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

Marcello Scala^{1

2

3}, Majid Mojarrad^{4

5

6}, Saima Riazuddin⁷, Karlla W Brigatti⁸, Zineb Ammous⁹, Julie S Cohen¹⁰, Heba Hosny¹¹, Muhammad A Usmani⁷, Mohsin Shahzad¹², Sheikh Riazuddin^{12

13}, Valentina Stanley¹⁴, Atiye Eslahi^{4

15}, Richard E Person¹⁶, Hasnaa M Elbendary¹⁷, Anne M Comi¹⁰, Laura Poskitt⁸, Vincenzo Salpietro^{1

2

3}, Queen Square Genomics¹, Jill A Rosenfeld¹⁸, Katie B Williams¹⁹, Dana Marafi¹⁸, Fan Xia¹⁸, Marta Biderman Waberski²⁰, Maha S Zaki¹⁷, Joseph Gleeson¹⁴, Erik Puffenberger⁸, Henry Houlden¹, Reza Maroofian¹

Affiliations

¹ UCL Queen Square Institute of Neurology, University College London, London, UK.
² Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy.
³ Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
⁴ Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
⁵ Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
⁶ Genetic Center of Khorasan Razavi, Mashhad, Iran.
⁷ Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD 21201, USA.
⁸ Clinic for Special Children, Strasburg, PA, USA.
⁹ Community Health Clinic, Topeka, IN, USA.
¹⁰ Departments of Neurology and Pediatrics, Kennedy Krieger Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
¹¹ National Institute of Neuromotor System, Cairo, Egypt.
¹² Center for Genetic Diseases, Shaheed Zulfiqar Ali Bhutto Medical University, Pakistan Institute of Medical Sciences, Islamabad, Pakistan.
¹³ National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore 53700, Pakistan.
¹⁴ Department of Neuroscience, Rady Children's Institute for Genomic Medicine, Howard Hughes Medical Institute, University of California, San Diego, CA, USA.
¹⁵ Medical Genetics Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
¹⁶ GeneDx, Gaithersburg, Maryland, USA.
¹⁷ Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo 12311, Egypt.
¹⁸ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
¹⁹ Department of Pediatrics, University of Wisconsin Hospitals and Clinics, Madison, WI, USA.
²⁰ Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.

PMID: 32227164
PMCID: PMC7174030
DOI: 10.1093/brain/awaa070

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

Marcello Scala et al. Brain. 2020.

. 2020 Apr 1;143(4):e31.

doi: 10.1093/brain/awaa070.

Authors

Affiliations

¹ UCL Queen Square Institute of Neurology, University College London, London, UK.
² Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy.
³ Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
⁴ Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
⁵ Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
⁶ Genetic Center of Khorasan Razavi, Mashhad, Iran.
⁷ Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD 21201, USA.
⁸ Clinic for Special Children, Strasburg, PA, USA.
⁹ Community Health Clinic, Topeka, IN, USA.
¹⁰ Departments of Neurology and Pediatrics, Kennedy Krieger Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
¹¹ National Institute of Neuromotor System, Cairo, Egypt.
¹² Center for Genetic Diseases, Shaheed Zulfiqar Ali Bhutto Medical University, Pakistan Institute of Medical Sciences, Islamabad, Pakistan.
¹³ National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore 53700, Pakistan.
¹⁴ Department of Neuroscience, Rady Children's Institute for Genomic Medicine, Howard Hughes Medical Institute, University of California, San Diego, CA, USA.
¹⁵ Medical Genetics Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
¹⁶ GeneDx, Gaithersburg, Maryland, USA.
¹⁷ Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo 12311, Egypt.
¹⁸ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
¹⁹ Department of Pediatrics, University of Wisconsin Hospitals and Clinics, Madison, WI, USA.
²⁰ Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.

PMID: 32227164
PMCID: PMC7174030
DOI: 10.1093/brain/awaa070

No abstract available

PubMed Disclaimer

Figures

**Figure 1**
**Genetic findings and clinical pictures of *RSRC1* patients.** (A) Schematic diagram of the longer *RSRC1* transcript (NM_001271838.1) consisting of 2597 nucleotides in 10 exons. The deletions encompassing exons 2 and 9–10 are represented by diagonal green lines. Single nucleotide variants are shown in red (previously reported patients) or in green (this study). (B) The RSRC1 protein (NP_001258767.1) consists of 334 amino acids encompassing an RS domain rich in arginine (R) and serine (S) that mediates the interactions with other RS-rich proteins involved in splicing regulation (SF2/ASF and U2AF35) and a coiled coil domain required for RSRC1/ERβ interaction as well as the enhancement of ERβ SUMOylation. The residues K196 and K 230 are necessary for RSRC1 SUMOylation by SUMO1 and the E3 ligases PIAS1 and PIAS3. Pathogenic amino acid changes reported in previous papers and identified in this study are shown in red and green, respectively. (C) Sequential pictures from selected patients. Patients from the Amish family (Patients 1–3) show prominent forehead, deep set eyes, depressed nasal bridge, protruding ears, and overbite with drooling. Redundant skin is evident in Patient 1. The Persian patient (Patient 7) shows straight eyebrows with mild synophrys, deep set eyes, and protruding ears. In the first Pakistani family (Patients 8 and 9) dysmorphic features include straight eyebrows with mild medial flaring, deep set eyes, wide nasal base, short philtrum, uplifted earlobes, and prominent chin. Subjects from the second Pakistani family (Patients 12–14) also show straight eyebrows with mild synophrys and deep set eyes, in addition to protruding ears with uplifted lobes (Patient 14). Patients from the Egyptian family (Patients 15–17) show thick eyebrows with medial sparing, deep set eyes, and prominent columella. (D) Graphic illustrations of the most common clinical findings in *RSRC1* patients in our cohort: the bar graph shows the percent distribution of the cardinal features of *RSRC1*-related intellectual disability, with the grey lines representing not available data; the pie charts show the percentage distribution of developmental delay/intellectual disability and the different behavioural abnormalities observed in *RSRC1* patients. Gene transcript and protein details available at: https://www.ensembl.org (RSRC1-215, transcript ID ENST00000611884.5), https://www.nextprot.org (NX_Q96IZ7), https://www.uniprot.org (Q96IZ7), https://www.proteomicsdb.org (Q96IZ7). ADHD = attention deficit hyperactivity disorder; ASD = autism spectrum disorder; DD = developmental delay; ID = intellectual disability; N/A = not available; Pt = patient; SCT = sluggish cognitive tempo; TT = temper tantrums.

See this image and copyright information in PMC

References

1. Berndt SI, Gustafsson S, Mägi R, Ganna A, Wheeler E, Feitosa MF, et al.Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture. Nat Genet 2013; 45: 501–12. - PMC - PubMed
1. Cazalla D, Newton K, Cáceres JF.. A novel SR-related protein is required for the second step of Pre-mRNA splicing. Mol Cell Biol 2005; 25: 2969–80. - PMC - PubMed
1. Chen L, Li W, Qiu W, Ren W, Li Q, Han B, et al.RSRC1 SUMOylation enhances SUMOylation and inhibits transcriptional activity of estrogen receptor β. FEBS Lett 2015; 589: 1476–84. - PubMed
1. Li X, Luo Z, Gu C, Hall LS, McIntosh AM, Zeng Y, et al.Common variants on 6q16.2, 12q24.31 and 16p13.3 are associated with major depressive disorder. Neuropsychopharmacology 2018; 43: 2146–53. - PMC - PubMed
1. Maddirevula S, Al Zahrani F, Anazi S, Almureikhi M, Ben-Omran T, Abdel-Salam GMH, et al.GWAS signals revisited using human knockouts. Genet Med 2018; 20: 64–8. - PubMed

Publication types

Actions
Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Molecular Biology Databases
- GlyGen glycoinformatics resource
- The Weizmann Institute of Science GeneCards and MalaCards databases

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Molecular Biology Databases