Nhej1, also known as 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), especially in post-mitotic neurons, and is also involved in V(D)J recombination for generating diverse T and B cell receptor repertoires [2,3,4].

Mutations in Nhej1 have been associated with severe combined immunodeficiency syndrome (SCID), microcephaly, growth retardation, and abnormal T and B cell receptor repertoires. For example, a novel splice site mutation in NHEJ1 led to loss of the NHEJ1 protein and presented as combined immunodeficiency, microcephaly, and growth retardation in a family [1]. In another case, a patient with a novel homozygous missense pathogenic variant in NHEJ1 showed SCID phenotype with clonally expanded T and B cells [3]. Nhej1 deficiency in developing rat brains, induced by in utero electroporation of inactivating small hairpin RNAs, 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 in the NHEJ pathway, which is crucial for normal immune function and central nervous system development. Studies on Nhej1-deficient models, such as the rat model with reduced Nhej1 expression, have revealed its role in preventing diseases like severe combined immunodeficiency and abnormal brain development.