TOR1AIP1-Associated Nuclear Envelopathies

Abstract

Human TOR1AIP1 encodes LAP1, a nuclear envelope protein expressed in most human tissues, which has been linked to various biological processes and human diseases. The clinical spectrum of diseases related to mutations in TOR1AIP1 is broad, including muscular dystrophy, congenital myasthenic syndrome, cardiomyopathy, and multisystemic disease with or without progeroid features. Although rare, these recessively inherited disorders often lead to early death or considerable functional impairment. Developing a better understanding of the roles of LAP1 and mutant TOR1AIP1-associated phenotypes is paramount to allow therapeutic development. To facilitate further studies, this review provides an overview of the known interactions of LAP1 and summarizes the evidence for the function of this protein in human health. We then review the mutations in the TOR1AIP1 gene and the clinical and pathological characteristics of subjects with these mutations. Lastly, we discuss challenges to be addressed in the future.

Keywords: LAP1; LAP1B; LAP1C; TOR1AIP1; clinical spectrum; inner nuclear membrane; lamina-associated polypeptide 1B; lamina-associated polypeptide 1C; lamina-associated protein 1; mutations.

Figure 1

Schematic of (top to bottom) human TOR1AIP1 gene, the transcript variants, and LAP1 protein isoforms. (A) TOR1AIP1 has 10 exons represented by colored boxes. Two start codons are found in exon 1. Alternative translation start sites produce distinct transcripts. (B) Two LAP1B transcripts have identical sequence apart from a CAG trinucleotide in exon 3, indicated by an asterisk (*). (C) LAP1C is truncated at the N-terminus relative to LAP1B. LAP1B and LAP1C proteins, which differ in the number of amino acids (AA) at the N-terminus, have three distinct domains: an N-terminal nucleoplasmic domain (ND), a transmembrane domain (TM), and a C-terminal luminal domain (LD). A zinc-finger motif (Z) is present in the C-terminal regions of both proteins. Mutations reported to date are indicated in transcript and protein schematics. Compound heterozygous mutations are indicated in red. Mutations that affect LAP1B seem to be associated with muscle involvement, whereas mutations that affect both isoforms result in early-onset multisystemic presentation.

Figure 2

Schematic of LAP1’s main interactions. The nuclear envelope formed by the outer and inner membranes (ONM and INM, respectively). The latter is underlaid by a network of type V intermediate filaments (A/C- and B-type lamins) forming the basal lamina. ONM is in direct contact with the endoplasmic reticulum. NE contains transport channels called nuclear pore complexes. LAP1 is located on the INM and interacts with emerin and lamins, either directly or via emerin, contributing to maintaining skeletal muscle and NE structure integrity. Activation of TorsinA ATPase activity requires interaction with LAP1 at the NE or LULL1 at the ER. PP1 mediates LAP1’s Ser306 and Ser310 residues dephosphorylation. In response to DNA damage, phosphorylated LAP1 interacts with TRF2 that is part of the shelterin complex, a structure ensuring telomer repair and genome integrity. ER: endoplasmic reticulum; INM: inner nuclear membrane; LAP1: lamina-associated protein 1; LULL1: luminal domain-like LAP1; NE: nuclear envelope; NPC: nuclear pore complex; ONM: outer nuclear membrane; PP1: protein phosphatase 1.