CAST gene

CAPN1 and CAPN2 genes; calpain-1 and calpain-2 proteins; calpastatin protein; ERK1 and ERK2 genes; ERK1/2 kinases;

CAST is a protein-coding gene located on chromosome 5q15. Alternately spliced transcript variants have been described that encode various isoforms.

The protein encoded by this gene is an endogenous calpain inhibitor (calpastatin = calcium-dependent cysteine protease). It consists of an N-terminal domain L and four repeating calpain inhibition domains (domains 1–4) and is involved in the proteolysis of the amyloid precursor protein. Calpastatin is localized in the cytosol, the endoplasmic reticulum, the membrane, and the plasma membrane, where it plays a role in membrane fusion processes, among other things. It is involved in the proteolysis of the amyloid precursor protein as well as in processes such as the exocytosis of neuronal vesicles and the aggregation of platelets and red blood cells.

The calpain-calpastatin system is involved in numerous membrane fusion processes, such as the exocytosis of neural vesicles and the aggregation of platelets and red blood cells. It is also believed that the protein encoded by this gene influences the expression levels of genes that encode structural or regulatory proteins.

A biallelic loss-of-function variant in the CAST gene leads to calpastatin deficiency with inadequate control of calpain activity. This is associated with impaired epidermal integrity and keratinization. Clinically, this condition is known as PLACK syndrome. 

PLACK stands for:

- P – Peeling skin

- L – Leukonychia

- A – Acral punctate keratoses

- C – Cheilitis

- K – Knuckle pads

1. Boggs JME et al. (2021) PLACK syndrome resulting from a novel homozygous variant in CAST. Pediatr Dermatol 38:210–212.
2. Hanna RA et al. (2008): Calcium-bound structure of calpain and its mechanism of inhibition by calpastatin. Nature 456:409–412.
3. Hu B et al. (2023) PLACK syndrome caused by novel pathogenic variants in CAST: a case report and literature review. Clin Exp Dermatol 48:1052–1055.
4. Ono Y et al. (2012): Regulation and physiological roles of the calpain system in muscular disorders. Cardiovasc Res 96:11–22.
5. Starska K et al. (2016) Gene/protein expression of CAPN1/2-CAST system members is associated with ERK1/2 kinase activity as well as progression and clinical outcome in human laryngeal cancer. Tumor Biol 37:13185–13203.
6. Wendt A et al. (2004) Interaction of calpastatin with calpain: a review. Biol Chem 3185:465–472.