A Drosophila model for the Zellweger spectrum of peroxisome biogenesis disorders.

[zellweger syndrome]

Human peroxisome biogenesis disorders are lethal genetic diseases in which abnormal peroxisome assembly compromises overall peroxisome and cellular function . Peroxisomes are ubiquitous membrane-bound organelles involved in several important biochemical processes , notably lipid metabolism and the use of reactive oxygen species for detoxification . Using cultured cells , we systematically characterized the peroxisome assembly phenotypes associated with dsRNA-mediated knockdown of 14 predicted Drosophila homologs of PEX genes (encoding peroxins ; required for peroxisome assembly and linked to peroxisome biogenesis disorders ), and confirmed that at least 13 of them are required for normal peroxisome assembly . We also demonstrate the relevance of Drosophila as a genetic model for the early developmental defects associated with the human peroxisome biogenesis disorders . Mutation of the PEX 1 gene is the most common cause of peroxisome biogenesis disorders and is one of the causes of the most severe form of the disease , Zellweger syndrome . Inherited mutations in Drosophila Pex 1 correlate with reproducible defects during early development . Notably , Pex 1 mutant larvae exhibit abnormalities that are analogous to those exhibited by Zellweger syndrome patients , including developmental delay , poor feeding , severe structural abnormalities in the peripheral and central nervous systems , and early death . Finally , microarray analysis defined several clusters of genes whose expression varied significantly between wild-type and mutant larvae , implicating peroxisomal function in neuronal development , innate immunity , lipid and protein metabolism , gamete formation , and meiosis .

Diseases
Validation

Diseases presenting "developmental delay" symptom

22q11.2 deletion syndrome

achondroplasia

alexander disease

alpha-thalassemia

aniridia

canavan disease

child syndrome

classical phenylketonuria

coats disease

cohen syndrome

congenital diaphragmatic hernia

congenital toxoplasmosis

cowden syndrome

gm1 gangliosidosis

harlequin ichthyosis

hirschsprung disease

holt-oram syndrome

homocystinuria without methylmalonic aciduria

kabuki syndrome

kallmann syndrome

krabbe disease

lamellar ichthyosis

monosomy 21

neonatal adrenoleukodystrophy

phenylketonuria

primary hyperoxaluria type 1

proteus syndrome

pyruvate dehydrogenase deficiency

sneddon syndrome

triple a syndrome

wolf-hirschhorn syndrome

zellweger syndrome

This symptom has already been validated