RSRC1 loss-of-function variants cause mild to moderate autosomal recessive intellectual disability

Scala, Marcello; Mojarrad, Majid; Riazuddin, Saima; Brigatti, Karlla W.; Ammous, Zineb; Cohen, Julie S.; Hosny, Heba; Usmani, Muhammad A.; Shahzad, Mohsin; Riazuddin, Sheikh; Stanley, Valentina; Eslahi, Atiye; Person, Richard; Elbendary, Hasnaa M; Comi, Anne M.; Poskitt, Laura; Salpietro, Vincenzo; Genomics, Queen Square; Rosenfeld, Jill A.; Williams, Katie B; Marafi, Dana; Xia, Fan; Waberski, Marta Biderman; Zaki, Maha S.; Gleeson, Joseph G.; Puffenberger, Erik G.; Houlden, Henry; Maroofian, Reza

doi:10.1093/brain/awaa070

Cited by 10 publications

(9 citation statements)

References 16 publications

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“…1A ). The Shox2 TAD only contains one other protein coding gene, Rsrc1 , located adjacent to Shox2 on the upstream (telomeric) side and known for roles in pre-mRNA splicing and neuronal transcription 50,51 ( Fig. 1A ).…”

Section: Resultsmentioning

confidence: 99%

A gene desert required for regulatory control of pleiotropicShox2expression and embryonic survival

Abassah-Oppong

Mannion

Tissières

et al. 2020

Preprint

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The Shox2 homeodomain transcriptional regulator is known for its critical functions during mouse embryogenesis, enabling accurate development of limbs, craniofacial structures, neural populations and the cardiac conduction system. At the genomic level, the Shox2 gene is flanked by an extensive gene desert, a continuous non-coding genomic region spanning over 500 kilobases that contains a multitude of evolutionarily conserved elements with predicted cis-regulatory activities. However, the transcriptional enhancer potential of the vast majority of these elements in combination with the biological necessity of the gene desert have not yet been explored. Using transgenic reporter assays in mouse embryos to validate an extensive set of stringent epigenomic enhancer predictions, we identify several novel gene desert enhancers with distinct tissue-specific activities in Shox2 expressing tissues. 4C-seq chromatin conformation capture further uncovers a repertoire of gene desert enhancers with overlapping activities in the proximal limb, in a compartment essential for Shox2-mediated stylopod formation. Leveraging CRISPR/Cas9 to delete the gene desert region contained in the Shox2 topologically associated domain (TAD), we demonstrate that this complex cis-regulatory platform is essential for embryonic survival and required for control of region-specific Shox2 expression in multiple developing tissues. While transcription of Shox2 in the embryonic limb is only moderately affected by gene desert loss, Shox2 expression in craniofacial and cardiac domains is nearly abolished. In particular, Shox2 transcripts in the sinus venosus (SV) encompassing the sinoatrial node (SAN) were depleted in embryos lacking the gene desert, likely accounting for the embryonic lethality due to Shox2-dependency of the SAN pacemaker. Finally, we discover a 1.5kb SV enhancer within the deleted gene desert region, which may act as a genomic module controlling the development of the cardiac conduction system. In summary, our results identify a gene desert indispensable for pleiotropic patterning and highlight the importance of these extensive regulatory landscapes for embryonic development and viability.

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Section: Resultsmentioning

confidence: 99%

A gene desert required for regulatory control of pleiotropicShox2expression and embryonic survival

Abassah-Oppong

Mannion

Tissières

et al. 2020

Preprint

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“…Mature IGF-2 does not have glycosylation sites but E-domain of pro-IGF-2 may be glycosylated by up to four O-linked sugars. Amino acid residues that serve as glycosylation sites are Ser 71 , Ser 72 , Ser 75 and Thr 139 . Various sugars used for glycosylation have O-glycan backbone decorated with different number of sialic acid residues [35,117].…”

Section: Glycosylationmentioning

confidence: 99%

“…On the other hand, decreased IGFBP3 expression level may also be associated with intellectual disability. RSRC1 (Arginine And Serine Rich Coiled-Coil 1) is a protein involved in splicing regulation [ 139 ]; RSRC1 loss-of-function mutation in humans leads to drastically decreased IGFBP3 expression in neural progenitor cells [ 140 ]. It was later confirmed that RSRC1 loss-of-function causes mild to moderate autosomal recessive intellectual disability [ 139 ].…”

Section: Igf-binding Proteinsmentioning

confidence: 99%

Insulin-Like Growth Factor 2 As a Possible Neuroprotective Agent and Memory Enhancer—Its Comparative Expression, Processing and Signaling in Mammalian CNS

Beletskiy

Чеснокова

Bal

2021

IJMS

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A number of studies performed on rodents suggest that insulin-like growth factor 2 (IGF-2) or its analogs may possibly be used for treating some conditions like Alzheimer’s disease, Huntington’s disease, autistic spectrum disorders or aging-related cognitive impairment. Still, for translational research a comparative knowledge about the function of IGF-2 and related molecules in model organisms (rats and mice) and humans is necessary. There is a number of important differences in IGF-2 signaling between species. In the present review we emphasize species-specific patterns of IGF-2 expression in rodents, humans and some other mammals, using, among other sources, publicly available transcriptomic data. We provide a detailed description of Igf2 mRNA expression regulation and pre-pro-IGF-2 protein processing in different species. We also summarize the function of IGF-binding proteins. We describe three different receptors able to bind IGF-2 and discuss the role of IGF-2 signaling in learning and memory, as well as in neuroprotection. We hope that comprehensive understanding of similarities and differences in IGF-2 signaling between model organisms and humans will be useful for development of more effective medicines targeting IGF-2 receptors.

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“…dental abnormality has also been reported (5). The association of autosomal recessive missense/nonsense variants with mild mental retardation has been demonstrated (23,24). However, mental retardation has not been described in SALL4 genetic syndromes.…”

Section: Discussionmentioning

confidence: 99%

A de novo mutation of SALL4 in a Chinese family with Okihiro syndrome

Huang

Guo

et al. 2022

Mol Med Rep

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okihiro syndrome is an autosomal dominant condition characterized by duane anomaly and radial ray defects. The present study aimed to analyze the clinical manifestations of a patient with okihiro syndrome and perform genetic testing on the proband and his family to determine the biological pathogenesis. clinical data were collected from the proband and his family and genomic dna was extracted from peripheral blood. Whole exome sequencing was performed by high-throughput sequencing and mutation sites of the proband and his parents were validated by Sanger sequencing. The proband was diagnosed with okihiro syndrome, which is characterized by bone abnormality in the arms and hands (radial ray malformation, absence of thumbs) and sensorineural hearing loss. a pathogenic heterozygous c.3060delG variant was identified in exon 4 of spalt-like transcription factor 4 (SALL4) gene in the proband. This is a frameshift mutation that changes increases the length of SALL4 protein from 1,053 to 1,076 amino acids. The variant was classed as a de novo mutation because the parents of the proband showed no variation at this site. This variant is not included in the clinVar database and, to the best of our knowledge, has not previously been reported. The de novo heterozygous c.3060delG variant was the molecular pathological cause of okihiro syndrome in the present study and expanded the database of known SALL4 variants. Materials and methodsCase data. The proband was from Yunnan, china, had profound congenital sensorineural deafness and went to the hospital in July 2020. He received a cochlear implant from Kunming Children's Hospital (KCH). Clinical data from the proband (male, 23 months old) and his father (28 years old) and

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RSRC1 loss-of-function variants cause mild to moderate autosomal recessive intellectual disability

Cited by 10 publications

References 16 publications

A gene desert required for regulatory control of pleiotropicShox2expression and embryonic survival

A gene desert required for regulatory control of pleiotropicShox2expression and embryonic survival

Insulin-Like Growth Factor 2 As a Possible Neuroprotective Agent and Memory Enhancer—Its Comparative Expression, Processing and Signaling in Mammalian CNS

A de novo mutation of SALL4 in a Chinese family with Okihiro syndrome

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