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

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.

Two novel cases further expand the phenotype of TOR1AIP1-associated nuclear envelopathies

“…Here, we present two unrelated individuals with striking clinical similarities bearing biallelic loss-of-function variants in TOR1AIP1 affecting both LAP1 isoforms. In comparison to the abovementioned study (Fichtman et al 2019), one individual survived until 16 years of age and the other is alive at 34 years of age, respectively, and they were affected by multisystem anomalies and progeroid appearance that progressed with age. Moreover, we present the cellular characterization of primary fibroblasts of one of the affected individuals.…”

“…(Ghaoui et al 2016). Furthermore, a recent study identified a homozygous Palestinian founder variant, p.(Arg321*), in seven individuals from five likely related families affected by early onset multisystem anomalies with progeroid appearance and lethality in the 1st decade of life (Fichtman et al 2019). Only those bearing the p.(Arg321*) had a loss of both LAP1B and LAP1C protein isoforms.…”

The Role of Torsin AAA+ Proteins in Preserving Nuclear Envelope Integrity and Safeguarding Against Disease

“…Importantly, many of these mutations map to regions on TorsinA at the inter-subunit interface, suggesting they perturb Torsin/Torsin or Torsin/cofactor binding [4,12,67]. Supporting the idea that interrupting the Torsin/cofactor interaction is detrimental are reports of patients with mutations in the LAP1 gene, TOR1AIP1, who display dystonic-like symptoms [15,68], cardiomyopathy [14,15,68,69], deafness [14,68], and muscular dystrophy [16,69] (Figure 2A). Although many of these phenotypes arising from the TOR1AIP1 mutation are distinct from those observed in patients with TOR1A mutations, a subset of TOR1AIP1 patients experience dystonic symptoms similar to those presented by DYT1 dystonia (TOR1A mutation) patients.…”

“…Further underscoring the importance of the Torsin/cofactor assembly during development is a recent report describing a mutation within the LAP1 gene TOR1AIP1 that results in a loss of LAP1 expression in patients with dystonia-like symptoms, along with other pathology (see below, Figure 2A,B) [14]. In fact, several disease-associated mutations have been reported for LAP1 ( Figure 2A,B) [14][15][16] but none for LULL1, suggesting critical roles for the Torsin/LAP1 complex at the NE [14][15][16]. Torsins are implicated in multiple essential cellular processes at the nuclear envelope (NE) and endoplasmic reticulum (ER).…”

“…When considering the members of the Torsin family of ATPases, significant efforts have been placed in elucidating the biological roles of TorsinA due to its direct clinical significance in the highly debilitating movement disorder DYT1 early-onset dystonia [1]. Phenotypic effects of DYT1 dystonia usually manifest in early adolescence and are typified by sustained muscle contractions and involuntary twisting of individual or multiple muscle groups [1,15]. The most penetrant form of this disorder results from the autosomal dominant inheritance of a TOR1A variant bearing an in-frame deletion [1].…”