Table 2.

MANF deficiency interrupts neurodevelopment

Subjects	Types of deficiency	Ages	Phenotypes	References
C. elegans	manf-1 mutation	Adult (day 3–9)	Viable and healthy, slower growth rate, normal neuronal development, degeneration of dopaminergic neurons in adult, increased systemic ER stress	[66, 90]
Drosophila	Zygotic DmManf mutation	1st instar	Lethal at 1st instar, loss of dopaminergic neurites and reduced dopamine	[18]
	Maternal zygotic DmManf mutation	Embryonic stage 16	Lethal at embryonic stage, loss of all TH-positive neurites and nonapoptotic neuron death	[18]
Zebrafish	Morpholino manf knockdown	3 days post fertilization	Decrease of th1- and th2-expressing dopaminergic neurons, reduced dopamine level, upregulation of pax2a and nr4a2b	[17]
Mouse	Global Manf knockout	E15.5-P7	Slower neuron migration, decreased neurite extension, altered cerebral cortex thickness and cell density, activated UPR and decreased protein synthesis	[20]
	Neuron-specific Manf knockout	E13.5-P14, adult, aging	Activated UPR, increased neurogenesis	[89, 91]
Human	Homozygous frameshift variant in MANF	17 years old	Childhood-onset of diabetes, short stature, bilateral sensorineural deafness, microcephaly, and developmental delay	[88]
	Homozygous MANF splice site mutation	22 years old	Childhood-onset of diabetes, obesity, short stature, hypothyroidism, primary hypogonadism, alopecia, myopia, bilateral sensorineural deafness, microcephaly, and mild intellectual disability	[87]