Lecture Notes

Definition and Cause

• 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.