Combined loss of LAP1B and LAP1C results in an early onset multisystemic nuclear envelopathy

Nuclear envelopathies comprise a heterogeneous group of diseases caused by mutations in genes encoding nuclear envelope proteins. Lamina-associated polypeptide1 (LAP1) is a ubiquitously expressed protein located in the inner nuclear membrane. Mutations in LAP1 have been reported to result in two discrete phenotypes of muscular dystrophy and progressive dystonia with cerebellar atrophy.

Here we report 7 patients of similar ethnic background who are homozygous for a nonsense mutation in the TOR1AIP1 gene, resulting in the loss of both protein isoforms LAP1B and LAP1C. The patients present at birth with severe progressive neurological impairment, bilateral cataract, growth retardation and early lethality.

Patient-derived primary skin fibroblast exhibit changes in nuclear envelope morphology including reduced anti-lamin A/C nuclear rim staining intensity in addition to the emergence of large channels containing trapped cytoplasmic organelles and traversing the nucleus. The patient fibroblasts also displayed functional cellular impairment demonstrated by decreased and inefficient directional as well as random cell motility. Transduction with LAP1-coding constructs succeeded in rescuing multiple cellular phenotypes and hinted at a differential effect of the two protein isoforms.

Our study describes the complete absence of both major human LAP1 isoforms, underscoring their crucial role in early development and organogenesis. LAP1-associated defects may thus comprise a broad clinical spectrum, varying in severity and organ involvement, depending on the availability of both isoforms in the nuclear envelope throughout life.