This document summarizes research on a syndrome caused by mutations in the CCDC174 gene. The syndrome is characterized by hypotonia, psychomotor delay, and abducens nerve palsy. Two families with affected individuals were studied and found to have homozygous mutations in CCDC174. Studies showed that CCDC174 interacts with EIF4A3 and is part of the exon junction complex, playing a role in early neural development. A mutation found in both families was shown to lead to depletion of the RYR1 protein in muscle and cell death in neuroblastoma cells.

1. CCDC174 mutation underlies a syndrome of
hypotonia and psychomotor developmental
delay with abducens nerve palsy
Presented by: Michael Volodarsky
Supervisor: Prof. Ohad S. Birk
The Morris Kahn Laboratory of Human Genetics at the NIBN.
The Shraga Segal Department of Microbiology, Immunology and Genetics,
Faculty of Health Sciences, Ben-Gurion University of the Negev, Israel.

2. • Small VSD (Ventricular Septal Defect)
• Psycho-motor delay
• Thin corpus callosum
• Pectus excavatum (sunken chest)
• Myopathic changes represented by
replacement of muscle fibers by fibrous tissue
and marked variation in fiber size
Family 1
Ethiopian Jews

3. Homozygosity mapping (250k)-family 1
3.5 Mb, 24 genes

4. Whole-exome sequencing
Chr3:11646954-15055905 (3.5Mb)
3 novel mutations
GRIP2
c.916G>A,
p.Gly306Arg
NUP210
c.3068C>T,
p.Ala1023Val
CCDC174
c.1404A>G,
p.*468Trpext*6

5. Family 2
Muslim Arabs
Hypotonia phenotype similar to family 1

6. 18Mb, 147 genes
Homozygosity mapping (6k)-family 2

7. Whole-exome sequencing
Chr3:8749171-27253971 (18Mb)
2 novel mutations
GRIP2
c.916G>A,
p.Gly306Arg
CCDC174
c.1404A>G,
p.*468Trpext*6

8. Homozygosity Mapping (250k)-Family 1+2 combined
0.57Mb, 4 genes
CCDC174
c.1404A>G,
p.*468Trpext*6
Single mutation,
unique to all hypotonia patients

9. EntrezGeneIDA GeneSymbolA EntrezGeneIDB GeneSymbolB Y2H
9775 EIF4A3 51244 CCDC174 +
Found ~2800 interactions (300 new) and…

10. The EJC is involved in mRNA
maturation and composed of
four core proteins, MAGO,
Y14, EIF4A3 and BTZ.

12. ControlAffected
Anti-RYR1 immunohistochemistry

13. Early neural differentiation markers
ccdc174 knockdown in Xenopus

14. CCDC174
CCDC174 and EIF4a3 are nuclear and co-localized in neuroblastoma cells
EIF4A3 CCDC174 CCDC174EIF4A3 Merge

15. Summary
• CCDC174 is a ubiquitously expressed nuclear protein
• CCDC174 interacts with EIF4A3 and is part of the exon junction complex
• CCDC174 is crucial for early neuronal development in Xenopus
• Interracial p.*468Trpext*6 in CCDC174 leads to depletion of RYR1 protein in
muscle and massive cell death in neuroblastoma cell line

16. Thanks to all lab members:
• Rotem Kadir
• Yonatan Perez
• Miora Feinstein
• Regina Ohayon
• Sara Sivan
• Head of laboratory: Prof. Ohad Birk
• Hava Lichtig
• Dale Frank