elektronický časopis
elektronický časopis
- Conspectus
- Psychiatrie
- NML Fields
- pediatrie
- psychiatrie
- zdravotně postižení
- NML Publication type
- elektronické časopisy
elektronický časopis
elektronický časopis
- Conspectus
- Psychiatrie
- NML Fields
- pediatrie
- psychiatrie
- zdravotně postižení
- NML Publication type
- elektronické časopisy
sv.
- MeSH
- Education, Special methods MeSH
- Education of Persons with Intellectual Disabilities MeSH
- Child, Exceptional education MeSH
- Developmental Disabilities MeSH
- Publication type
- Periodical MeSH
- Conspectus
- Psychiatrie
- NML Fields
- psychiatrie
- psychologie, klinická psychologie
- sociální lékařství
Microtubule associated proteins (MAPs) are widely expressed in the central nervous system, and have established roles in cell proliferation, myelination, neurite formation, axon specification, outgrowth, dendrite, and synapse formation. We report eleven individuals from seven families harboring predicted pathogenic biallelic, de novo, and heterozygous variants in the NAV3 gene, which encodes the microtubule positive tip protein neuron navigator 3 (NAV3). All affected individuals have intellectual disability (ID), microcephaly, skeletal deformities, ocular anomalies, and behavioral issues. In mouse brain, Nav3 is expressed throughout the nervous system, with more prominent signatures in postmitotic, excitatory, inhibiting, and sensory neurons. When overexpressed in HEK293T and COS7 cells, pathogenic variants impaired NAV3 ability to stabilize microtubules. Further, knocking-down nav3 in zebrafish led to severe morphological defects, microcephaly, impaired neuronal growth, and behavioral impairment, which were rescued with co-injection of WT NAV3 mRNA and not by transcripts encoding the pathogenic variants. Our findings establish the role of NAV3 in neurodevelopmental disorders, and reveal its involvement in neuronal morphogenesis, and neuromuscular responses.
- MeSH
- Chlorocebus aethiops MeSH
- COS Cells MeSH
- Zebrafish genetics MeSH
- Child MeSH
- HEK293 Cells MeSH
- Humans MeSH
- Intellectual Disability * genetics MeSH
- Microcephaly * genetics pathology MeSH
- Mice MeSH
- Neurons metabolism pathology MeSH
- Child, Preschool MeSH
- Microtubule-Associated Proteins genetics metabolism MeSH
- Nerve Tissue Proteins genetics metabolism MeSH
- Developmental Disabilities * genetics MeSH
- Animals MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Male MeSH
- Mice MeSH
- Child, Preschool MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
elektronický časopis
- MeSH
- Intellectual Disability rehabilitation MeSH
- Persons with Disabilities MeSH
- Developmental Disabilities MeSH
- Conspectus
- Psychologie
- NML Fields
- psychologie, klinická psychologie
- zdravotně postižení
- psychiatrie
- NML Publication type
- elektronické časopisy
Mutations that alter signaling of RAS/MAPK-family proteins give rise to a group of Mendelian diseases known as RASopathies. However, among RASopathies, the matrix of genotype-phenotype relationships is still incomplete, in part because there are many RAS-related proteins and in part because the phenotypic consequences may be variable and/or pleiotropic. Here, we describe a cohort of ten cases, drawn from six clinical sites and over 16,000 sequenced probands, with de novo protein-altering variation in RALA, a RAS-like small GTPase. All probands present with speech and motor delays, and most have intellectual disability, low weight, short stature, and facial dysmorphism. The observed rate of de novo RALA variants in affected probands is significantly higher (p = 4.93 x 10(-11)) than expected from the estimated random mutation rate. Further, all de novo variants described here affect residues within the GTP/GDP-binding region of RALA; in fact, six alleles arose at only two codons, Val25 and Lys128. The affected residues are highly conserved across both RAL- and RAS-family genes, are devoid of variation in large human population datasets, and several are homologous to positions at which disease-associated variants have been observed in other GTPase genes. We directly assayed GTP hydrolysis and RALA effector-protein binding of the observed variants, and found that all but one tested variant significantly reduced both activities compared to wild-type. The one exception, S157A, reduced GTP hydrolysis but significantly increased RALA-effector binding, an observation similar to that seen for oncogenic RAS variants. These results show the power of data sharing for the interpretation and analysis of rare variation, expand the spectrum of molecular causes of developmental disability to include RALA, and provide additional insight into the pathogenesis of human disease caused by mutations in small GTPases.
- MeSH
- Facies MeSH
- Phenotype MeSH
- Genotype MeSH
- Guanosine Diphosphate metabolism MeSH
- Guanosine Triphosphate metabolism MeSH
- Protein Interaction Domains and Motifs genetics MeSH
- Protein Conformation MeSH
- Humans MeSH
- Intellectual Disability genetics MeSH
- Mutation, Missense MeSH
- Mitochondrial Proteins chemistry genetics MeSH
- Models, Molecular MeSH
- Mutation * MeSH
- ral GTP-Binding Proteins chemistry genetics MeSH
- ras Proteins chemistry genetics MeSH
- Developmental Disabilities genetics MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
elektronický časopis
BACKGROUND: Chromosomal microarray analysis has been shown to be a valuable and cost effective assay for elucidating copy number variants (CNVs) in children with intellectual disability and developmental delay (ID/DD). METHODS: In our study, we performed array-based comparative genomic hybridization (array-CGH) analysis using oligonucleotide-based platforms in 542 Czech patients with ID/DD, autism spectrum disorders and multiple congenital abnormalities. Prior to the array-CGH analysis, all the patients were first examined karyotypically using G-banding. The presence of CNVs and their putative derivation was confirmed using fluorescence in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA) and predominantly relative quantitative polymerase chain reaction (qPCR). RESULTS: In total, 5.9% (32/542) patients were positive for karyotypic abnormalities. Pathogenic/likely pathogenic CNVs were identified in 17.7% of them (96/542), variants of uncertain significance (VOUS) were detected in 4.8% (26/542) and likely benign CNVs in 9.2% of cases (50/542). We identified 6.6% (36/542) patients with known recurrent microdeletion (24 cases) and microduplication (12 cases) syndromes, as well as 4.8% (26/542) patients with non-recurrent rare microdeletions (21 cases) and microduplications (5 cases). In the group of patients with submicroscopic pathogenic/likely pathogenic CNVs (13.3%; 68/510) we identified 91.2% (62/68) patients with one CNV, 5.9% (4/68) patients with two likely independent CNVs and 2.9% (2/68) patients with two CNVs resulting from cryptic unbalanced translocations. Of all detected CNVs, 21% (31/147) had a de novo origin, 51% (75/147) were inherited and 28% (41/147) of unknown origin. In our cohort pathogenic/likely pathogenic microdeletions were more frequent than microduplications (69%; 51/74 vs. 31%; 23/74) ranging in size from 0.395 Mb to 10.676 Mb (microdeletions) and 0.544 Mb to 8.156 Mb (microduplications), but their sizes were not significantly different (P = 0.83). The pathogenic/likely pathogenic CNVs (median 2.663 Mb) were significantly larger than benign CNVs (median 0.394 Mb) (P < 0.00001) and likewise the pathogenic/likely pathogenic CNVs (median 2.663 Mb) were significantly larger in size than VOUS (median 0.469 Mb) (P < 0.00001). CONCLUSIONS: Our results confirm the benefit of array-CGH in the current clinical genetic diagnostics leading to identification of the genetic cause of ID/DD in affected children.
- MeSH
- Child MeSH
- Cohort Studies MeSH
- Infant MeSH
- Humans MeSH
- Intellectual Disability genetics MeSH
- Adolescent MeSH
- Infant, Newborn MeSH
- Child, Preschool MeSH
- Oligonucleotide Array Sequence Analysis * MeSH
- Comparative Genomic Hybridization * MeSH
- DNA Copy Number Variations * MeSH
- Developmental Disabilities genetics MeSH
- Check Tag
- Child MeSH
- Infant MeSH
- Humans MeSH
- Adolescent MeSH
- Male MeSH
- Infant, Newborn MeSH
- Child, Preschool MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Geographicals
- Czech Republic MeSH
