10.6084/m9.figshare.12149238.v1
Freya Morgan
Freya
Morgan
David Kavanagh
David
Kavanagh
Elizabeth Van Swol
Elizabeth Van
Swol
Sneha S Mokashi
Sneha S
Mokashi
Robert Anholt
Robert
Anholt
Trudy Mackay
Trudy
Mackay
A Drosophila model for Sanfilippo Syndrome
TAGC 2020
2020
Drosophila melanogaster
Genetic diseases and disorders
Disease models
Rare disease
Autosomal recessive
Sanfilippo Syndrome
Mucopolysaccharidosis type III
Behavior
Lifespan
Drosophila Activity Monitor
Positive Phototaxis
DGRP
Genetics
Diseases
2020-04-20 22:42:19
Poster
https://tagc2020.figshare.com/articles/poster/A_Drosophila_model_for_Sanfilippo_Syndrome/12149238
<p></p><p>Sanfilippo syndrome (Mucopolysaccharidosis Type III, MPS
III) is a rare, autosomal recessive disorder, caused by a deficiency in enzymes
involved in the breakdown of heparan sulfate. The disease is characterized by
the accumulation of heparan sulfate in lysosomes, which leads to degeneration
of the central nervous system. Patients exhibit developmental regression,
hyperactivity, sleep irregularity, coarse features and a reduced lifespan. The
genome of Drosophila melanogaster contains conserved orthologs of human
disease genes. We obtained Drosophila
lines with CRISPR-Cas9 generated deletions of fly orthologs of SGSH and NAGLU,
mutations in which cause MPS IIIA and MPS IIIB. A deletion in CG14291, which is
orthologous to SGSH, displayed phenotypes reminiscent of human Sanfilippo
Syndrome. Flies of this line showed reduced lifespan (-28.8%, males; -15.1%,
females) and reduced productivity (-78.7% at 2 weeks old) compared to the
control. Males of this line exhibited a significant increase in average
activity (p<0.0001) and showed impaired phototaxis compared to the control.
Thus, the CG14291 deletion line can serve as a model for Sanfilippo syndrome.
However, the same mutation in an independently obtained mutant did not
replicate these phenotypes, suggesting the existence of genetic modifiers in
the strain used to generate the deletions. Naturally segregating epistatic
partners that affect penetrance of the mutation can be identified by crossing
the CG14291 deletion line to lines of the Drosophila melanogaster Genetic
Reference Panel and screening for the observed phenotypes.</p><br><p></p>