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Aspartoacylase gene knockout in the mouse: impact on reproduction
Sankar Surendran1, Sylvia Szucs, Stephen K Tyring
1Department of Internal Medicine, The University of Texas Medical Branch, Galveston, TX 77555, USA. ssurendr@utmb.edu
Abstract:
Canavan disease (CD) is an autosomal recessive disorder caused by aspartoacylase (ASPA) gene mutations resulting enzyme deficiency. The homozygous knockout mouse for CD showed symptoms similar observed in patients with CD. Canavan disease leads to early death. Therefore, a role of ASPA in reproduction was investigated using the mouse model for CD. Homozygous (KO/KO) pups, produced by mating female heterozygous (KO/+) mouse with KO/+ males had approximately 12% death incidence rates in the first 2 months of life. KO/KO mothers mated with KO/+ males showed fetal death. KO/KO mothers produced fewer offspring compared to KO/+ mothers. These data suggest that ASPA is necessary for normal reproduction and postnatal survival.
Insights
Aspartoacylase (ASPA) deficiency causes Canavan disease (CD) and impacts reproduction. This study found that ASPA is essential for normal reproduction and survival in mice with Canavan disease.
Area of Science:
- Genetics and Molecular Biology
- Reproductive Biology
- Neuroscience
Background:
- Canavan disease (CD) is a severe, early-onset autosomal recessive neurological disorder.
- It results from mutations in the aspartoacylase (ASPA) gene, leading to a deficiency of the ASPA enzyme.
- The homozygous knockout mouse model (KO/KO) recapitulates key features of human CD, including early mortality.
Purpose of the Study:
- To investigate the role of the aspartoacylase (ASPA) enzyme in reproductive function and offspring survival.
- To determine if ASPA deficiency impacts fertility and litter size in a mouse model of Canavan disease.
Main Methods:
- Utilized a homozygous knockout mouse model (KO/KO) for Canavan disease.
- Crossed heterozygous (KO/+) female mice with KO/+ males to generate KO/KO offspring.
- Monitored reproductive outcomes, including fetal survival, litter size, and postnatal mortality rates in KO/KO mothers and offspring.
Main Results:
- Homozygous knockout (KO/KO) pups exhibited approximately 12% mortality within the first two months of life.
- KO/KO mothers mated with KO/+ males experienced significant fetal death.
- Reproductive output was reduced in KO/KO mothers compared to wild-type (KO/+) mothers.
Conclusions:
- Aspartoacylase (ASPA) plays a critical role in successful reproduction.
- ASPA deficiency negatively impacts fetal development and survival.
- The enzyme is essential for normal postnatal survival in offspring affected by Canavan disease.
