PUBLICATION

Novel pre-clinical model for CDKL5 Deficiency Disorder

Authors

Serrano, R.J., Lee, C., Douek, A.M., Kaslin, J., Bryson-Richardson, R.J., Sztal, T.E.

ID

ZDB-PUB-211217-11

Date

2021

Source

Disease models & mechanisms 15(3): (Journal)

Registered Authors

Bryson-Richardson, Robert, Douek, Alon M., Kaslin, Jan, Serrano, Rita, Sztal, Tamar Esther

Keywords

CDKL5 Deficiency Disorder, Locomotion, Microcephaly, Motor neurons, Seizure, Zebrafish

MeSH Terms

Epileptic Syndromes
Quality of Life
Neurodegenerative Diseases*
Zebrafish*/genetics
Animals
Humans
Spasms, Infantile
Protein Serine-Threonine Kinases/genetics

(all 8)

PubMed

34913468 Full text @ Dis. Model. Mech.

Abstract

Cyclin-Dependent Kinase-Like-5 (CDKL5) Deficiency Disorder (CDD) is a severe X-linked neurodegenerative disease characterized by early-onset epileptic seizures, low muscle tone, progressive intellectual disability, and severe motor function. CDD affects approximately 1 in 60,000 live births with many patients experiencing a reduced quality of life due to the severity of their neurological symptoms and functional impairment. There are no effective therapies for CDD with current treatments focusing on improving symptoms rather than addressing the underlying causes of the disorder. Zebrafish offer many unique advantages for high-throughput pre-clinical evaluation of potential therapies for neurological diseases, including CDD. In particular, the large number of offspring produced, together with the possibilities for in vivo imaging and genetic manipulation, allows for the detailed assessment of disease pathogenesis and therapeutic discovery. We have characterised a loss of function zebrafish model for CDD, containing a nonsense mutation in cdkl5. cdkl5 mutant zebrafish display defects in neuronal patterning, seizures, microcephaly, and reduced muscle function caused by impaired muscle innervation. This study provides a powerful vertebrate model to investigate CDD disease pathophysiology and allow high-throughput screening for effective therapies.

Genes / Markers

Figures

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Expression

Gene	Fish	Conditions	Stage	Anatomy	Assay	Figure
cdkl5	cdkl5^{sa21938/sa21938}	standard conditions	Protruding-mouth	whole organism	RTPCR	Fig. 1.
cdkl5	cdkl5^sa21938/+	standard conditions	Protruding-mouth	whole organism	RTPCR	Fig. 1.
cdkl5	WT	standard conditions	Prim-5	brain	ISH	Fig. S1
cdkl5	WT	standard conditions	Protruding-mouth	brain	ISH	Fig. S1
cdkl5	WT	standard conditions	Long-pec	brain	ISH	Fig. S1
cdkl5	WT	standard conditions	Protruding-mouth	eye	ISH	Fig. S1
cdkl5	WT	standard conditions	Long-pec	eye	ISH	Fig. S1
cdkl5	WT	standard conditions	Prim-5	eye	ISH	Fig. S1
cdkl5	WT	standard conditions	Protruding-mouth	gut	ISH	Fig. S1
cdkl5	WT	standard conditions	Protruding-mouth	heart	ISH	Fig. S1

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
WT + MO1-cdkl5	control	Prim-5	whole organism cdkl5 expression decreased amount, abnormal	Fig. S4
WT + MO1-cdkl5	control	Long-pec	trunk muscle cell organization quality, normal	Fig. S4
WT + MO1-cdkl5	control	Long-pec	trunk muscle cell organized, normal	Fig. S4
WT + MO1-cdkl5	control	Long-pec	whole organism cdkl5 expression decreased amount, abnormal	Fig. S4
WT + MO1-cdkl5	control	Protruding-mouth	spinal accessory motor neuron axon branchiness, normal	Fig. S4
WT + MO1-cdkl5	control	Protruding-mouth	spinal accessory motor neuron axon normal distribution, normal	Fig. S4
WT + MO1-cdkl5	control	Day 6	spinal accessory motor neuron neuron projection decreased branchiness, abnormal	Fig. S4
WT + MO1-cdkl5	control	Day 6	whole organism cdkl5 expression decreased amount, abnormal	Fig. S4
WT + MO1-cdkl5	control	Day 6	whole organism swimming behavior decreased process quality, abnormal	Fig. S4
cdkl5^sa21938/+	standard conditions	Protruding-mouth	whole organism cdkl5 expression decreased amount, abnormal	Fig. 1.

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
jf5Tg	Tg(elavl3:Hsa.H2B-GCaMP6s)	Transgenic Insertion
knu3Tg	Tg(elavl3:EGFP)	Transgenic Insertion
rw0Tg	Tg(isl1a:GFP)	Transgenic Insertion
sa21938		Point Mutation	cdkl5

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Human Disease / Model

Human Disease	Fish	Conditions	Evidence
epilepsy			TAS
microcephaly			TAS

Sequence Targeting Reagents

Target	Reagent	Reagent Type
cdkl5	MO1-cdkl5	MRPHLNO

Fish

Fish
cdkl5^{sa21938/sa21938}
cdkl5^{sa21938/sa21938}; jf5Tg
cdkl5^{sa21938/sa21938}; knu3Tg
cdkl5^{sa21938/sa21938}; rw0Tg
cdkl5^sa21938/+
jf5Tg
knu3Tg
rw0Tg
rw0Tg + MO1-cdkl5
WT

Antibodies

Name	Type	Isotypes	Host Organism
Ab1-actn	monoclonal	IgG1	Mouse
Ab1-glul	monoclonal	IgG2a	Mouse
Ab1-tuba	monoclonal	IgG2b	Mouse
Ab-A4.1025	monoclonal	IgG2a	Mouse
Ab-SV2	monoclonal	IgG1	Mouse

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Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
EGFP	EFG	EGFP
GCaMP	EFG	GCaMP
GFP	EFG	GFP

Mapping

Serrano et al., 2021 ZDB-PUB-211217-11 PMID:34913468

Novel pre-clinical model for CDKL5 Deficiency Disorder

Serrano et al., 2021

ZDB-PUB-211217-11
PMID:34913468