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Integrating Molecular and Organismal Analyses of Rai1, The Causal Gene for Smith-Magenis Syndrome

ABSTRACT: Integrating Molecular and Organismal Analyses of Rai1, The Causal Gene for Smith-Magenis Syndrome

PROVIDER: PRJNA320885 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR3480140_1.fastq.gz	Fastqsanger.gz
	SRR3480140_2.fastq.gz	Fastqsanger.gz
	SRR3480220_1.fastq.gz	Fastqsanger.gz
	SRR3480220_2.fastq.gz	Fastqsanger.gz
	SRR3480141_1.fastq.gz	Fastqsanger.gz

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Integrating Molecular and Organismal Analyses of Rai1, The Causal Gene for Smith-Magenis Syndrome

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2017-01-03 | GSE81207 | GEO

Identification of a RAI1-associated disease network through integration of exome sequencing, transcriptomics and 3D genomics

Project description:Smith-Magenis syndrome (SMS) is a developmental disability/multiple congenital anomaly disorder resulting from haploinsufficiency of RAI1. It is characterized by distinctive facial features, brachydactyly, sleep disturbances and stereotypic behaviors. We investigated a cohort of 15 individuals with a clinical suspicion of SMS, who showed neither deletion in the SMS critical region nor damaging variants in RAI1. Potentially deleterious variants were identified in nine of these subjects using whole-exome sequencing. Eight of these changes affect KMT2D, ZEB2, MAP2K2, GLDC, CASK, MECP2, KDM5C and POGZ, known to be associated with Kabuki syndrome 1, Mowat-Wilson syndrome, cardiofaciocutaneous syndrome, glycine encephalopathy, mental retardation and microcephaly with pontine and cerebellar hypoplasia, X-linked mental retardation 13, X-linked mental retardation Claes-Jensen type and White-Sutton syndrome, respectively. The ninth individual carries a de novo variant in JAKMIP1, a regulator of neuronal translation that was recently found deleted in a patient with autism spectrum disorder. Analyses of coexpression and biomedical text mining suggest that these pathologies and SMS are part of the same disease network. Further support for this hypothesis was obtained from transcriptome profiling that showed that the expression levels of both Zeb2 and Map2k2 are perturbed in Rai1-/- mice. As an orthogonal approach to potentially contributory disease gene variants, we used chromatin conformation capture to reveal chromatin contacts between RAI1 and the loci flanking ZEB2 and GLDC, as well as between RAI1 and human orthologs of the genes that show perturbed expression in our Rai1-/- mouse model. These holistic studies of RAI1 and its interactions allow insights into SMS and other disorders associated with intellectual disability and behavioral abnormalities. Our findings support a pan-genomic approach to the molecular diagnosis of a distinctive disorder.

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Project description:rAAV-CRISPRa therapy corrects Rai1 haploinsufficiency and rescues selective disease features in Smith-Magenis syndrome mice

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Project description:Smith-Magenis syndrome (SMS) is a genomic disorder caused by the deletion of a chromosomal region at 17p11.2. Individuals with SMS are frequently diagnosed with autism and have profound cortical deficits, including reduced cortex volume, mild ventriculomegaly, and epilepsy. Here, we developed human induced pluripotent stem cell (hiPSC)-derived neuronal models to understand how del(17)p11.2 affects cortical development. Hi-C identified local fusion and global reorganization of topological domains, as well as genome-wide miswiring of chromatin 3-dimensional (3D) interactions in SMS hiPSC and 3D cortical organoids. Single-nucleus RNA-seq of SMS cortical organoids identified neuropsychiatric disease-enriched transcriptional signatures and dysregulation of genes involved in catabolic and biosynthetic pathways, cell cycle processes, and neuronal signalling. SMS cortical organoids had reduced growth, enlarged ventricles, and impaired cell cycle progression. In a complementary hiPSC-derived 2D cortical neuronal model, we found SMS cortical neurons had accelerated dendritic growth, followed by neuronal hyperexcitability that was associated with a reduced potassium conductance. Our study demonstrates that del(17)p11.2 disrupts multiple steps of human cortical development, from chromatin wiring, transcriptional regulation, cell cycle progression, and morphological maturation to neurophysiological properties, and hiPSC-derived models recapitulate key neuroanatomical and neurophysiological features of SMS.

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