Atg7-conditional knockout mice, which were specifically autophagy-deficient in forebrain excitatory neurons, exhibited ASD-like behaviors and dendritic spine pruning defects (Tang et al., 2014). A paternally-transmitted nonsense variant in the ATG7 gene was identified in both affected siblings in a multiplex ASD family from the iHART cohort in Ruzzo et al. 2019, while a compound heterozygous missense variant in this gene was identified in a male ASD proband from the Simons Simplex Collection but not observed in the proband's unaffected sibling (Wang et al., 2020). Collier et al., 2021 identified twelve patients from five families with biallelic variants in ATG7 presenting with a complex neurodevelopmental disorder characterized by intellectual disability, structural brain abnormalities, and dysmorphic features; one of these individuals was reported to present with autism spectrum disorder.
Molecular Function
This gene encodes a E1-like activating enzyme involved in the 2 ubiquitin-like systems required for cytoplasm to vacuole transport (Cvt) and autophagy; this enzyme also plays a key role in the maintenance of axonal homeostasis and the prevention of axonal degeneration.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits.
Case Report: Whole Exome Sequencing Revealed Disease-Causing Variants in Two Genes in a Patient With Autism Spectrum Disorder, Intellectual Disability, Hyperactivity, Sleep and Gastrointestinal Distur
Atg7 null mice die within one day of birth. Loss of Atg7 specifically in hematopoietic stem cells leads to severe myeloproliferation, and death of mice within weeks. Loss of Atg7 in the liver leads to liver adenomas.
References
Type
Title
Author, Year
Primary
Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits.
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Conditional deletion of exons 14-17 of the Atg7 using CamkIIcre mice in excitatory neurons of the forebrain
Allele Type: Targeted (conditional ready))
Strain of Origin: (C57BL/6NCrlj x CBA/JNCrlj)F
Genetic Background: C57BL/6
ES Cell Line: TT2
Mutant ES Cell Line: Model Source: JAX
Description: At p29-30, atg7 cn ko mice had significantly increased spines in layer v pyramidal neurons of the auditory and sec. somatosensory cortex , indicating a deficit in spinal pruning that reduces the number of spines by this age in wild type littermate controls
Exp Paradigm: NA
Description: Macroautophagy is decreased between p21-30 in atg7 cn ko mice as determined by decrease in levels of atg5-12 and lc3-ii protein
Exp Paradigm: Western blot: atg5-12 and lc3-ii from mouse brain homogenate
Description: Macroautophagy is decreased between p21-30 in atg7 cn ko mice as determined by decrease in levels of atg5-12 and lc3-ii protein
Exp Paradigm: Immunohistochemistry
Description: Atg7 cn ko mice do not spend more time with a new social target (new mouse) compared to a familiar mouse in the three chamber test, unlike control littermates
Exp Paradigm: NA
Description: Atg7 cn ko mice spend less time sniffing the social stimulus mouse than control littermates, in the reciprocal social interaction test
Exp Paradigm: NA
Description: Increased p 62 levels were seen between p21-p30 in atg7 cn ko mice, indicating an accumulation of the protein which is an indication of deficit in autophagy
Exp Paradigm: NA
