Abstract
Original language | English |
---|---|
Pages (from-to) | 663-680 |
Number of pages | 18 |
Journal | American journal of human genetics |
Volume | 110 |
Issue number | 4 |
DOIs | |
Publication status | Published - 6 Apr 2023 |
Keywords
- Mendelian disorder
- alternative splicing
- gene discovery
- monogenic diseases
- progressive spasticity
- rare diseases
- spliceosome
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In: American journal of human genetics, Vol. 110, No. 4, 06.04.2023, p. 663-680.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Bi-allelic SNAPC4 variants dysregulate global alternative splicing and lead to neuroregression and progressive spastic paraparesis
AU - Frost, F. Graeme
AU - Morimoto, Marie
AU - Sharma, Prashant
AU - Ruaud, Lyse
AU - Belnap, Newell
AU - Calame, Daniel G.
AU - Uchiyama, Yuri
AU - Matsumoto, Naomichi
AU - Oud, Machteld M.
AU - Ferreira, Elise A.
AU - Narayanan, Vinodh
AU - Rangasamy, Sampath
AU - Huentelman, Matt
AU - Emrick, Lisa T.
AU - Sato-Shirai, Ikuko
AU - Kumada, Satoko
AU - Wolf, Nicole I.
AU - Steinbach, Peter J.
AU - Huang, Yan
AU - Pusey, Barbara N.
AU - Passemard, Sandrine
AU - Levy, Jonathan
AU - Drunat, S. verine
AU - Vincent, Marie
AU - Guet, Agnès
AU - Agolini, Emanuele
AU - Novelli, Antonio
AU - Digilio, Maria Cristina
AU - Rosenfeld, Jill A.
AU - Murphy, Jennifer L.
AU - Lupski, James R.
AU - Vezina, Gilbert
AU - Macnamara, Ellen F.
AU - Adams, David R.
AU - Acosta, Maria T.
AU - Tifft, Cynthia J.
AU - Undiagnosed Diseases Network
AU - Gahl, William A.
AU - Malicdan, May Christine V.
N1 - Funding Information: The authors thank the patients and their families for participating in this work, as well as Dr. C. Christopher Lau (National Human Genome Research Institute, National Institutes, of Health) for his assistance interpreting genomic data for individual 1. We are grateful to Prof. C. van Karnebeek, Dr. M. Langeveld, Prof. H. Waterham, Dr. Saskia van der Crabben (Amsterdam UMC), and the ZOEMBA team in the Netherlands for their research contributions. This work was supported in part by the Common Fund , Office of the Director, National Institutes of Health ; the Intramural Research Program of National Human Genome Research Institute of the National Institutes of Health; the Office of Science Management and Operations (OSMO) of the National Institute of Allergy and Infectious Diseases , NIH; the Japan Agency for Medical Research and Development (AMED) (grant numbers JP22ek0109486 , JP22ek0109549 , JP22ek0109348 ); JSPS KAKENHI (grant number JP21k15907 ); Takeda Science Foundation ; United for Metabolic Diseases, The Netherlands; and Stichting Metakids, The Netherlands. J.R.L. was supported by a US National Human Genome Research Institute (NHGRI) and National Heart, Lung, and Blood Institute grant to Baylor-Hopkins Center for Mendelian Genomics ( UM1 HG006542 ), US NHGRI grant to the Baylor College of Medicine Genomics of Research Elucidates the Genetics of Rare disease (GREGoR) Research Center ( U01 HG011758 ), US National Institute of Neurological Disorders and Stroke ( R35NS105078 ), the Spastic Paraplegia Foundation , and the Muscular Dystrophy Association ( MDA 512848 ). D.G.C. was supported by an NIH Brain Disorders and Development Training Grant ( T32 NS043124-19 ) and Muscular Dystrophy Association grant 873841 . Funding Information: The authors thank the patients and their families for participating in this work, as well as Dr. C. Christopher Lau (National Human Genome Research Institute, National Institutes, of Health) for his assistance interpreting genomic data for individual 1. We are grateful to Prof. C. van Karnebeek, Dr. M. Langeveld, Prof. H. Waterham, Dr. Saskia van der Crabben (Amsterdam UMC), and the ZOEMBA team in the Netherlands for their research contributions. This work was supported in part by the Common Fund, Office of the Director, National Institutes of Health; the Intramural Research Program of National Human Genome Research Institute of the National Institutes of Health; the Office of Science Management and Operations (OSMO) of the National Institute of Allergy and Infectious Diseases, NIH; the Japan Agency for Medical Research and Development (AMED) (grant numbers JP22ek0109486, JP22ek0109549, JP22ek0109348); JSPS KAKENHI (grant number JP21k15907); Takeda Science Foundation; United for Metabolic Diseases, The Netherlands; and Stichting Metakids, The Netherlands. J.R.L. was supported by a US National Human Genome Research Institute (NHGRI) and National Heart, Lung, and Blood Institute grant to Baylor-Hopkins Center for Mendelian Genomics (UM1 HG006542), US NHGRI grant to the Baylor College of Medicine Genomics of Research Elucidates the Genetics of Rare disease (GREGoR) Research Center (U01 HG011758), US National Institute of Neurological Disorders and Stroke (R35NS105078), the Spastic Paraplegia Foundation, and the Muscular Dystrophy Association (MDA 512848). D.G.C. was supported by an NIH Brain Disorders and Development Training Grant (T32 NS043124-19) and Muscular Dystrophy Association grant 873841. J.R.L. has stock ownership in 23andMe, is a paid consultant for Regeneron Genetics Center, and is a co-inventor on multiple US and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, genomic disorders, and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic and genomic testing conducted at Baylor Genetics (BG); J.R.L. serves on the Scientific Advisory Board (SAB) of BG. Publisher Copyright: © 2023
PY - 2023/4/6
Y1 - 2023/4/6
N2 - The vast majority of human genes encode multiple isoforms through alternative splicing, and the temporal and spatial regulation of those isoforms is critical for organismal development and function. The spliceosome, which regulates and executes splicing reactions, is primarily composed of small nuclear ribonucleoproteins (snRNPs) that consist of small nuclear RNAs (snRNAs) and protein subunits. snRNA gene transcription is initiated by the snRNA-activating protein complex (SNAPc). Here, we report ten individuals, from eight families, with bi-allelic, deleterious SNAPC4 variants. SNAPC4 encoded one of the five SNAPc subunits that is critical for DNA binding. Most affected individuals presented with delayed motor development and developmental regression after the first year of life, followed by progressive spasticity that led to gait alterations, paraparesis, and oromotor dysfunction. Most individuals had cerebral, cerebellar, or basal ganglia volume loss by brain MRI. In the available cells from affected individuals, SNAPC4 abundance was decreased compared to unaffected controls, suggesting that the bi-allelic variants affect SNAPC4 accumulation. The depletion of SNAPC4 levels in HeLa cell lines via genomic editing led to decreased snRNA expression and global dysregulation of alternative splicing. Analysis of available fibroblasts from affected individuals showed decreased snRNA expression and global dysregulation of alternative splicing compared to unaffected cells. Altogether, these data suggest that these bi-allelic SNAPC4 variants result in loss of function and underlie the neuroregression and progressive spasticity in these affected individuals.
AB - The vast majority of human genes encode multiple isoforms through alternative splicing, and the temporal and spatial regulation of those isoforms is critical for organismal development and function. The spliceosome, which regulates and executes splicing reactions, is primarily composed of small nuclear ribonucleoproteins (snRNPs) that consist of small nuclear RNAs (snRNAs) and protein subunits. snRNA gene transcription is initiated by the snRNA-activating protein complex (SNAPc). Here, we report ten individuals, from eight families, with bi-allelic, deleterious SNAPC4 variants. SNAPC4 encoded one of the five SNAPc subunits that is critical for DNA binding. Most affected individuals presented with delayed motor development and developmental regression after the first year of life, followed by progressive spasticity that led to gait alterations, paraparesis, and oromotor dysfunction. Most individuals had cerebral, cerebellar, or basal ganglia volume loss by brain MRI. In the available cells from affected individuals, SNAPC4 abundance was decreased compared to unaffected controls, suggesting that the bi-allelic variants affect SNAPC4 accumulation. The depletion of SNAPC4 levels in HeLa cell lines via genomic editing led to decreased snRNA expression and global dysregulation of alternative splicing. Analysis of available fibroblasts from affected individuals showed decreased snRNA expression and global dysregulation of alternative splicing compared to unaffected cells. Altogether, these data suggest that these bi-allelic SNAPC4 variants result in loss of function and underlie the neuroregression and progressive spasticity in these affected individuals.
KW - Mendelian disorder
KW - alternative splicing
KW - gene discovery
KW - monogenic diseases
KW - progressive spasticity
KW - rare diseases
KW - spliceosome
UR - http://www.scopus.com/inward/record.url?scp=85151470438&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.ajhg.2023.03.001
DO - https://doi.org/10.1016/j.ajhg.2023.03.001
M3 - Article
C2 - 36965478
SN - 0002-9297
VL - 110
SP - 663
EP - 680
JO - American journal of human genetics
JF - American journal of human genetics
IS - 4
ER -