MAN1

MAN1 is a nuclear envelope protein encoded by the LEMD3 gene in humans. It is one of the LEM-domain family members, commonly referred to by the alias MAN1, and functions as an inner nuclear membrane component involved in chromatin organization and signaling regulation.

The MAN1 protein localizes to the inner membrane of the nuclear envelope and interacts with chromatin through the LEM domain, which binds barrier-to-autointegration factor (BAF). Its C-terminal region associates with lamins A/C, contributing to nuclear envelope integrity. Through these interactions, MAN1 participates in shaping nuclear architecture and influencing how chromatin is organized within the nucleus.

Functionally, MAN1 has a role in modulating signaling pathways that govern cell fate and development, notably the TGF-β and BMP pathways. It can bind Smad transcription factors at the nuclear envelope, acting as a negative regulator by sequestering Smads away from target genes and thereby dampening Smad-dependent transcription. This regulatory activity links nuclear envelope contact to broader gene expression programs and cellular responses to extracellular signals.

Clinical significance is most clearly illustrated by LEMD3 mutations. Germline alterations in LEMD3 can cause osteopoikilosis, a rare bone dysplasia, and Buschke-Ollendorff syndrome, which combines osteopoikilosis with connective tissue nevi. Somatic mutations in LEMD3 have been associated with melorheostosis, a sclerosing bone disorder. These conditions underscore the protein’s role in bone development and signaling regulation.

In summary, MAN1/LEMD3 encodes a nuclear envelope protein essential for nuclear architecture and signaling modulation, with notable implications for skeletal development when mutated.