huTCF4-R580W Mouse

Pitt-Hopkins syndrome (PTHS) is a rare autosomal dominant neurodevelopmental disorder. It is primarily caused by abnormal development of the nervous system. Patients may present with severe intellectual disability, global developmental delay, characteristic facial features, respiratory abnormalities, epilepsy, severe constipation and gastroesophageal reflux as manifestations of autonomic dysfunction, as well as language absence or severe limitation, motor developmental delay, and behavioral abnormalities ^[1]. The pathogenesis of PTHS is mainly associated with haploinsufficiency of the transcription factor 4 (TCF4) gene. The TCF4 gene is located on chromosome 18q21.2 and encodes a type I basic helix‑loop‑helix transcription factor that plays a critical role in nervous system development and function maintenance, participating in neuronal differentiation and migration, regulation of neuronal excitability, and neuroplasticity ^[2-3]. Loss of TCF4 function leads to aberrant expression of its downstream target genes, thereby affecting normal cerebral cortical development and ultimately causing PTHS. The c.1738C>T (p.R580W) mutation, which substitutes arginine with tryptophan at position 580 of the TCF4 protein, abolishes the in vitro DNA‑binding ability of TCF4 homodimers and is one of the pathogenic missense mutations causing PTHS ^[4]. Unlike the common founder mutations in familial dysautonomia, TCF4 p.R580W usually occurs as a de novo heterozygous mutation, not detected in the parents, and carries a low familial recurrence risk ^[2]. The overall prevalence of PTHS is estimated at approximately one in several tens to hundreds of thousands of newborns. Currently, there is no precise targeted therapy; treatment mainly consists of multidisciplinary management ^[2,5].

The huTCF4-R580W mouse is a humanized mutant model generated by gene editing technology, in which the p.R580W (CGG→TGG) point mutation is introduced into exon 18 of the human TCF4 gene in the huTCF4 mouse (Catalog No.: C002071). This model serves as a key preclinical model for Pitt‑Hopkins syndrome (PTHS) and can be used for studying PTHS disease mechanisms, drug screening, and preclinical pharmacological efficacy evaluation.