NSD2 Gene: Function, Mutations, and Disease Associations | NCBI, UniProt, OMIM

NSD2 (Nuclear Receptor Binding SET Domain Protein 2), also known as WHSC1 or MMSET, encodes a histone methyltransferase that primarily catalyzes dimethylation of histone H3 at lysine 36 (H3K36me2). This modification is critical for chromatin regulation, transcriptional elongation, and DNA repair. The gene is located in the Wolf-Hirschhorn syndrome critical region on chromosome 4p16.3. NSD2 is recurrently overexpressed or mutated in multiple myeloma due to t(4;14) translocations, and loss-of-function mutations cause Wolf-Hirschhorn syndrome. It is also implicated in various solid tumors and developmental disorders.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• Histone methylation (H3K36me2)

• Chromatin remodeling

• Transcriptional elongation by RNA polymerase II

• DNA double-strand break repair via homologous recombination

• Oncogenic signaling in multiple myeloma (t(4;14))

NSD2 is a 1365-amino-acid nuclear protein containing a SET domain, PWWP domains, and PHD fingers. It functions as a histone methyltransferase that specifically dimethylates histone H3 at lysine 36 (H3K36me2), a mark associated with active transcription and chromatin accessibility. NSD2 interacts with nuclear receptors and transcription factors to regulate gene expression. Its overexpression due to t(4;14) translocation is a hallmark of a subset of multiple myeloma, while loss-of-function mutations cause Wolf-Hirschhorn syndrome. The protein also plays roles in DNA repair and development.