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PEX19 gene

Overview

Gene (OMIM No.)
Function of gene/protein
  • Protein: peroxisome biogenesis factor 19
  • Involved in peroxisome assembly and peroxisome matrix protein import via interaction with PEX3
  • Binds and stabalises newly synthesised peroxisomal membrane proteins in the cytoplasm
  • Peroxisomes are cellular structures involved in breaking down fatty acids, uric acids and reactive oxygen species
  • Also involved in biosynthesis of plasmalogens (a type of phospholipid crucial to normal functioning of the brain and lungs)
Clinical phenotype
(OMIM phenotype no.)
  • Peroxisome biogenesis disorder 12A (PBD12A; Zellweger syndrome) (#614886)
  • PBD12A is at the severe end of the Zellwenger syndrome spectrum (ZSS) caused by pathogenic mutations in PEX19
Inheritance
  • Autosomal recessive
Ocular features
Systemic featuresPBD12A/Zellwenger syndrome (ZS)
  • Most severe phenotype due to severely reduced/absent PEX19 function
  • Earliest onset and usually result in death within the 1st year of life
  • Neuronal migration defects causing structural abnormalities in the brain (microgyria, pachygyria and heterotopia) resulting in seizures and hypotonia
  • Characteristic craniofacial dysmorphism (large anterior frontanelle, prominent and high forehead, hypertelorism, epicanthic folds, high arched palate, micrognathia)
  • Liver dysfunction
  • Other features in Additional information
Key investigations
  • B-scan USS to measure axial length to document microphthalmia and detect any posterior abnormalities
  • Electrophysiology: absent rod and cone responses/rod-cone dystrophy in full field ERG
  • FAF and OCT: Outer retinal and RPE disruption/loss
  • Systemic assessment with a pediatrician and other relevant specialists
  • MRI brain
  • Biochemical investigations to assess the various peroxisomal pathways (blood, urine and cultured skin fibroblasts)
Molecular diagnosisNext generation sequencing
  • Targeted gene panels (cataract)
  • Whole exome sequencing
  • Whole genome sequencing
ManagementOcularSystemic
  • Multidisciplinary approach
Therapies under research
Further information

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Additional information

Peroxisome biogenesis disorders (PBDs) are disorders of peroxisome assembly and function due to mutations in any of the 14 peroxin encoding genes (PEX).[1] PBDs manifest as either Zellwenger syndrome spectrum (ZSS) or rhizomelic chondrodysplasia punctata type 1 (due to mutations in PEX7).[2]

The ZSS encompasses conditions of variable severity (related to age of onset) with overlapping features. Three distinct phenotypes have been described historically which are now classed under the ZSS umbrella. These conditions are:

  • Zellwenger syndrome (ZS; most severe phenotype with the earliest onset)
  • Neonatal adrenoleukodystrophy (NALD; intermediate phenotype)
  • Infantile Refsum disease (IRD; mild phenotype)

Pathogenic mutations in PEX19 give rise to PBD12A (Zellwenger syndrome), a phenotype that lies on the severe end of the spectrum.[3] The disease severity of ZSS depends upon the type of mutation where missense variants tend to be associated with a milder form of disease, while null mutations result in more severe clinical phenotypes.[2,5]

Zellwenger syndrome

The most severe phenotype, Zellwenger syndrome is an early onset (neonatal period) and fatal disease, with death usually occurring within the first year of life.[6] It is usually associated with biallelic null mutations, which results in a truncated and dysfunctional PEX19 protein.[6] ZS is characterised by:

  • Severe neurological dysfunction (neonatal seizures and hypotonia) due to neuronal migration defects
  • Characteristic craniofacial dysmorphism– large anterior frontanelle, prominent and high forehead, hypertelorism, epicanthic folds, high arched palate, micrognathia
  • Liver dysfunction and hepatomegaly
  • Failure to thrive, poor feeding
  • Psychomotor delay
  • Congenital cataract
  • Severe sensorineural hearing loss
  • Chondrodysplasia punctata (especially in the knees and hips)
  • Cardiovascular and respiratory anomalies
  • Renal cysts
  • Adrenal insufficiency

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References

  1.  Braverman NE, D’Agostino MD, Maclean GE. Peroxisome biogenesis disorders: Biological, clinical and pathophysiological perspectives. Dev Disabil Res Rev. 2013;17(3):187-196
  2.  Braverman NE, Raymond GV, Rizzo WB, et al. Peroxisome biogenesis disorders in the Zellweger spectrum: An overview of current diagnosis, clinical manifestations, and treatment guidelines. Mol Genet Metab. 2016;117(3):313-321
  3.  Yik WY, Steinberg SJ, Moser AB, Moser HW, Hacia JG. Identification of novel mutations and sequence variation in the Zellweger syndrome spectrum of peroxisome biogenesis disorders. Hum Mutat. 2009;30(3):E467-E480
  4.  Ebberink MS, Mooijer PA, Gootjes J, Koster J, Wanders RJ, Waterham HR. Genetic classification and mutational spectrum of more than 600 patients with a Zellweger syndrome spectrum disorder
  5.  Walter C, Gootjes J, Mooijer PA, et al. Disorders of peroxisome biogenesis due to mutations in PEX1: phenotypes and PEX1 protein levels. Am J Hum Genet. 2001;69(1):35-48
  6.  Argyriou C, D’Agostino MD, Braverman N. Peroxisome biogenesis disorders. Transl Sci Rare Dis. 2016;1(2):111-144
  7.  Mohamed S, El-Meleagy E, Nasr A, Ebberink MS, Wanders RJ, Waterham HR. A mutation in PEX19 causes a severe clinical phenotype in a patient with peroxisomal biogenesis disorder. Am J Med Genet A. 2010;152A(9):2318-2321
  8.  Götte K, Girzalsky W, Linkert M, et al. Pex19p, a farnesylated protein essential for peroxisome biogenesis. Mol Cell Biol. 1998;18(1):616-628

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Updated on November 30, 2020
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