Table 2 Mutant CLN genes and underlying pathophysiology of various forms of NCLs

CLN1

Ubiquitously expressed, CNS, brain

X

X

X

X

X

protein response

CLN2

Ubiquitously expressed, brain, neurons, cerebrospinal fluid

X

X

X

Endocytic pathway dysfunction

CLN3

Ubiquitously expressed, CNS, immune and circulatory systems, iPSC, neural progenitor cells, colorectal cancer cells

X

X

X

X

X

TGN is impaired, localized on the lysosome, cellular proliferation, apoptosis and synaptic transmission

CLN4

Ubiquitously expressed, neuronal synapses (1% of total synaptic vesicle-associated proteins)

X (Type A)

X

X

–

–

Type: B manifests movement abnormalities with dementia

CLN5

Ubiquitously expressed in human tissue, CNS, peripheral organs and tissues, neurons (ganglionic eminence) and microglia

X

X

X

Endosomal sorting, the stability of sortilin and CIMPR both declines, defective myelination

CLN6

Ubiquitously expressed

X

X

X

X

manifest characteristic cholesterol and subunit c of mitochondrial ATP synthase (SCMAS), aberrant biometal metabolism

CLN7

Ubiquitously expressed at a very low level, its expression in the liver, heart, and pancreas (markedly higher)

X

X

X

X

loss of CLN7 causes depletion of soluble proteins in the lysosomes impairing reactivation of mTOR

CLN8

Ubiquitously expressed, high level expression in cerebral cortex and hippocampus in electrical kindling model of epilepsy

X

X

X

X

progressive motor neuron dysfunction and retinal degeneration, lysosomal β-glucosidase deficiency,

CLN9

Currently designated as CLN4

–

–

–

–

–

CLN10

Ubiquitously expressed, brain

X

X

X

X

CTSD-processing

CLN11

Ubiquitously expressed, CNS, neuron, microglia, astrocytes, and endothelial cells

X

X

X

–

–

significantly activated microglia after TBI, the elevated lysosomal biogenesis in activated microglia, which increased cerebrocortical neuron damage, reduces lysosomal biogenesis

CLN12

Ubiquitously expressed, ventral midbrain, including substantia nigra (high lever), kidney and skeletal muscle (low level)

X

X

X

–

–

extrapyramidal involvement, oxidative-stress in neuroblastoma cells; dysregulated neurotransmission

CLN13

CTSF is expressed at a high level in cerebrocortical, hippocampal and cerebellar neurons

X

X

X

–

–

neurons showed accumulation of eosinophilic granules

CLN14

Ubiquitously expressed, cerebrocortical and cerebellar Purkinje cells, pyramidal cell layers of the hippocampus (high levels)

X

X

X

–

–

disrupt KCTD7-Cullin-3 interactions