Homozygous SYNE1 mutation causes congenital onset of muscular weakness with distal arthrogryposis: a genotype–phenotype correlation

Abstract

The exceptionally large SYNE1 (spectrin repeat-containing nuclear envelope protein 1) gene encodes different nesprin-1 isoforms, which are differentially expressed in striated muscle and in cerebellar and cerebral neurons. Nesprin-1 isoforms can function in cytoskeletal, nuclear, and vesicle anchoring. SYNE1 variants have been associated with a spectrum of neurological and neuromuscular disease. Homozygosity mapping combined with exome sequencing identified a disease-causing nonsense mutation in the ultimate exon of full-length SYNE1 transcript in an 8-year-old boy with distal arthrogryposis and muscular hypotonia. mRNA analysis showed that the mutant transcript is expressed at wild-type levels. The variant truncates nesprin-1 isoforms for the C-terminal KASH (Klarsicht-ANC-Syne homology) domain. This is the third family with recessive arthrogryposis caused by homozygous distal-truncating SYNE1 variants. There is a SYNE1 genotype-phenotype correlation emerging, with more proximal homozygous SYNE1 variants causing recessive cerebellar ataxia of variable onset (SCAR8; ARCA-1).

Emery‐Dreifuss muscular dystrophy type 4: A new SYNE1 mutation associated with hypertrophic cardiomyopathy masked by a perinatal distress‐related spastic diplegia

“…Targeted region capture sequencing performed on the young patient affected by spastic diplegia revealed a heterozygous missense mutation in SYNE1. SYNE1 gene comprises 516 Mbp on chromosome 6q25, contains 146 exons, and encodes for Nesprin‐1 (spectrin repeat‐containing nuclear envelope protein (a), a protein which belongs to the nesprin family of nuclear and cytoskeletal proteins . The mutation reported is localized into a central domain composed of multiple spectrin repeats (SR), which supports interactions with other proteins such as emerin, with the Emerin Binding Domain (EBD), or lamins, with the Lamin Binding Domain (LBD) .…”

Impairments in contractility and cytoskeletal organisation cause nuclear defects in nemaline myopathy

“…Perhaps associated with this is the frequent observation of chromatin abnormalities in NM patients by EM and light microscopy (Fig 3, Supplementary Fig S2), since both nuclear shape and the nuclear envelope are known to play a role in transcriptional regulation via chemical and mechanical control of chromatin organisation [17][18][19][20][21][22] . Analogously, similar effects on chromatin are seen in myonuclei of patients with mutations affecting nesprins or lamins 46,50,51 . Indeed, broad alterations in the transcriptional profile of skeletal muscle is observed in patients with NM (including in genes related to metabolism and calcium homeostasis), and this may partially be the result of nuclear shape and envelope alterations and/or reorganised chromatin 52 .…”

Mouse models of nesprin-related diseases

“…Muscle biopsies derived from EDMD patients carrying nesprin-1/2 mutations exhibited centralised nuclei with increased variability of fibre size [31,34]. Further studies demonstrated cellular changes with misshapen nuclei, invaginated and detached NE and reduced heterochromatin density in EDMD and AMC patient cells carrying nesprin-1/2 mutations [12,37]. In agreement with these observed changes in patient samples, 10 nesprin-1/2 mouse models exhibited either mis-positioning of non-synaptic and synaptic nuclei in skeletal muscle or reduced distance between adjacent nuclei, or elongated nuclei in cardiac muscle, whilst 2 strains (nesprin-2 KASH KO and nesprin-1/2 KASH DKO) revealed the defect in neuronal migration [29, 38, 40-42, 49, 50].…”

“…To date, majority of nesprin variants identified in SYNE-1 and SYNE-2 genes have been shown to contribute to pathogenesis of muscle diseases including EDMD, DCM, congenital muscular dystrophy (CMD), arthrogryposis multiplex congenita (AMC) [12,[29][30][31][32][33][34][35][36][37]62] and CNS disorders such as ARCA1, autism spectrum disorder and bipolar disorder respectively [63][64][65][66][67][68][69].…”

“…Intriguingly, many nesprin-1/2 isoforms that lack KASH domains exist and localise to various sub-cellular compartments, such as the sarcomere, sarcoplasmic reticulum, mitochondria, focal adhesions, Golgi and promyelocytic leukemia (PML) bodies, suggesting that nesprins possess additional functions [2,7,27,28]. So far, over 80 disease associated variants, have been identified in SYNE-1/2 genes, which result in muscular or central nervous system (CNS) disorders including autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD), dilated cardiomyopathy (DCM) and autosomal recessive cerebellar ataxia type 1 (ARCA1) [12,[29][30][31][32][33][34][35][36][37].…”