MeSH
• Názvy látek
• glypikany MeSH

Neurodevelopmental disorders (NDDs) result from highly penetrant variation in hundreds of different genes, some of which have not yet been identified. Using the MatchMaker Exchange, we assembled a cohort of 27 individuals with rare, protein-altering variation in the transcriptional coregulator ZMYM3, located on the X chromosome. Most (n = 24) individuals were males, 17 of which have a maternally inherited variant; six individuals (4 male, 2 female) harbor de novo variants. Overlapping features included developmental delay, intellectual disability, behavioral abnormalities, and a specific facial gestalt in a subset of males. Variants in almost all individuals (n = 26) are missense, including six that recurrently affect two residues. Four unrelated probands were identified with inherited variation affecting Arg441, a site at which variation has been previously seen in NDD-affected siblings, and two individuals have de novo variation resulting in p.Arg1294Cys (c.3880C>T). All variants affect evolutionarily conserved sites, and most are predicted to damage protein structure or function. ZMYM3 is relatively intolerant to variation in the general population, is widely expressed across human tissues, and encodes a component of the KDM1A-RCOR1 chromatin-modifying complex. ChIP-seq experiments on one variant, p.Arg1274Trp, indicate dramatically reduced genomic occupancy, supporting a hypomorphic effect. While we are unable to perform statistical evaluations to definitively support a causative role for variation in ZMYM3, the totality of the evidence, including 27 affected individuals, recurrent variation at two codons, overlapping phenotypic features, protein-modeling data, evolutionary constraint, and experimentally confirmed functional effects strongly support ZMYM3 as an NDD-associated gene.

• Klíčová slova
• X-linked intellectual disability, ZMYM3, chromatin modifiers, neurodevelopmental disorder, transcriptional coregulators,
• MeSH
• fenotyp MeSH
• histondemethylasy genetika   MeSH
• jaderné proteiny genetika   MeSH
• lidé MeSH
• malformace nervového systému * MeSH
• mentální retardace * genetika   MeSH
• neurovývojové poruchy * genetika   MeSH
• obličej MeSH
• regulace genové exprese MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• histondemethylasy MeSH
• jaderné proteiny MeSH
• KDM1A protein, human MeSH Prohlížeč
• ZMYM3 protein, human MeSH Prohlížeč