PUBLICATION

Disruption of Abcc6 Transporter in Zebrafish Causes Ocular Calcification and Cardiac Fibrosis

Authors

Sun, J., She, P., Liu, X., Gao, B., Jin, D., Zhong, T.P.

ID

ZDB-PUB-210103-1

Date

2020

Source

International Journal of Molecular Sciences 22(1): (Journal)

Registered Authors

Jin, Daqing, Zhong, Tao P.

Keywords

ABCC6, PXE, cardiac fibrosis, ocular calcification, vitamin K

MeSH Terms

ATP-Binding Cassette Transporters/genetics*
ATP-Binding Cassette Transporters/metabolism
Animals
Calcinosis/genetics*
Calcinosis/pathology*
Eye/metabolism
Eye/pathology
Fibrosis/genetics*
Fibrosis/pathology*
Genetic Predisposition to Disease
Mutation
Myocardium/metabolism
Myocardium/pathology
Vitamin K/metabolism
Vitamin K/pharmacology
Zebrafish
Zebrafish Proteins/genetics*
Zebrafish Proteins/metabolism

(all 18)

PubMed

33383974 Full text @ Int. J. Mol. Sci.

Abstract

Pseudoxanthoma elasticum (PXE), caused by ABCC6/MRP6 mutation, is a heritable multisystem disorder in humans. The progressive clinical manifestations of PXE are accompanied by ectopic mineralization in various connective tissues. However, the pathomechanisms underlying the PXE multisystem disorder remains obscure, and effective treatment is currently available. In this study, we generated zebrafish abcc6a mutants using the transcription activator-like effector nuclease (TALEN) technique. In young adult zebrafish, abcc6a is expressed in the eyes, heart, intestine, and other tissues. abcc6a mutants exhibit extensive calcification in the ocular sclera and Bruch's membrane, recapitulating part of the PXE manifestations. Mutations in abcc6a upregulate extracellular matrix (ECM) genes, leading to fibrotic heart with reduced cardiomyocyte number. We found that abcc6a mutation reduced levels of both vitamin K and pyrophosphate (PPi) in the serum and diverse tissues. Vitamin K administration increased the gamma-glutamyl carboxylated form of matrix gla protein (cMGP), alleviating ectopic calcification and fibrosis in vertebrae, eyes, and hearts. Our findings contribute to a comprehensive understanding of PXE pathophysiology from zebrafish models.

Genes / Markers

Marker	Marker Type	Name
abcc6a	GENE	ATP-binding cassette, sub-family C (CFTR/MRP), member 6a
col17a1b	GENE	collagen, type XVII, alpha 1b
col1a1a	GENE	collagen, type I, alpha 1a
col2a1a	GENE	collagen, type II, alpha 1a
col2a1b	GENE	collagen, type II, alpha 1b
col4a5	GENE	collagen, type IV, alpha 5 (Alport syndrome)
fn1b	GENE	fibronectin 1b
myl7	GENE	myosin, light chain 7, regulatory
tncb	GENE	tenascin Cb
tnr	GENE	tenascin R (restrictin, janusin)

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Figures

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Expression

Gene	Fish	Conditions	Stage	Anatomy	Assay	Figure
abcc6a	AB	standard conditions	Long-pec	cleithrum	ISH	Figure 1
abcc6a	AB	standard conditions	75%-epiboly	forerunner cell group	ISH	Figure 1
abcc6a	AB	standard conditions	Day 4	heart	ISH	Figure 1
abcc6a	AB	standard conditions	Adult	heart	RTPCR	Figure 1
abcc6a	AB	standard conditions	Long-pec	heart	ISH	Figure 1
abcc6a	AB	standard conditions	Prim-5	hindbrain	ISH	Figure 1
abcc6a	AB	standard conditions	5-9 somites	Kupffer's vesicle	ISH	Figure 1
abcc6a	AB	standard conditions	Prim-5	midbrain hindbrain boundary	ISH	Figure 1
abcc6a	AB	standard conditions	Day 4	notochord	ISH	Figure 1
abcc6a	AB	standard conditions	Long-pec	opercular flap	ISH	Figure 1

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
abcc6a^{zf3475/zf3475} (AB)	control	Adult	blood plasma Gla protein decreased amount, abnormal	Figure 4
abcc6a^{zf3475/zf3475} (AB)	control	Adult	blood plasma vitamin K decreased amount, abnormal	Figure 4
abcc6a^{zf3475/zf3475} (AB)	control	Adult	Bruch's membrane increased thickness, abnormal	Figure 4
abcc6a^{zf3475/zf3475} (AB)	control	Adult	compact layer of ventricle Collagen increased amount, abnormal	Figure 4
abcc6a^{zf3475/zf3475} (AB)	control	Adult	compact layer of ventricle Fibronectin increased amount, abnormal	Figure 4
abcc6a^{zf3475/zf3475} (AB)	control	Adult	eye Gla protein decreased amount, abnormal	Figure 4
abcc6a^{zf3475/zf3475} (AB)	control	Adult	eye vitamin K decreased amount, abnormal	Figure 4
abcc6a^{zf3475/zf3475} (AB)	control	Adult	heart fibrotic, abnormal	Figure 4
abcc6a^{zf3475/zf3475} (AB)	control	Adult	heart Gla protein decreased amount, abnormal	Figure 4
abcc6a^{zf3475/zf3475} (AB)	control	Adult	heart vitamin K decreased amount, abnormal	Figure 4

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
ci5Tg	Tg(-6.5kdrl:mCherry)	Transgenic Insertion
s843Tg	Tg(kdrl:EGFP)	Transgenic Insertion
zf3475		Small Deletion	abcc6a
zf3476		Small Deletion	abcc6a

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Human Disease / Model

Human Disease	Fish	Conditions	Evidence
pseudoxanthoma elasticum			TAS

Sequence Targeting Reagents

Target	Reagent	Reagent Type
abcc6a	TALEN1-abcc6a	TALEN

Fish

Fish
AB
abcc6a^{zf3475/zf3475} (AB)
abcc6a^{zf3476/zf3476} (AB)
ci5Tg (AB)
s843Tg (AB)
WT

Antibodies

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
EGFP	EFG	EGFP
mCherry	EFG	mCherry

Mapping

Sun et al., 2020 ZDB-PUB-210103-1 PMID:33383974

Disruption of Abcc6 Transporter in Zebrafish Causes Ocular Calcification and Cardiac Fibrosis

Sun et al., 2020

ZDB-PUB-210103-1
PMID:33383974