A group of genetic inborn errors affecting ubiquitination and proteasomal degradation of proteins is now emerging.

The relevant genes involved encode ubiquitin, ubiquitin enzymes (E1 and many E2s and E3s), deubiquitinating enzymes, proteasomal subunits, and substrates undergoing ubiquitination.

Classification

 disorders of E3 ligases

• Angelman syndrome: maternal deficiency of the E6-AP ubiquitin E3 ligase (gene symbol UBE3A)
• autosomal recessive juvenile Parkinson disease
• APECED form of autoimmune polyendocrinopathy syndrome
• von Hippel-Lindau syndrome
• congenital polycythemia

 disorders of ubiquitin regulatory signaling

• two subtypes of Fanconi anemia
• BRCA1 and BRCA2 forms of breast and ovarian cancer susceptibility
• incontinentia pigmenti
• cylindromatosis

 disorders affecting ubiquitin pathways secondarily.

Genetic classes

 mutations in the UBB ubiquitin gene
 mutations in enzymes of ubiquitination including E1, E2, E3, and related proteins
 mutations in deubiquitinases
 mutations in proteasomal subunits
 mutations in substrates of ubiquitination

Functional classes

 defects in proteolytic degradation,
 ubiquitin signaling, and
 subcellular localization of substrates

References

 Jiang YH, Beaudet AL. Human disorders of ubiquitination and proteasomal degradation. Curr Opin Pediatr. 2004 Aug;16(4):419-26. PMID: #15273504#