PUBLICATION

Lysosomes and the pathogenesis of merosin-deficient congenital muscular dystrophy

Authors

Smith, S.J., Fabian, L., Sheikh, A., Noche, R., Cui, X., Moore, S.A., Dowling, J.J.

ID

ZDB-PUB-210928-11

Date

2021

Source

Human molecular genetics 31(5): 733-747 (Journal)

Registered Authors

Keywords

laminin alpha 2lysosomesmuscular dystrophyMDC1A

MeSH Terms

Muscle, Skeletal/pathology
Zebrafish*/genetics
Humans
Transcription Factors
Animals
Muscular Dystrophies*/pathology
Laminin/genetics
Lysosomes/genetics
Lysosomes/pathology

(all 9)

PubMed

34568901 Full text @ Hum. Mol. Genet.

Abstract

Congenital muscular dystrophy type 1A (MDC1A), the most common congenital muscular dystrophy in Western countries, is caused by recessive mutations in LAMA2, the gene encoding laminin alpha 2. Currently, no cure or disease modifying therapy has been successfully developed for MDC1A. Examination of patient muscle biopsies revealed altered distribution of lysosomes. We hypothesized that this redistribution was a novel and potentially druggable aspect of disease pathogenesis. We explored this hypothesis using candyfloss (caf), a zebrafish model of MDC1A.We found that lysosome distribution in caf zebrafish was also abnormal. This altered localization was significantly associated with fiber detachment and could be prevented by blocking myofiber detachment. Overexpression of TFEB, a transcription factor that promotes lysosomal biogenesis, led to increased lysosome content and decreased fiber detachment. We conclude that genetic manipulation of the lysosomal compartment is able to alter the caf zebrafish disease process, suggesting that lysosome function may be a target for disease modification.

Genes / Markers

Figures

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Expression

Phenotype

Fish	Conditions	Stage	Phenotype	Figure
dmd^{ta222a/ta222a}	control	Day 4	lysosome localization occurrence, normal	Fig. 4
lama2^{teg15a/teg15a}	control	Protruding-mouth	muscle dystrophic, abnormal	Fig. 10
lama2^{teg15a/teg15a}	control	Protruding-mouth	muscle refractivity, abnormal	Fig. 10
lama2^{teg15a/teg15a}	control	Protruding-mouth	swimming behavior decreased process quality, abnormal	Fig. 10
lama2^{teg15a/teg15a}	control	Day 5	autophagy increased occurrence, abnormal	Fig. 8
lama2^{teg15a/teg15a}	control	Day 5	lysosome localization disrupted, abnormal	Fig. 2
lama2^{teg15a/teg15a}	control	Day 5	myotome lysosome displaced to myoseptum, abnormal	Fig. 2
lama2^{teg15a/teg15a}	control	Day 5	myotome lysosome increased amount, abnormal	Fig. 5
lama2^{teg15a/teg15a}	control	Day 5	protein ubiquitination increased occurrence, abnormal	Fig. 10
lama2^{teg15a/teg15a}	chemical treatment: N-benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal	Protruding-mouth	muscle dystrophic, ameliorated	Fig. 10

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
ta222a		Point Mutation	dmd
teg15a		Point Mutation	lama2

Human Disease / Model

Human Disease	Fish	Conditions	Evidence
congenital merosin-deficient muscular dystrophy 1A	lama2^{teg15a/teg15a}	standard conditions	TAS

Sequence Targeting Reagents

Fish

Fish
dmd^{ta222a/ta222a}
lama2^{teg15a/teg15a}

Antibodies

Name	Type	Antigen Genes	Isotypes	Host Organism
Ab1-dmd	monoclonal	dmd	IgG1	Mouse
Ab2-lamp1	polyclonal		IgG	Rabbit
Ab3-actb	polyclonal			Rabbit
Ab6-map1lc3b	polyclonal		IgG	Rabbit

Orthology

Engineered Foreign Genes

Mapping

Smith et al., 2021 ZDB-PUB-210928-11 PMID:34568901

Lysosomes and the pathogenesis of merosin-deficient congenital muscular dystrophy

Smith et al., 2021

ZDB-PUB-210928-11
PMID:34568901