Variants in SCAF4 Cause a Neurodevelopmental Disorder and Are Associated with Impaired mRNA Processing.
Animals
Child
Drosophila melanogaster
/ genetics
Female
Gene Knockdown Techniques
Genetic Variation
/ genetics
Heterozygote
Humans
Intellectual Disability
/ genetics
Locomotion
/ genetics
Male
Mutation
/ genetics
Neurodevelopmental Disorders
/ genetics
RNA Polymerase II
/ genetics
RNA Processing, Post-Transcriptional
/ genetics
RNA, Messenger
/ genetics
Seizures
/ genetics
Serine-Arginine Splicing Factors
/ genetics
Exome Sequencing
SCAF4
epilepsy
intellectual disability
mRNA processing
neurodevelopmental disorder
seizures
Journal
American journal of human genetics
ISSN: 1537-6605
Titre abrégé: Am J Hum Genet
Pays: United States
ID NLM: 0370475
Informations de publication
Date de publication:
03 09 2020
03 09 2020
Historique:
received:
17
04
2020
accepted:
25
06
2020
pubmed:
31
7
2020
medline:
21
10
2020
entrez:
31
7
2020
Statut:
ppublish
Résumé
RNA polymerase II interacts with various other complexes and factors to ensure correct initiation, elongation, and termination of mRNA transcription. One of these proteins is SR-related CTD-associated factor 4 (SCAF4), which is important for correct usage of polyA sites for mRNA termination. Using exome sequencing and international matchmaking, we identified nine likely pathogenic germline variants in SCAF4 including two splice-site and seven truncating variants, all residing in the N-terminal two thirds of the protein. Eight of these variants occurred de novo, and one was inherited. Affected individuals demonstrated a variable neurodevelopmental disorder characterized by mild intellectual disability, seizures, behavioral abnormalities, and various skeletal and structural anomalies. Paired-end RNA sequencing on blood lymphocytes of SCAF4-deficient individuals revealed a broad deregulation of more than 9,000 genes and significant differential splicing of more than 2,900 genes, indicating an important role of SCAF4 in mRNA processing. Knockdown of the SCAF4 ortholog CG4266 in the model organism Drosophila melanogaster resulted in impaired locomotor function, learning, and short-term memory. Furthermore, we observed an increased number of active zones in larval neuromuscular junctions, representing large glutamatergic synapses. These observations indicate a role of CG4266 in nervous system development and function and support the implication of SCAF4 in neurodevelopmental phenotypes. In summary, our data show that heterozygous, likely gene-disrupting variants in SCAF4 are causative for a variable neurodevelopmental disorder associated with impaired mRNA processing.
Identifiants
pubmed: 32730804
pii: S0002-9297(20)30228-7
doi: 10.1016/j.ajhg.2020.06.019
pmc: PMC7477272
pii:
doi:
Substances chimiques
RNA, Messenger
0
SCAF4 protein, human
0
Serine-Arginine Splicing Factors
170974-22-8
RNA Polymerase II
EC 2.7.7.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
544-554Subventions
Organisme : NINDS NIH HHS
ID : K08 NS092898
Pays : United States
Organisme : NIH HHS
ID : P40 OD018537
Pays : United States
Investigateurs
Stanley F Nelson
(SF)
Wayne W Grody
(WW)
Hane Lee
(H)
Joshua L Deignan
(JL)
Sung-Hae Kang
(SH)
Valerie A Arboleda
(VA)
T Niroshi Senaratne
(TN)
Naghmeh Dorrani
(N)
Marina S Dutra-Clarke
(MS)
Jessica Kianmahd
(J)
Franceska L Hinkamp
(FL)
Ahna M Neustadt
(AM)
Julian A Martinez-Agosto
(JA)
Brent L Fogel
(BL)
Fabiola Quintero-Rivera
(F)
Informations de copyright
Copyright © 2020 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
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