The nuclear envelope consists of a double-layered membrane and separates the nucleoplasm from the cytoplasm of the cell. Numerous proteins are anchored in the inner nuclear membrane, interacting with the lamina and participating in essential nuclear processes. Genetic variants impacting on the function of these membrane proteins can lead to specific disorders called nuclear envelopathies. Lamina-associated polypeptide 1 (LAP1) is such a membrane protein. It has at least two functional isoforms, LAP1A and LAP1B, encoded by the TOR1AIP1 gene. Recessive mutations in TOR1AIP1 are known to be associated with two distinct phenotypes of muscle dystrophy and a neurological disorder with dystonia and progressive cerebellar atrophy.

In a recently published study, scientists report on a homozygous nonsense mutation in TOR1AIP1 which they identified in seven patients with a multisystemic disease who presented with a severe progressive neurological impairment, heart malformations, bilateral cataract, growth retardation and early lethality. As a result of this mutation, patient-derived fibroblasts showed an absence of both LAP1 isoforms. The researchers observed changes in nuclear envelope structure and specific nuclear spanning channels that contained trapped cytoplasmic organelles. In addition, these cells showed decreased motility. These changes resulting from a complete loss of LAP1 function underscore the protein’s importance in early development and organogenesis. Depending on the availability or absence of one or both isoforms in the nuclear envelope, LAP1-associated defects may thus give rise to a broad spectrum of clinical manifestations.

The results of this study have been published in Nature Communications.