Familial dysautonomia (FD) is a rare autosomal recessive genetic neurological disorder. Patients with FD exhibit symptoms such as excessive sweating, intermittent hypertension, drooling, abnormal glandular secretion, difficulty swallowing, urinary and fecal incontinence, breathing difficulties, periodic vomiting, and physical developmental abnormalities, including intellectual disability and osteoporosis. FD primarily results from underdeveloped cervical sympathetic ganglia, with mutations in the ELP1 gene being a significant genetic factor. The ELP1 gene, also known as IKBKAP, encodes components of the elongation complex essential for tRNA modification. This widely expressed protein plays a crucial role in neuronal development and function. Mutations in both copies of the ELP1 gene can lead to decreased or absent ELP1 protein levels, causing neuronal damage and potentially contributing to FD symptoms^[1]. There is no mature cure for FD. Treatment primarily focuses on symptomatic relief and supportive care to alleviate symptoms and prevent complications. Gene therapy, a promising approach, targets the underlying cause of FD---gene mutations---enhancing treatment efficiency and persistence. This field is expected to be the next breakthrough. At present, the ELP1 targeted drug pipeline has begun to be laid out. The preclinical animal models are mostly transgenic humanized mice. Compared with randomly inserted, humanized region-restricted transgenic humanized mice, more scientific and efficient whole-genome humanized animal models will help promote the potential therapy targeting ELP1 to accelerate into the clinical stage. This strain is a mouse Elp1 gene humanized model and can be used to research Familial dysautonomia (FD). The homozygous huELP1 mice are viable and fertile. In addition, based on the independently developed TurboKnockout fusion BAC recombination technology, Cyagen can also generate hot mutation (ELP1 IVS20+6T>C) models based on this strain and provide customized services for specific mutations.

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.

Psmb2 is located on chromosome 4 of mice. Nuclease Technology will be used to design sgRNA; Psmb2 knockout mice will be obtained by applying high-throughput electroporation of fertilized eggs. After sexual maturity, sperm were collected for cryopreservation.

Qrfprl is located on chromosome 6 of mice. SgRNA and ssDNA will be designed using Nuclease Technology; Qrfprl conditional knockout mice will be obtained by high-throughput electroporation of fertilized eggs. After sexual maturity, sperm will be collected for cryopreservation.