Nuclear envelopathies are diseases resulting from mutations in genes encoding parts of the inner nuclear membrane, nuclear lamina, and outer nuclear membrane.
Key components include Emerin, MAN1, LAP2, LBR, Lamins A and C, Lamins B1, and Nesprins (Janin et al., 2017).
Mutations in Emerin, Lamins A/C, and Nesprins are rarer compared to other nuclear envelope components.
Historical Note
The first Emerin mutation was identified in 1994 in a small cohort of five patients, including a peculiar family from our cohort (Bione et al., 1994).
SUN Proteins
SUN1 and SUN2 are inner nuclear membrane proteins playing a major role in nuclear-cytoplasmic connection by forming the LINC complex (Haque et al., 2010).
This complex contributes to nuclear positioning and cellular vitality, establishing nuclear-cytoskeletal connections and maintaining cellular architecture (Rajgor et al., 2013).
Nesprin Genes and Isoforms
Four nesprin genes: SYNE1, SYNE2, SYNE3, and SYNE4.
Nesprin-1, nesprin-2, nesprin-3, and nesprin-4 are encoded by these genes.
Multiple nesprin protein isoforms are generated through alternative transcription, localizing to multiple compartments of the nuclear membrane (Janin et al., 2017; Rajgor et al., 2013).
These isoforms provide additional functions beyond nuclear envelope linkage, leading to variable neurological disease phenotypes.
Neurological Disorders
Mutations in SYNE1 and SYNE2 are associated with various neurological disorders.
SYNE4 mutations cause autosomal recessive hearing deficit (Horn et al., 2013).
SYNE3 mutations have not been linked to any genetic disorder.
Clinical Manifestations
Clinical abnormalities from nesprin-1 and nesprin-2 mutations include:
Cerebellar ataxia
Emery-Dreifuss muscular dystrophy
Arthrogryposis
Isolated cardiomyopathies (Puckelwartz et al., 2010)
These distinct features make nesprinopathies interesting for clinicians.
Notable Studies
In 2007, recessive mutations in SYNE1 were identified as a cause of pure cerebellar ataxia in French-Canadian families, termed SCAR8 or ARCA1 (Gros-Louis et al., 2007).
Japanese patients with SYNE1 mutations showed SCAR8 with motor neuron disease, mimicking juvenile-onset ALS several years before developing cerebellar ataxia (Izumi et al., 2007).
Turkish patients exhibited early-onset lower motor neuron disease with slow progression and ataxia, linked to SYNE1 mutations (Ozoguz et al., 2015).
European studies highlighted non-French-Canadian patients with SYNE1 ataxia showing variable combinations of cerebellar and extra-cerebellar neurological dysfunctions (Synofzik et al., 2016; Mademan et al., 2016).
Muscular Disorders
EDMD type 4 is thought to be caused by changes in the interactions between nesprin, lamin, and emerin. These changes are dominant in SYNE1 and SYNE2 (Fanin et al., 2017; Chen et al., 2015).
A 2007 study found four heterozygous missense mutations in SYNE1 and SYNE2 genes in patients with EDMD-like phenotypes (Zhang et al., 2007).
SYNE1 mutations are also responsible for Arthrogryposis Multiplex Congenita (AMC), causing infantile-onset musculoskeletal disease (Synofzik et al., 2016).
Phenotypic Spectrum
SYNE1 ataxia patients also show scoliosis/kyphosis, restrictive lung disease, foot deformities, and other neuromuscular abnormalities.
This suggests arthrogryposis syndromes are part of the continuum of SYNE1 disease.
Genotype-Phenotype Correlation
Mutations in the C-terminal regions (KASH domain) of SYNE1 and SYNE2 genes are associated with muscular disorders (Attali et al., 2009; Baumann et al., 2017).
Mutations in the N-terminus (CHD) are linked to ataxia.
A 2018 Austrian study noted C-terminal mutations ending with spastic paraplegia and cardiomyopathy (Indelicato et al., 2018).
Recent Findings
Kölbel et al. (2020) outlined a spectrum of SYNE1 disorders using next-generation genetic approaches, including:
Myopathic type resembling Emery-Dreifuss muscular dystrophy with dilated cardiomyopathy.
Complicated ataxia with mental retardation and peripheral neuropathy.
Arthrogrypotic form with congenital myopathy, restrictive lung disease, and clubfeet.
Shared features among these patients include thumb abnormalities and ultrastructural alterations of the nuclear envelope, predicting possible glial and neuronal involvement.
Conclusion
Clinical and genetic data on nesprinopathies are escalating.
These multi-system disorders, with features of ataxia, myopathy, and early multiple joint contractures, are now a consideration for clinicians.
