Seipin

Seipin is a homo-oligomeric integral membrane protein in the endoplasmic reticulum (ER) that concentrates at junctions with cytoplasmic lipid droplets (LDs).

[3] Though it was initially dubbed "mysterious protein",[4] recent empirical studies are gradually starting to unveil some of seipin's most compelling physiological functions.

[3] Celia's encephalopathy is associated with a mutation in BSCL2 that leads to increased alternative splicing of the pre-mRNA to an mRNA that lacks the seventh exon, corresponding to the second transmembrane domain of the protein product.

[17] The protein has a short cytoplasmic region, a transmembrane alpha-helix, a water-soluble beta-sandwich domain located in endoplasmic reticulum, and second TM helix.

Overexpression of mutated seipin proteins N88S or S90L can also activate autophagy, and substantially altering the sub-cellular distribution of the autophagosome marker GFP-LC3, which leads to a number of large vacuoles appearing in the cytoplasm.

Seipin mutations have been associated with congenital generalized lipodystrophy (see below), and mutations in an N-glycosylation motif links seipin to two other disorders, i.e. Silver syndrome and autosomal-dominant distal hereditary motor neuropathy type V.[20] CGL (congenital generalized lipodystrophy) is a heterogeneous genetic disorder characterized by almost complete loss of adipose tissue (both metabolic and mechanical adipose depots) and an increase of ectopic fat storage in liver and muscle.

[21] Furthermore, these patients could suffer dyslipidemia, hepatic steatosis, insulin resistance and hypertrophic cardiomyopathy due to a cell-autonomous defect in cardiomyocytes.

Spermatids devoid of seipin in germ cells are morphologically abnormal with large ectopic lipid droplets and aggregate in dysfunctional clusters.