Nhej1, also known as non-homologous end-joining factor 1 and Cernunnos/XLF, is a key component of the non-homologous end-joining (NHEJ) DNA repair pathway. This pathway is crucial for repairing DNA double-strand breaks (DSBs) in mammalian cells, especially in post-mitotic neurons where it is the only available DSB repair pathway. Nhej1 interacts with Xrcc4 and Lig4 to execute this repair function, and its proper function is essential for maintaining genomic stability and normal biological processes [2].

In humans, Nhej1 deficiency can lead to severe combined immunodeficiency (SCID), microcephaly, growth retardation, and abnormal T and B cell receptor repertoires. For example, a novel splice site mutation in NHEJ1 led to the loss of NHEJ1 protein in a family with affected siblings presenting with combined immunodeficiency, microcephaly, and growth retardation [1]. Another study reported a novel missense pathogenic variant in NHEJ1 in a patient with SCID phenotype, along with microcephaly, recurrent pneumonia, and failure to thrive [3]. In rats, decreasing Nhej1 expression during neuronal migration phases caused severe neuronal migration defects and abnormal cortical development, indicating its importance in proper cortical development [2].

In conclusion, Nhej1 is essential for DNA double-strand break repair through the NHEJ pathway. Its deficiency in humans and experimental animal models is associated with severe immunodeficiency, neurological disorders, and abnormal development. The study of Nhej1 in these models has significantly enhanced our understanding of the molecular mechanisms underlying these disease conditions, potentially guiding the development of new diagnostic and therapeutic strategies.