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 in two discrete phenotypes of muscular dystrophy and progressive dystonia with cerebellar atrophy. We report 7 patients presenting at birth with severe progressive neurological impairment, bilateral cataract, growth retardation and early lethality. All the patients are homozygous for a nonsense mutation in the TOR1AIP1 gene resulting in the loss of both protein isoforms LAP1B and LAP1C. Patient-derived fibroblasts exhibit changes in nuclear envelope morphology and large nuclear-spanning channels containing trapped cytoplasmic organelles. Decreased and inefficient cellular motility is also observed in these fibroblasts. 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 depending on the availability of both isoforms in the nuclear envelope throughout life.
Highlights
Nuclear envelopathies comprise a heterogeneous group of diseases caused by mutations in genes encoding nuclear envelope proteins
Recessive mutations in the TOR1AIP1 gene have been reported to result in two separate phenotypes, both arising during childhood following asymptomatic infancy, of muscular dystrophy with cardiac involvement[23,24] and a neurological phenotype dominated by dystonia and progressive cerebellar atrophy[25]
The present study describes seven patients manifesting a distinct phenotype dominated by early progressive neurological impairment, congenital heart malformations, congenital cataract, and moderate intra-uterine and severe post-natal growth retardation
Summary
Nuclear envelopathies comprise a heterogeneous group of diseases caused by mutations in genes encoding nuclear envelope proteins. All the patients are homozygous for a nonsense mutation in the TOR1AIP1 gene resulting in the loss of both protein isoforms LAP1B and LAP1C. Mutations in genes encoding essential protein components of the NE are known to be associated with specific human diseases collectively termed nuclear envelopathies[6,7]. We report seven patients of similar ethnic background presenting at birth with a multisystemic disease dominated by profound psychomotor retardation, cataract, heart malformation, sensorineural deafness, and peculiar facial appearance associated with homozygosity for a TOR1AIP1 loss-of-function mutation. Patient-derived fibroblasts exhibit a set of unique phenotypes that differ from the common cellular hallmarks of other nuclear envelopathies. These include reduced anti-lamin nuclear rim staining, large nuclear-spanning channels containing trapped cytoplasmic organelles, and severely impaired cellular motility
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
