B6-hIGHMBP2 Mice

Figure 1. Diagram of the gene editing strategy of B6-hIGHMBP2 mice. Since there is an opposing gene upstream of the mouse Ighmbp2 gene, to avoid affecting the expression of the upstream gene, choose exon 5-15 as the humanized region. The exon 5-15 and flanking sequence of mouse Ighmbp2 was replaced with the entire human IGHMBP2 gene and ~10 kb of human IGHMBP2 promoter, and the human sequence was inserted in reverse to prevent disruption of mouse Mrpl12 gene function.

● Research on Spinal muscular atrophy with respiratory distress type 1 (SMARD1).

● Research on Charcot-Marie-Tooth disease type 2S.

1. Detection of human IGHMBP2 gene expression

Figure 2. Human IGHMBP2 gene expression in the thymus and spleen of wild-type mice (WT) and B6-hIGHMBP2 mice (hIGHMBP2). The RT-qPCR analysis results showed that the human IGHMBP2 gene was expressed in both the thymus and spleen of B6-hIGHMBP2 mice, while there was no expression of the human IGHMBP2 gene in wild-type mice.
ND: Not detected

 

2. Detection of mouse Ighmbp2 gene expression

Figure 3. Mouse Ighmbp2 gene expression in the thymus and spleen of wild-type mice (WT) and B6-hIGHMBP2 mice (hIGHMBP2). The RT-qPCR analysis results showed that the mouse Ighmbp2 gene was expressed in both the thymus and spleen of wild-type mice, while there was no expression of the mouse Ighmbp2 gene in B6-hIGHMBP2 mice.

1. Basic information about the IGHMBP2 gene

https://rddc.tsinghua-gd.org/en/gene/3508

2. IGHMBP2 clinical variants

https://rddc.tsinghua-gd.org/en/ai/pathogenicity/result?id=6758ac59-2680-43da-b939-4c54bb12b16e

3. Disease introduction

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a rare autosomal recessive motor neuron disease, with its main clinical symptom being diaphragmatic paralysis leading to respiratory distress, occurring mostly in infants aged 6 to 12 months. In addition, SMARD1 can also cause severe muscle atrophy that progresses from the distal to the proximal limbs, intrauterine growth retardation, weak crying, and sensory and autonomic nervous system defects^[1]. Restrictive cardiomyopathy may be one of the phenotypes of SMARD1^[2].

Charcot-Marie-Tooth disease type 2S (CMT2S) is a rare hereditary neurological disease and is a subtype of Charcot-Marie-Tooth disease type 2 (CMT2). CMT2 is a group of hereditary peripheral neuropathies characterized by abnormal fibers or axons extending from the nerve cell body to muscles or sensory organs, reducing the strength of nerve impulses. The clinical characteristics of CMT2S include symmetrical distal limb weakness and muscle atrophy, with severe peripheral nerve damage.

4. IGHMBP2 gene and mutations

The human IGHMBP2 gene is located on chromosome 11 and encodes an ATP-dependent helicase that is expressed throughout the body. This gene contains 15 exons and includes a helicase structural domain, a single-stranded nucleic acid binding domain, and one zinc finger motif. It is involved in the regulation of DNA replication, mRNA splicing, transcription, and translation. Mutations in the IGHMBP2 gene can occur in both exons and introns.

5. IGHMBP2-targeted gene therapy

Research on IGHMBP2-targeted drugs is currently in the early stages, and two different gene therapies, ASO drugs, and AAV delivery, have emerged. Gene therapy is expected to become one of the most promising treatments for related diseases.

In summary, the IGHMBP2 gene is an important pathogenic gene for spinal muscular atrophy with respiratory distress type 1 (SMARD1) and Charcot-Marie-Tooth disease type 2S (CMT2S), with a complex pathogenic mechanism. As an important target for the treatment of SMARD1 and CMT2S, two different drug pipelines, ASO drugs, and gene therapies based on AAV delivery, have emerged in the field of gene therapy. Since most ASO and AAV-delivered therapies act on the human IGHMBP2 gene, considering the differences between animals and humans in genes, humanizing the mouse gene will help promote the further clinical translation of therapies targeting IGHMBP2. IGHMBP2 whole-genome humanized mice from Cyagen can be used for preclinical research on SMARD1 and CMT2S, and customized services can also be provided for different point mutations.