Table 1.

Autophagy-deficient mouse models and human diseases linked to defects in specific autophagy genes

Autophagy gene and function (human/mouse)	Human disease linked to mutation/inactivation	Mouse model phenotype	References
ATG16L/Atg16L			32 – 35
Atg16L complexes with conjugated Atg5–Atg12 to promote expansion and curvature of the nascent phagophore	T300A mutation in ATG16L linked to Crohn's disease, discovered by GWAS	Loss of Atg16L1 inhibits autophagy in Paneth cells, reducing secretion of granules of antimicrobial peptides that influence intestinal microbiota and causing increased inflammation
BECN1/Becn1			16,17
Beclin1 regulates the kinase activity of Vps34 at the ER; complex includes regulatory components UVRAG, Atg14L, Rubicon and Ambra	BECN1 is mono-allelically deleted in breast, ovarian and prostate cancer	Becn1-null mice are embryonic lethal, showing a defect in cavitation of the blastocyst. Becn1 heterozygotes are predisposed to lymphoma, hepatocellular carcinoma and other cancers
UVRAG/Uvrag			18
UVRAG complexes with Beclin1 and Vps34 at the ER to promote autophagy	UVRAG is mono-allelically deleted in colon cancer	N/A
IRGM/Irgm			36
Immunity-related GTPase stimulates autophagy and promotes clearance of pathogenic bacteria	Deletion of upstream regulatory sequences segregates with Crohn's disease and is associated with altered IRGM expression	N/A
CLN3/Cln3			45
Associated with Golgi, endosomes and lipid rafts and may play a role in transporting ceramide and other sphingolipids to lipid rafts	Accumulation of proteolipids in children with Batten disease leads to neurodegeneration and is due to inactivation of the CLN3 gene, which promotes autophagosome fusion with the lysosome	Immature autophagosomes in tissues from mice with knock-in of mutant forms of Cln3
Parkin			63,64
A E3 ubiquitin ligase that localizes to the mitochondria and is required for mitophagy	Parkinson's disease (PD) is associated with cell death of dopaminergic neurons and progressive loss of cognitive and motor function. Mutation of several genes are linked to PD, including Parkin	N/A
p62/SQSTM1			39,49,50,52,53
A multifunctional adaptor protein that promotes turnover of polyubiquitinated protein aggregates through interaction with LC3 at the autophagosome	p62 mutations are linked to Paget's disease in which increased bone turnover results in abnormal bone architecture. Associated with deregulated NF-κB signalling and reduced turnover of ubiquitinated proteins	p62-null mice are resistant to Rasdriven lung carcinogenesis. Loss of p62 prevents accumulation of ubiquitin-positive protein aggregates in the liver and neurons of Atg7-deficient mice
Lamp2			46
A lysosomal membrane protein required for fusion of the autophagosome with the lysosome	Danon disease is an X-linked disease resulting in hypertrophic cardiomyopathy and accumulation of autophagosomes in the heart muscle	Increased autophagosome numbers in multiple tissues, cardiomyopathy, skeletal myopathy, periodontitis associated with inflammation due to defective clearance of intracellular pathogens