B6;129P2-Arsa^tm1Gie/J

Stock number: 030911
Product name: ASA knock-out [nondemyelinating MLD model]
Research areas: Neurobiology Research, Research Tools

Description

Mice homozygous for the ASA knock-out allele, called ASA(-/-) or "nondemyelinating MLD" mice, exhibit abnormal sulfatide storage patterns in the nervous system that is reminiscent of preclinical (non-demyelinating) stages of metachromatic leukodystrophy (MLD). These "nondemyelinating MLD" mice may be useful for studying MLD as well as other lysosomal and non-lysosomal storage disorders.

Detailed description

Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by functional deficiency of lysosomal enzyme arylsulfatase A (Arsa; ASA) - this leads to intralysosomal accumulation of the sphingolipid 3-O-sulfogalactosylceramide (sulfatide), demyelination of the central nervous system (CNS), severe neurological symptoms and premature death.

Dr. Volkmar Gieselmann donated mice harboring the ASA knock-out allele on a C57BL/6NJ mixed/undefined genetic background (Stock No. 030911). The phenotype description summarized below is as published on a C57BL/6;129 mixed genetic background [Hess et al. 1996 PNAS 93:14821, Ramakrishnan et al. 2007 J Neurosci 27:9482, Stein et al. 2015 Mol Ther 23:1160]. The donating investigator reports these descriptions are also accurate for the same animals when backcrossed onto the C57BL/6N genetic background [October 2017].

Stock No. 030911: Mice homozygous for the ASA knock-out allele, called ASA(-/-) or "nondemyelinating MLD" mice, exhibit abnormal sulfatide storage patterns in the nervous system that is reminiscent of preclinical (non-demyelinating) stages of MLD. ASA(-/-) mice have normal life expectancy and do not show progressive/widespread demyelination. Homozygotes are viable and fertile. However, homozygous males exhibit diminished fertility older than 8 months of age [which is presumably due to lipid accumulation in testis]. Mice heterozygous for the ASA knock-out allele [ASA(+/-)] are viable and fertile, with no detectable nervous system sulfatide storage abnormalities.

Development

The ASA knock-out allele was created in the laboratory of Dr. Volkmar Gieselmann (University of Bonn) to have a neomycin selection cassette inserted into exon 4 (disrupting the open reading frame) of the arylsulfatase A locus (Arsa) on chromosome 15. The construct was electroporated into 129P2/OlaHsd-derived E14.1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts, and chimeric males were bred with C57BL/6J females for germline transmission. Mutant mice were bred to 129P2/OlaHsd wildtype mice, and thereafter maintained on a C57BL/6;129 mixed genetic background for several generations. Following at least one additional breeding to C57BL/6J (Stock No. 000664), mutant mice were sent to The Jackson Laboratory Repository in 2020.

Allele

Symbol: Arsa^tm1Gie
Name: targeted mutation 1, Volkmar Gieselmann
MGI accession ID: MGI:2180363
Generation method: Targeted
Attributes: Null/Knockout
Synonyms: As2^-; ASA(-)
Marker symbol: Arsa
Marker name: arylsulfatase A
Marker synonyms: As2; As-2; ASA; AS-A; MLD
Chromosome: 15
Strain of origin: 129P2/OlaHsd
Molecular note: A neomycin selection cassette was inserted into exon 4, disrupting the open reading frame. Complete absence of enzyme activity was confirmed by Northern blot analysis and by the sulfatide loading assay.