Peroxisomal Biogenesis Factor 19 (PEX19) is part of a group of constitutive housekeeping genes termed peroxins that are involved in peroxisome biogenesis. PEX19 encodes a predominantly cytoplasmic protein that binds the hydrophobic domains of class I peroxisomal membrane proteins (PMP); PEX19 stabilizes and targets PMPs towards peroxisome assembly. PEX19-PMP binds the peroxisome transmembrane protein PEX3 in order to facilitate importing of class I PMPs into the peroxisome membrane. PEX19 is additionally thought to downregulate tumorsuppressor function; the peroxin interacts with p19ARF in the cytoplasm restricting its access to the nucleolus, where it normally prevents transcriptional silencing of p53 and Mdm2 mediated degradation of p53.
Peroxin dysfunction clinically results in various subtypes of Zellweger syndrome, the most severe phenotypic class of peroxisome biogenesis disorders. PEX19 dysfunction is specifically associated with autosomal recessive peroxisome biogenesis disorder 12A (PBD12A).
PEX19 is located on the q arm of chromosome 1 and is 9,540 bases long, ranging from position 160,276,809 to 160,286,348 base pairs pter. It translates into a 299 amino acid long protein with a molecular weight of 32,807 Da. 2 main isoforms have been identified, with isoform 1 ubiquitously expressed in all tissues, and isoform 2 predominantly expressed in utero. In addition to the C-terminal PMP-binding and N-terminal PEX3-docking domains, PEX19 comprises a unique C-terminal farnesylation motif (CAAX box) which is thought to be essential for efficient interaction with PMP proteins.
Homozygous mutations in PEX19 result in peroxisome biogenesis disorder 12A, a subtype of Zellweger syndrome. This fatal congenital disorder is characterized biochemically by the presence of very long fatty acid chains and absence of peroxisomes.
Mohamed et al., (2010) identified a novel mutation in a Saudi infant diagnosed with peroxisome biogenesis disorder 12A. Biochemical analysis of very long fatty acid chains and dihydroxyacetone-phosphate acyltransferase (DHAPAT) revealed abnormally high C26:0 levels (9.7µmol/L) and negligible DHAPAT activity (0.6nmol/mg/2hr) respectively; the absence of fibroblast peroxisomes lead to complementation testing of the possible dysfunctional peroxin genes, narrowing the search to PEX19. Mutation analysis revealed a homozygous deletion c.320delA causing the frameshift mutation p.K107SfsX13; the infant’s first-cousin parents carried the same mutation. Functional analysis could not be performed; however the authors noted a less severe clinical course and longer survival relative to patients exhibiting the only other reported mutation in PEX19 (c.763_764insA). The authors suggest that the index mutation results in a truncated PEX19 protein that exhibits residual function. She had succumbed to symptoms at 16 months of age.