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

• DOI: 10.1038/s41467-019-08493-7
• Publication Date: 2019-02-05T11:04:11Z
• Authors: Boris Fichtman; Fadia Zagairy; Nitzan Biran; Yiftah Barsheshet; Elena Chervinsky; Ziva Ben Neriah; Avraham Shaag; Michael Assa; Orly Elpeleg; Amnon Harel; Ronen Spiegel
• Keywords: Nuclear lamina; Nonsense mutation

Abstract Nuclear envelopathies comprise a heterogeneous group of diseases caused by mutations in genes encoding nuclear envelope proteins. Mutations affecting lamina-associated polypeptide 1 (LAP1) result two discrete phenotypes muscular dystrophy and progressive dystonia with cerebellar atrophy. We report 7 patients presenting at birth severe neurological impairment, bilateral cataract, growth retardation early lethality. All the are homozygous for nonsense mutation TOR1AIP1 gene resulting loss both protein isoforms LAP1B LAP1C. Patient-derived fibroblasts exhibit changes morphology large nuclear-spanning channels containing trapped cytoplasmic organelles. Decreased inefficient cellular motility is also observed these fibroblasts. Our study describes complete absence major human LAP1 isoforms, underscoring their crucial role development organogenesis. LAP1-associated defects may thus broad clinical spectrum depending on availability throughout life.