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

Abstract

Biallelic variants in TOR1AIP1, encoding the integral nuclear membrane protein LAP1 (lamina-associated polypeptide 1) with two functional isoforms LAP1B and LAP1C, have initially been linked to muscular dystrophies with variable cardiac and neurological impairment. Furthermore, a recurrent homozygous nonsense alteration, resulting in loss of both LAP1 isoforms, was identified in seven likely related individuals affected by multisystem anomalies with progeroid-like appearance and lethality within the 1st decade of life. Here, we have identified compound heterozygosity in TOR1AIP1 affecting both LAP1 isoforms in two unrelated individuals affected by congenital bilateral hearing loss, ventricular septal defect, bilateral cataracts, mild to moderate developmental delay, microcephaly, mandibular hypoplasia, short stature, progressive muscular atrophy, joint contractures and severe chronic heart failure, with much longer survival. Cellular characterization of primary fibroblasts of one affected individual revealed absence of both LAP1B and LAP1C, constitutively low lamin A/C levels, aberrant nuclear morphology including nuclear cytoplasmic channels, and premature senescence, comparable to findings in other progeroid forms of nuclear envelopathies. We additionally observed an abnormal activation of the extracellular signal-regulated kinase 1/2 (ERK 1/2). Ectopic expression of wild-type TOR1AIP1 mitigated these cellular phenotypes, providing further evidence for the causal role of identified genetic variants. Altogether, we thus further expand the TOR1AIP1associated phenotype by identifying individuals with biallelic loss-of-function variants who survived beyond the 1st decade of life and reveal novel molecular consequences underlying the TOR1AIP1-associated disorders.

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

“…Additional mutant alleles of TOR1A in patients with varying phenotypic severities have been reported (Figure 2A,B) [56][57][58][59][60][61][62][63][64][65][66]. 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).…”

“…Mutation of the TorsinA homolog OOC-5 (abnormal OOCyte formation-5) in Caenorhabditis elegans prompts the mislocalization of nucleoporins (Nup) and subsequently impairs nuclear trafficking [51]. Moreover, phenylalanine-glycine repeat nucleoporins (FG-Nups) localize to the 'neck' regions of blebs while their luminal contents are enriched in ubiquitylated proteins suggesting that these blebs may represent an aberrant NPC intermediate stalled prior to the fusion of the INMs and outer nuclear membranes (ONM) during NPC assembly [30,67]. Changes in the localization of nuclear transport machinery were also observed in neuronal tissue of mouse models bearing conditional TorsinA alleles upon tissue-specific deletion to bypass perinatal lethality [31].…”

“…The perforation of the NE during interphase NPC biogenesis poses an intriguing problem for how the fusion of the INM and ONM is coordinated while maintaining the overall structural integrity and compartmentalization of the nucleus. It is therefore tempting to speculate that the NE blebs observed upon Torsin deletion or manipulation result from defects in membrane fusion or remodeling during NPC biogenesis [30,67,83]. Moreover, it is difficult to rationalize why higher eukaryotes conserved a mechanism for NPC assembly that requires Torsin ATPases when lower eukaryotes lack an identifiable Torsin ortholog.…”

“…The question remains as to why interphase assembly is disrupted in Torsin-deficient cells prior to membrane fusion. The potential for Torsins to be functionally connected to a fusogenic molecular machine is an attractive concept and has been previously proposed [67,83,101].…”

The Nuclear Envelope in Lipid Metabolism and Pathogenesis of NAFLD

“…Combined loss of LAP1B and LAP1C causes multisystem disease and death during childhood [ 73 ]. Compound heterozygosity in the TOR1AIP1 that leads to diminished expression of both isoforms causes multisystem alterations in the affected individuals [ 74 ] ( Table 1 ). There have been no reports of mutations in TOR1AIP1 causing NAFLD in humans.…”