Molecular Pathogenesis
Gene structure.
SYNE1 is one of the largest genes in the human genome with 0.5 Mb of genomic DNA. Alternatively spliced transcript variants encoding different protein isoforms have been described. The longest transcript NM_182961.3 (27,748 bp; variant 1) has 146 exons, of which exons 1 and 2 are noncoding. A shorter transcript variant NM_033071.3 (27,439 bp; variant 2) has 146 exons with exon 1 noncoding; this variant has multiple differences in the coding region but maintains the same reading frame as transcript variant 1.
See Table A, Gene for a detailed summary of gene, transcripts, and protein isoforms.
Pathogenic variants. Most pathogenic variants associated with the ARCA1 phenotype are nonsense or frameshift and are localized throughout the gene, excluding the KASH domain [Yoshinaga et al 2017]. Pathogenic variants associated with arthrogryposis multiplex congenita (AMC) are distal truncating variants that are expected to lead to a truncated Nesprin1α (or Nesprin1α2) isoform, which is muscle and retina specific [Duong et al 2014, Potter et al 2017].
Normal gene product.
SYNE1 encodes a multi-isomeric protein called nesprin1, a scaffold protein involved in the binding of the nuclear membrane and the cytoskeleton. Nesprin-1 localizes at the outer nuclear membrane, where it interacts with SUN proteins located at the inner nuclear membrane to form the linker of the nucleoskeleton and cytoskeleton (LINC) complex [Sosa et al 2012]. The longest transcript variant NM_182961.3 encodes a 8,797-amino-acid protein (>1000 kd) known as the nesprin-1 giant isoform (Nes1g or isoform-1 or enaptin) (NP_892006.3) [Gros-Louis et al 2007]. The nesprin-1 giant protein contains two N-terminal paired calponin homology domains that bind cytoskeletal actin, a transmembrane domain, multiple spectrin repeats that mediate anchoring and interaction with other proteins and organelles, and a C-terminal KASH domain that localizes the protein to the nuclear envelope. Transcript variant NM_033071.3 encodes an 8,749-amino-acid protein known as KLNes1g (or nesprin-1 isoform 2) (NP_149062.1) [Razafsky & Hodzic 2015]. The shorter KLNes1g isoform lacks the C-terminal KASH domain.
Two isoforms of the proteins are specifically expressed in the central nervous system when compared with other isoforms and with the related Nesprin2 protein: Nes1g is particularly expressed in CNS tissues along with its KLNes1g, which is abundantly expressed in the cerebellum [Gros-Louis et al 2007, Duong et al 2014, Razafsky & Hodzic 2015].
SYNE1 has multiple alternative start and termination sites that allow for multiple isoforms lacking certain specific domains [Rajgor et al 2012; see also Razafsky & Hodzic 2015, Yoshinaga et al 2017, Potter et al 2018, and references therein]. These isoforms are present in multiple subcellular locations beyond the nuclear envelope and serve to link these structures to the actin skeleton [Zhang et al 2007]. Specific isoforms appear to have a tissue-specific transcription, and this transcription is highly adaptable according to cell needs for maintaining homeostasis [Rajgor et al 2012].
Abnormal gene product. Most pathogenic variants associated with the ARCA1 phenotype are nonsense or frameshift and are localized throughout the gene, excluding the KASH domain [Yoshinaga et al 2017]. Hence, these pathogenic variants are expected to affect the structure of the KLNes1g isoform, whose loss of function is thought to lead to ARCA1 [Razafsky & Hodzic 2015]. Indeed, the KLNes1g isoform is abundantly expressed in the cerebellum, where it localizes to essential synapses between mossy fibers and cerebellar granule neurons within the granule cell layer [Potter et al 2018]. Analyses in murine models suggest that this isoform is involved in vesicular trafficking and dendritic membrane structural organization, which indicates that defective synaptic transmission may underlie ARCA1 pathology; however, this remains to be confirmed [Razafsky & Hodzic 2015]. Pathogenic variants that alter the more C-terminal region of the protein have the potential to also alter the ubiquitously expressed Nesprin1β isoform, which may underlie the more complex multisystem phenotype observed in some individuals [Potter et al 2018].
Pathogenic variants associated with arthrogryposis multiplex congenita (AMC) are distal truncating variants that are expected to lead to a truncated Nesprin1α (or Nesprin1α2) isoform, which is muscle and retina specific [Duong et al 2014, Potter et al 2017]. There is mounting evidence that Nesprin1α is involved in skeletal muscle function: Nesprin1α is upregulated during myogenic differentiation and is required for the recruitment of centrosomal proteins to the nuclear envelope, which ensures proper nuclear positioning [Gimpel et al 2017]. Aberrant nuclear positioning is associated with other muscular diseases, suggesting that proper nuclear localization is essential for skeletal muscle function [Stroud et al 2017]. In murine studies of different Nesprin1 isoforms, loss of Nesprin1α2 led to severe nuclear mispositioning and postnatal lethality, suggesting that this is the isoform essential for skeletal muscle function [Stroud et al 2017]. Hence, loss of the Nesprin1α isoform may underlie muscular involvement in SYNE1 deficiency.
All SYNE1 pathogenic variants would also affect the Nesprin1 giant (Nes1g) isoform, which is predominantly expressed in the central nervous system at the nuclear envelope of Bergmann glia and at ciliary rootlets of ependymal cells [Baumann et al 2017, Potter et al 2018]. Mouse models with loss of Nes1g did not show any cerebellar phenotype but presented ventricular enlargement potentially reflecting cilia dysfunction [Potter et al 2018]. Of interest, scoliosis, respiratory insufficiency, and cognitive impairment are all clinical findings that have been reported in association with other ciliopathies, suggesting that loss of the Nes1g isoform may underlie some non-cerebellar and non-muscular features of the phenotype [Potter et al 2018].
