PUBLICATION

Zebrafish type I collagen mutants faithfully recapitulate human type I collagenopathies

Authors

Gistelinck, C., Kwon, R.Y., Malfait, F., Symoens, S., Harris, M.P., Henke, K., Hawkins, M.B., Fisher, S., Sips, P., Guillemyn, B., Bek, J.W., Vermassen, P., De Saffel, H., Witten, P.E., Weis, M., De Paepe, A., Eyre, D.R., Willaert, A., Coucke, P.J.

ID

ZDB-PUB-180808-7

Date

2018

Source

Proceedings of the National Academy of Sciences of the United States of America 115(34): E8037-E8046 (Journal)

Registered Authors

Coucke, Paul, Fisher, Shannon, Harris, Matthew, Henke, Katrin, Kwon, Ronald, Willaert, Andy, Witten, P. Eckhard

Keywords

osteogenesis imperfecta, skeletal phenomics, type I collagen, type I collagenopathies, zebrafish models

MeSH Terms

Humans
Collagen Type I*/genetics
Collagen Type I*/metabolism
Animals
Osteogenesis Imperfecta*/genetics
Osteogenesis Imperfecta*/metabolism
Osteogenesis Imperfecta*/pathology
Animals, Genetically Modified
Ehlers-Danlos Syndrome*/genetics
Ehlers-Danlos Syndrome*/metabolism
Ehlers-Danlos Syndrome*/pathology
Disease Models, Animal*
Zebrafish*/genetics
Zebrafish*/metabolism

(all 14)

PubMed

30082390 Full text @ Proc. Natl. Acad. Sci. USA

Abstract

The type I collagenopathies are a group of heterogeneous connective tissue disorders, that are caused by mutations in the genes encoding type I collagen and include specific forms of osteogenesis imperfecta (OI) and the Ehlers-Danlos syndrome (EDS). These disorders present with a broad disease spectrum and large clinical variability of which the underlying genetic basis is still poorly understood. In this study, we systematically analyzed skeletal phenotypes in a large set of zebrafish, with diverse mutations in the genes encoding type I collagen, representing different genetic forms of human OI, and a zebrafish model resembling human EDS, which harbors a number of soft connective tissues defects, typical of EDS. Furthermore, we provide insight into how zebrafish and human type I collagen are compositionally and functionally related, which is relevant in the interpretation of human type I collagen-related disease models. Our studies reveal a high degree of intergenotype variability in phenotypic expressivity that closely correlates with associated OI severity. Furthermore, we demonstrate the potential for select mutations to give rise to phenotypic variability, mirroring the clinical variability associated with human disease pathology. Therefore, our work suggests the future potential for zebrafish to aid in identifying unknown genetic modifiers and mechanisms underlying the phenotypic variability in OI and related disorders. This will improve diagnostic strategies and enable the discovery of new targetable pathways for pharmacological intervention.

Genes / Markers

Figures

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Expression

Phenotype

Fish	Conditions	Stage	Phenotype	Figure
bmp1a^{sa2416/sa2416}	standard conditions	Adult	bone mineralization increased process quality, abnormal	Table 2
bmp1a^{sa2416/sa2416}	standard conditions	Adult	centrum bone mineralization increased process quality, abnormal	Fig. 2
bmp1a^{sa2416/sa2416}	standard conditions	Adult	centrum increased thickness, abnormal	Fig. 2
bmp1a^{sa2416/sa2416}	standard conditions	Adult	centrum increased volume, abnormal	Fig. 2
bmp1a^{sa2416/sa2416}	standard conditions	Adult	cranial vault morphology, abnormal	Fig. S1
bmp1a^{sa2416/sa2416}	standard conditions	Adult	cranium anterior-most region decreased size, abnormal	Fig. S1
bmp1a^{sa2416/sa2416}	standard conditions	Adult	hemal arch bone mineralization increased process quality, abnormal	Fig. 2
bmp1a^{sa2416/sa2416}	standard conditions	Adult	hemal arch increased thickness, abnormal	Fig. 2
bmp1a^{sa2416/sa2416}	standard conditions	Adult	neural arch bone mineralization increased process quality, abnormal	Fig. 2
bmp1a^{sa2416/sa2416}	standard conditions	Adult	neural arch increased thickness, abnormal	Fig. 2

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Mutations / Transgenics

Allele	Type	Affected Genomic Region
dc124	Point Mutation	col1a1a
dmh13	Point Mutation	col1a1a
dmh14	Point Mutation	col1a1a
dmh15	Point Mutation	col1a2
dmh29	Point Mutation	col1a1b
sa1748	Point Mutation	col1a1a
sa1768	Point Mutation	plod2
sa2416	Point Mutation	bmp1a
sa12931	Point Mutation	col1a1b
sa17981	Point Mutation	col1a2

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Human Disease / Model

Human Disease	Fish	Conditions	Evidence
Bruck syndrome			TAS
Ehlers-Danlos syndrome	col1a2^{sa17981/sa17981}	standard conditions	TAS
osteogenesis imperfecta	col1a1a^sa1748/+; col1a1b^sa12931/+	standard conditions	TAS
osteogenesis imperfecta	col1a2^dmh15/+	standard conditions	TAS
osteogenesis imperfecta	col1a1a^dmh13/+	standard conditions	TAS
osteogenesis imperfecta	col1a1a^dmh14/+	standard conditions	TAS
osteogenesis imperfecta	col1a1b^dmh29/+	standard conditions	TAS
osteogenesis imperfecta type 13	bmp1a^{sa2416/sa2416}	standard conditions	TAS
osteogenesis imperfecta type 3	col1a1a^dc124/+	standard conditions	TAS

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Sequence Targeting Reagents

Fish

Fish
bmp1a^{sa2416/sa2416}
col1a1a^dc124/+
col1a1a^dmh13/+
col1a1a^dmh14/+
col1a1a^{sa1748/sa1748}
col1a1a^sa1748/+
col1a1a^sa1748/+; col1a1b^sa12931/+
col1a1a^tt281/tt281
col1a1b^dmh29/+
col1a1b^{sa12931/sa12931}

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Antibodies

Orthology

Engineered Foreign Genes

Mapping

Gistelinck et al., 2018 ZDB-PUB-180808-7 PMID:30082390

Zebrafish type I collagen mutants faithfully recapitulate human type I collagenopathies

Gistelinck et al., 2018

ZDB-PUB-180808-7
PMID:30082390