SYNE1

SYNE1 encodes nesprin-1, a family of spectrin-repeat proteins produced from a very large gene by alternative promoters and splicing. The giant isoform (enaptin, ~1 MDa) has paired N-terminal calponin-homology actin-binding domains, a long spectrin-repeat rod, and a C-terminal transmembrane KASH domain that anchors it in the outer nuclear membrane. In the perinuclear space the KASH peptide binds trimeric SUN1/SUN2 (with a SUN-KASH disulfide) to form LINC (linker of nucleoskeleton and cytoskeleton) complexes, which connect the actin and microtubule cytoskeletons, and associated dynein-dynactin and kinesin-1 motors, to the nuclear lamina. Through this bridge nesprin-1 transmits force across the nuclear envelope and functions in nuclear anchorage and positioning (notably of myonuclei and synaptic nuclei), nuclear shape, centrosome-nucleus coupling, and, redundantly with nesprin-2, nuclear migration in developing brain. Shorter isoforms lacking the actin-binding domain (nesprin-1alpha/myne-1, beta) are enriched in muscle and associate with lamin A/C and emerin at the nuclear envelope, while other isoforms localize to the Golgi, sarcomeric Z-lines, or processing bodies. Biallelic SYNE1 loss-of-function causes autosomal recessive cerebellar ataxia (SCAR8/ARCA1); SYNE1 variants are also associated with Emery-Dreifuss muscular dystrophy 4 and myogenic arthrogryposis.

Disorders

Relationship is the entry's genetic[].relationship_type. untyped means the entry has a genetic record for the gene but does not type it; its free-text association is shown instead.

An entry matches when ClinGen's MONDO disease is the entry's own disease term, a subtype term, or an exact-match mapping. An amber status marks an entry ClinGen supports the gene for (Definitive, Strong or Moderate) whose own record does not type it. A Limited, Disputed or Refuted tier on such an entry is not a gap.