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). The mouse 3110043O21Rik locus is the orthologue of human C9orf72. The C919 BAC transgenic mouse line (C9B77) expresses multiple copies of a human ALS patient-derived C9orf72 gene encoding a truncated short C9ORF72 isoform (222 aa; exons 1-5 with TAA site and polyA signal) with hexanucleotide repeat expansions (GGGGCC) in intron 1a. C919 mice have multiple transgene copies integrated at the same locus that segregate together - with individual transgene copies expressing C9ORF72 with ~90 hexanucleotide repeats or C9ORF72 with ~450 hexanucleotide repeats. The BAC includes ~140 kbp of sequence transcriptionally upstream of C9orf72 exon 1a that is likely to contain regulatory regions needed to control sense/antisense transcript expression in a temporal and spatial pattern that mimics expression in the human disease. The hexanucleotide repeat sizes are generationally stable to date (October 2017), but should be monitored (described in greater detail further below). The BAC transgene insertion site, copy number and incidence of transgene silencing (if any) are described in greater detail further below. C919 hemizygous mice are viable and fertile, but their neurological phenotype has not been characterized to date (October 2017). The phenotype of C919 homozygous mice has not been investigated. Regarding hexanucleotide repeat size/stability, the donating investigator reports that C919 mice show two hexanucleotide repeat sizes (~90 and ~450) that are stably inherited through several generations of mice - no hexanucleotide repeat contraction/expansion has yet been observed (October 2017). When using mouse models where repeat number is subject to germline and somatic instability, and may expand or contract, it is strongly recommended the repeat number be quantified in all the experimental animals; all animals in all experimental groups should carry comparable hexanucleotide repeat sizes. The donating investigator's protocol for quantifying the number of hexanucleotide repeats is <a href="http://Jackson.jax.org/rs/444-BUH-304/images/JR029102_HexaNT_assay_June2016.pdf">available here</a>. This protocol has not been tested/validated by The Jackson Laboratory. The Jackson Laboratory Southern Blot Protocol for this transgene is <a href="https://media.jax.org/m/1fd0d41d4d0b9ac8/original/Microsoft-Word-C9Orf72_DIG_Southern_Protocol_JAX.pdf">available here</a> [2019]. Using this protocol, Stock No. 030581 has two expected band sizes - one slightly less than 5 kbp and the other at ~3.7 kbp. Regarding BAC transgene insertion site, copy number and transgene silencing in C919 mice, the donating investigator reports neither the genomic insertion site nor the exact number of transgene copies are known. They also report C919 hemizygotes have shown generationally stable transgene expression levels to date (October 2017) - but recommend monitoring C9ORF72 expression levels in progeny (e.g., in blood, or in post-mortem cortex) as another founder line (C9450B) had exhibited decreased transgene expression in 10-15% of the line.

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The C919 BAC transgenic mouse line (C9B77) expresses multiple copies of a truncated human C9orf72 gene modified in intron 1a to have a hexanucleotide repeat expansions (GGGGCC). Individual transgene copies express C9orf72 with ~90 hexanucleotide repeats or C9orf72 with ~450 hexanucleotide repeats. These mice may be useful for studying C9orf72 repeat length-dependent gain-of-toxicity in familial amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease) and frontotemporal dementia (FTD).

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