B6.Cg-Ighmbp2^nmd-2J Tg(Ttn-Ighmbp2)108Cx/Cx

Stock number: 006514
Research areas: Mouse/Human Gene Homologs, Neurobiology Research

Description

This strain carries the spontaneous mutation neuromuscular degeneration (nmd-2J) and a transgene expressing Ighmbp2 under the control of the muscle-specific titin (Ttn) promoter. The transgene extends lifespan by preventing primary dilated cardiac myopathy despite the presence of neuromuscular degeneration. This strain is useful for studies involving the role of Ighmpb2 in motor neuron disease and human cardiomyopathy.

Detailed description

Immunoglobulin mu binding protein 2 (IGHMBP2) is a DNA/RNA helicase implicated in transcriptional regulation and mRNA splicing. Mutations in IGHMBP2 are associated with the degeneration of alpha motor neurons and spinal muscular atrophy (DSMA1, SMARD1, HMN6) as well as dilated cardiac myopathy (DCM) and skeletal myopathy. nmd-2J mutant mice are characterized by a progressive paralysis that begins in the hindlimbs and moves to the forelimbs in the later stages of the disease. Homozygotes initially are identified by contracted hindlimbs and impaired movement beginning at two weeks of age. Mice rarely survive past 4 weeks of age. Combining nmd-2J mice with transgenic mice expressing Ighmbp2 under the control of the rat neuron-specific enolase promoter (Stock No. 003834, TgNI) halts neuromuscular degeneration, but reveals the presence of cardiac myopathy followed by premature death as a result of congestive heart failure (CHF).

In this strain, nmd-2J mice are combined with transgenic mice expressing Ighmbp2 under the control of the muscle-specific titin (Ttn) promoter (TgMI), the transgene extends lifespan by preventing primary DCM despite the presence of neuromuscular degeneration. Transgene founder lines 45 and 108 exhibit similar phenotypes. This strain is useful for studies involving the role of Ighmpb2 in motor neuron disease and human cardiomyopathy.

Development

A transgenic construct was designed with a full-length Ighmbp2 cDNA under the control of the mouse titin promoter. The construct was introduced into C57BL/6J donor eggs. Founder line 108 was consequently established. Transgenic mice were crossed to the spontaneous mutant B6.BKS-Ighmbp2^nmd-2J for two generations to generate transgene positive mice homozygous for the nmd-2J.

Allele

Symbol: Tg(Ttn-Ighmbp2)108Cx
Name: transgene insertion 108, Gregory A Cox
MGI accession ID: MGI:3785079
Generation method: Transgenic
Attributes: Inserted expressed sequence
Marker symbol: Tg(Ttn-Ighmbp2)108Cx
Marker name: transgene insertion 108, Gregory A Cox
Chromosome: UN
Strain of origin: C57BL/6J
Expressed genes: Ighmbp2,immunoglobulin mu binding protein 2,mouse, laboratory
Molecular note: a cDNA sequence encoding the full mouse Ighmbp2 was placed under the control of a modified 5.87 kb mouse genomic fragment containing the Ttn promoter, non-coding Ttn exon 1, intron 1, and 30 base pairs of Ttn exon 2 lacking the start codon. Transgene expression was limited to the heart and skeletal muscles as confirmed by RT-PCR expression using Ighmbp2 exon 1.

Allele

Symbol: Ighmbp2^nmd-2J
Name: neuromuscular degeneration 2 Jackson
MGI accession ID: MGI:1857648
Generation method: Spontaneous
Marker symbol: Ighmbp2
Marker name: immunoglobulin mu binding protein 2
Chromosome: 19
Strain of origin: BKS.Cg-Dock7^m +/+ Lepr^db/J
Molecular note: An A-to-G transition mutation in intron 4 results in the creation of a cryptic splice site and interferes with the normal splicing of the transcript. RT-PCR analysis on RNA derived from various tissues of homozygous mice demonstrated that approximately 20-25% of the transcripts were spliced normally, while 75-80% of the transcripts were spliced aberrantly. This allele also presents with a deletion of one of the two leucine codons at position 362 and 363 in exon 8 (SW:P40694).