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Biallelic variants in SREK1 downregulating SNORD115/116 cause a novel Prader-Willi-like syndrome

ABSTRACT: Biallelic variants in SREK1 downregulating SNORD115/116 cause a novel Prader-Willi-like syndrome

PROVIDER: PRJNA1241818 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR32858319_1.fastq.gz	Fastqsanger.gz
	SRR32858319_2.fastq.gz	Fastqsanger.gz
	SRR32858320_1.fastq.gz	Fastqsanger.gz
	SRR32858320_2.fastq.gz	Fastqsanger.gz
	SRR32858321_1.fastq.gz	Fastqsanger.gz

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Biallelic variants in SREK1 downregulating SNORD115/116 cause a novel Prader-Willi-like syndrome

Project description:Up to 10% of patients with severe early-onset obesity carry pathogenic variants in known obesity-related genes, mostly affecting the leptin-melanocortin pathway. Studying children with severe obesity from consanguineous populations provides a unique opportunity to uncover novel molecular mechanisms. Using whole-exome sequencing, followed by a rigorous analytical and filtration strategy, we identified three different homozygous missense variants in SREK1 (encoding Splicing Regulatory glutamic acid and lysine rich protein) in Pakistani children with severe obesity, from three unrelated consanguineous pedigrees. The wild type SREK1 gene of human induced pluripotent stem cell (iPSC)-derived hypothalamic neurons was individually replaced by each of the three variants and the impact of these changes on global gene expression was studied. Neurons expressing the two variants in the SREK1 RNA recognition domain p.P95L and p.T194M, but not the C-terminally located p.E601K, had markedly reduced expression of the small nucleolar RNA clusters SNORD115 and SNORD116, deficiency of which has been implicated in Prader-Willi syndrome (PWS). In addition to hyperphagic obesity the carriers of these two variants had other features of PWS, such as neonatal hypotonia. In conclusion, homozygous variants in SREK1 result in a subtype of severe early onset obesity sharing features with PWS.

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The noncoding RNA IPW regulates the imprinted DLK1-DIO3 locus in an induced pluripotent stem cell model of Prader-Willi syndrome

Project description:Parental imprinting is a form of epigenetic regulation that results in parent-of-origin differential gene expression. To study Prader-Willi syndrome (PWS), a developmental imprinting disorder, we generated patient-derived induced pluripotent stem cells (iPSCs) harboring distinct deletions in the affected region on chromosome 15. Studying PWS-iPSCs and human parthenogenetic iPSCs unexpectedly revealed substantial upregulation of virtually all maternally expressed genes (MEGs) in the imprinted DLK1-DIO3 locus on chromosome 14. Subsequently, we identified IPW, a long noncoding RNA in the critical region of the PWS locus, as a regulator of the DLK1-DIO3 region, as its over-expression in PWS and parthenogenetic iPSCs results in downregulation of the MEGs in this locus. We further show that gene expression changes in the DLK1-DIO3 region coincide with chromatin modifications, rather than DNA methylation levels. Our results suggest that a subset of PWS phenotypes may arise from dysregulation of an imprinted locus distinct from the PWS region. Gene expression analysis was performed on a total of 4 human cell lines, including 3 Prader-Willi Syndrome indcued pluripotent stem cell lines - derived from 3 affected individuals and one of their parental fibroblast cell line.

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