Chromosomal map of human brain malformations

Tyshchenko, Nataliya; Lurie, Iosif W.; Schinzel, Albert

doi:10.1007/s00439-008-0528-2

Cited by 11 publications

(10 citation statements)

References 54 publications

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“…To our knowledge, the deletion of this region has never been reported not only in MIH, but also in HPE (Tyshchenko et al, 2008). The deletion involving the EYA4 gene is not described in the decipher database at the present moment (https://decipher.sanger.ac.uk/).…”

Section: E953 Discussionmentioning

confidence: 88%

EYA4, deleted in a case with middle interhemispheric variant of holoprosencephaly, interacts withSIX3both physically and functionally

et al. 2009

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Holoprosencephaly (HPE) is the most common congenital malformation of the developing human forebrain, in which the two cerebral hemispheres fail to separate to various degrees. Although pathological mutations have been identified in up to nine genes, a number of other genes as well as environmental factors are likely to be involved in HPE. Here, we describe a case with the middle interhemispheric variant, a milder variant of HPE, carrying a deletion of ~10.4 Mb at 6q22.31-q23.2, which includes the EYA4 gene. EYA4 is one of four vertebrate orthologs of the Drosophila melanogaster gene, eyes absent. EYA4 was co-immunoprecipitated with SIX3, the product of one of the known HPE genes. Moreover, the EYA4 protein was observed to be recruited to the nucleus by the nuclear protein SIX3 under a confocal microscope. EYA4 is a transcriptional coactivator, and was shown to cooperate with transcription factor SIX3 by reporter gene assays. These results demonstrate physical and functional association between EYA4 and SIX3, suggesting that EYA4 is a novel candidate gene of HPE, whose haploinsufficiency leads to HPE through the compromised function of SIX3.

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Section: E953 Discussionmentioning

confidence: 88%

EYA4, deleted in a case with middle interhemispheric variant of holoprosencephaly, interacts withSIX3both physically and functionally

et al. 2009

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“…Deletions of the 1q41 − q44 locus encompassing TP53BP2 are significantly associated with posterior encephalocele, generally considered a NTD. 1,38,39 This suggests that TP53BP2 deficiency might also play a role in a subset of human NTDs.…”

Section: Resultsmentioning

confidence: 99%

“…Deletions in the chromosomal 1q41 − q44 region are significantly associated with central nervous system (CNS) defects including neural tube defects (NTDs), agenesis of corpus callosum, microcephaly and hydrocephalus. 1,2 In particular, small interstitial deletions in the 1q41q42 region are implicated in the 1q41q42 microdeletion syndrome with features of severe developmental delay, intellectual disability, and brain morphological abnormalities. A critical region comprising the genes FBXO28, TP53BP2, CAPN2, and CAPN8 has been proposed for the 1q41q42 microdeletion syndrome based on the smallest region of overlap (SRO).…”

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confidence: 99%

ASPP2 deficiency causes features of 1q41q42 microdeletion syndrome

et al. 2016

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Chromosomal abnormalities are implicated in a substantial number of human developmental syndromes, but for many such disorders little is known about the causative genes. The recently described 1q41q42 microdeletion syndrome is characterized by characteristic dysmorphic features, intellectual disability and brain morphological abnormalities, but the precise genetic basis for these abnormalities remains unknown. Here, our detailed analysis of the genetic abnormalities of 1q41q42 microdeletion cases identified TP53BP2, which encodes apoptosis-stimulating protein of p53 2 (ASPP2), as a candidate gene for brain abnormalities. Consistent with this, Trp53bp2-deficient mice show dilation of lateral ventricles resembling the phenotype of 1q41q42 microdeletion patients. Trp53bp2 deficiency causes 100% neonatal lethality in the C57BL/6 background associated with a high incidence of neural tube defects and a range of developmental abnormalities such as congenital heart defects, coloboma, microphthalmia, urogenital and craniofacial abnormalities. Interestingly, abnormalities show a high degree of overlap with 1q41q42 microdeletion-associated abnormalities. These findings identify TP53BP2 as a strong candidate causative gene for central nervous system (CNS) defects in 1q41q42 microdeletion syndrome, and open new avenues for investigation of the mechanisms underlying CNS abnormalities.

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“…A chromosomal map which associated human brain congenital malformations with specific chromosomal regions had been constructed, but this low resolution map is of limited value for identifying dosage-sensitive genes [14]. Current cytogenomic analysis has facilitated accurate subtractive mapping of critical regions or intervals for identifying candidate genes in an increasing number of patients.…”

Section: Introductionmentioning

confidence: 99%

Cytogenomic mapping and bioinformatic mining reveal interacting brain expressed genes for intellectual disability

Schulz

et al. 2014

Mol Cytogenet

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BackgroundMicroarray analysis has been used as the first-tier genetic testing to detect chromosomal imbalances and copy number variants (CNVs) for pediatric patients with intellectual and developmental disabilities (ID/DD). To further investigate the candidate genes and underlying dosage-sensitive mechanisms related to ID, cytogenomic mapping of critical regions and bioinformatic mining of candidate brain-expressed genes (BEGs) and their functional interactions were performed. Critical regions of chromosomal imbalances and pathogenic CNVs were mapped by subtracting known benign CNVs from the Databases of Genomic Variants (DGV) and extracting smallest overlap regions with cases from DatabasE of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources (DECIPHER). BEGs from these critical regions were revealed by functional annotation using Database for Annotation, Visualization, and Integrated Discovery (DAVID) and by tissue expression pattern from Uniprot. Cross-region interrelations and functional networks of the BEGs were analyzed using Gene Relationships Across Implicated Loci (GRAIL) and Ingenuity Pathway Analysis (IPA).ResultsOf the 1,354 patients analyzed by oligonucleotide array comparative genomic hybridization (aCGH), pathogenic abnormalities were detected in 176 patients including genomic disorders in 66 patients (37.5%), subtelomeric rearrangements in 45 patients (25.6%), interstitial imbalances in 33 patients (18.8%), chromosomal structural rearrangements in 17 patients (9.7%) and aneuploidies in 15 patients (8.5%). Subtractive and extractive mapping defined 82 disjointed critical regions from the detected abnormalities. A total of 461 BEGs was generated from 73 disjointed critical regions. Enrichment of central nervous system specific genes in these regions was noted. The number of BEGs increased with the size of the regions. A list of 108 candidate BEGs with significant cross region interrelation was identified by GRAIL and five significant gene networks involving cell cycle, cell-to-cell signaling, cellular assembly, cell morphology, and gene expression regulations were denoted by IPA.ConclusionsThese results characterized ID related cross-region interrelations and multiple networks of candidate BEGs from the detected genomic imbalances. Further experimental study of these BEGs and their interactions will lead to a better understanding of dosage-sensitive mechanisms and modifying effects of human mental development.

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Chromosomal map of human brain malformations

Cited by 11 publications

References 54 publications

EYA4, deleted in a case with middle interhemispheric variant of holoprosencephaly, interacts withSIX3both physically and functionally

EYA4, deleted in a case with middle interhemispheric variant of holoprosencephaly, interacts withSIX3both physically and functionally

ASPP2 deficiency causes features of 1q41q42 microdeletion syndrome

Cytogenomic mapping and bioinformatic mining reveal interacting brain expressed genes for intellectual disability

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