The most common genetic mutation associated with human amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is a hexanucleotide repeat expansion in a non-coding region of the chromosome 9 open reading frame 72 gene (C9orf72). Decreased expression of C9orf72 is seen in expansion carriers, suggesting loss of function may play a role in disease. The mouse 3110043O21Rik locus is the orthologue of human C9orf72. 
 The F12 C9orf72 null allele has a 79 bp deletion in exon 2 of the 3110043O21Rik locus (deletion extends from 38 nt upstream of ATG start codon in exon 2 to 38 nt downstream of the start codon [May 2020]). While mRNA expression levels from the mutant allele are similar to wildtype, western blot of brain lysates shows homozygous null F12 mice had complete loss of full-length C9orf72 protein. The presence/absence of proteins from any alternate transcripts identified more recently (e.g., transcript C9orf72-202 bypasses exon 2 and encodes a smaller 314 amino acid protein) has not been characterized to date (May 2020).
 Homozygous mice are viable, fertile and develop normally, with no evidence of motor neuron disease or histological neurodegeneration through advanced age (17 months). Instead, C9orf72 null mice develop progressive splenomegaly and lymphadenopathy with accumulation of engorged macrophage-like cells. C9orf72 expression is normally highest in myeloid cells, and loss of C9orf72 in these C9orf72 null mice leads to lysosomal accumulation and altered immune responses in macrophages and microglia, with age-related neuroinflammation similar to C9orf72 ALS but not sporadic ALS patient tissue. The only histologic abnormalities exhibited in the nervous system of homozygous mice are rare chromatolytic structures in gray and white matter of the spinal cord, that did not increase with age or show reactive gliosis. Homozygotes exhibit no abnormalities in weight gain, lifespan, sensorimotor coordination, limb strength, muscle electrophysiology and femoral motor and sensory axon counts. [May 2016]


Homozygous C9orf72 null mice exhibit lysosomal accumulation, altered immune responses in macrophages and microglia, as well as age-related neuro-inflammation similar to human C9orf72 amyotrophic lateral sclerosis (ALS). These mice may be useful in studying human ALS and frontotemporal dementia.

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