Human disorders of ubiquitination and proteasomal degradation.
OBJECTIVE
The goal of this review is to provide an overview of rapidly evolving information on a new group of genetic inborn errors affecting ubiquitination and proteasomal degradation of proteins and to suggest a classification scheme for these disorders. The relevant genes encode ubiquitin, ubiquitin enzymes (E1 and many E2s and E3s), deubiquitinating enzymes, proteasomal subunits, and substrates undergoing ubiquitination.


RESULTS
Since the initial recognition that Angelman syndrome is caused by maternal deficiency of the E6-AP ubiquitin E3 ligase (gene symbol UBE3A), several. other disorders of E3 ligases have been identified, including autosomal recessive juvenile Parkinson disease, the APECED form of autoimmune polyendocrinopathy syndrome, von Hippel-Lindau syndrome, and congenital polycythemia. Disorders that disturb ubiquitin regulatory signaling include at least two subtypes of Fanconi anemia, the BRCA1 and BRCA2 forms of breast and ovarian cancer susceptibility, incontinentia pigmenti, and cylindromatosis. Many disorders affect ubiquitin pathways secondarily.


CONCLUSIONS
The authors propose both a genetic and a functional classification for disorders of ubiquitination and proteasomal degradation, as follows. Genetic classes include mutations in (1) the UBB ubiquitin gene; (2) enzymes of ubiquitination including E1, E2, E3, and related proteins; (3) deubiquitinases; (4) proteasomal subunits; and (5) substrates of ubiquitination. Functional classes include defects in (1) proteolytic degradation, (2) ubiquitin signaling, and (3) subcellular localization of substrates. Additional functional classes are likely to be defined, and individual disorders may involve multiple functional defects.
Jiang
Yong-hui
YH
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
Beaudet
Arthur L
AL
D000544:Alzheimer Disease / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D017204:Angelman Syndrome / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D000818:Animals; D005199:Fanconi Anemia / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D030342:Genetic Diseases, Inborn / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D016884:Polyendocrinopathies, Autoimmune / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D044764:Ubiquitin-Activating Enzymes / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D014452:Ubiquitins / Q000378:metabolism*; D006623:von Hippel-Lindau Disease / Q000201:enzymology / Q000235:genetics / Q000378:metabolism
D016328:NF-kappa B; D014452:Ubiquitins; D044763:Ubiquitin-Conjugating Enzymes; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex; D044764:Ubiquitin-Activating Enzymes