huELP1-c.2204+6T>C Mouse

Familial dysautonomia (FD), also known as Riley-Day syndrome or hereditary sensory and autonomic neuropathy type III (HSAN III), is a rare autosomal recessive neurological disorder. The disease is primarily caused by developmental and functional abnormalities of the autonomic and sensory nervous systems. Patients with FD exhibit symptoms associated with autonomic dysfunction, including excessive sweating, intermittent hypertension, drooling, abnormal glandular secretion, difficulty swallowing, urinary and fecal dysfunction, breathing difficulties, and periodic vomiting, along with physical developmental abnormalities such as developmental delay, intellectual disability, and osteoporosis. FD is mainly associated with defects in the development of peripheral sensory and autonomic neurons, with biallelic mutations in the elongator complex protein 1 (ELP1) gene, also known as IKBKAP, representing the major genetic cause of this disease. ELP1 is a core subunit of the Elongator complex, which is essential for various tRNA modification processes and plays an important role in neuronal development, survival, and functional maintenance. Loss of ELP1 function results in reduced or abnormal ELP1 protein levels, leading to impaired neuronal function and neuronal damage, ultimately contributing to the development of familial dysautonomia (FD) ^[1]. The c.2204+6T>C variant is the most common pathogenic splice-site mutation associated with familial dysautonomia (FD) and represents one of the most prevalent founder mutations of this disease. Approximately 99% of FD patients in the Ashkenazi Jewish population carry this specific splice-site mutation ^[2].

The huELP1-c.2204+6T>C mouse model is a humanized mutation model generated via gene-editing technology, in which the sequences from upstream of exon 19 to downstream of exon 22 of the mouse Elp1 gene were replaced with the corresponding human ELP1 gene sequences, along with the introduction of a c.2204+6T>C mutation in intron 20 of the human ELP1 gene. This strain is homozygous lethal. This model is suitable for investigating the pathogenic mechanisms of the human ELP1 c.2204+6T>C mutation and familial dysautonomia (FD), as well as for the screening, development, and efficacy evaluation of targeted therapies.