Functional analysis of PEX13 mutation in a Zellweger syndrome spectrum patient reveals novel homooligomerization of PEX13 and its role in human peroxisome biogenesis.

[zellweger syndrome]

In humans , the concerted action of at least 13 different peroxisomal PEX proteins is needed for proper peroxisome biogenesis . Mutations in any of these PEX genes can lead to lethal neurometabolic disorders of the Zellweger syndrome spectrum (ZSS ). Previously , we identified the W 313 G mutation located within the SH 3 domain of the peroxisomal protein , PEX 13 . As this tryptophan residue is highly conserved in almost all known SH 3 proteins , we investigated the pathogenic mechanism of the W 313 G mutation and its role in PEX 13 interactions and functions in peroxisome biogenesis . Here , we report for the first time that human PEX 13 interacts with itself in peroxisomes in living cells . We demonstrate that the import of PTS 1 (peroxisomal targeting signal 1 ) proteins is specifically disrupted when homooligomerization of PEX 13 is interrupted . Live cell FRET microscopy in living cells as well as co -immunoprecipitation experiments reveal that the highly conserved W 313 residue is important for self-association of PEX 13 but is not required for interaction with PEX 14 , a well-established interaction partner at the peroxisomal membrane . Experiments with truncated constructs indicate that although the W 313 G mutation resides in the C-terminal SH 3 domain , the N-terminal half is necessary for peroxisomal localization , which in turn appears to be crucial for homooligomerization . Furthermore , rescue of homooligomerization in the W 313 G mutant cells through complementation with truncation constructs restores import of peroxisomal matrix proteins . Taken together , the thorough analyses of a ZSS patient mutation unraveled the general cell biological function of PEX 13 and its mechanism in the import of peroxisomal matrix PTS 1 proteins .

Diseases
Validation

Diseases presenting "first time" symptom

achondroplasia

acute rheumatic fever

adrenal incidentaloma

adrenomyeloneuropathy

alpha-thalassemia

aniridia

aromatase deficiency

canavan disease

carcinoma of the gallbladder

cholangiocarcinoma

classical phenylketonuria

congenital adrenal hyperplasia

congenital toxoplasmosis

cowden syndrome

cushing syndrome

cutaneous mastocytosis

dedifferentiated liposarcoma

dentin dysplasia

dentinogenesis imperfecta

dracunculiasis

dystrophic epidermolysis bullosa

epidermolysis bullosa simplex

erdheim-chester disease

erythropoietic protoporphyria

esophageal adenocarcinoma

esophageal carcinoma

esophageal squamous cell carcinoma

fabry disease

familial mediterranean fever

gm1 gangliosidosis

harlequin ichthyosis

heparin-induced thrombocytopenia

hirschsprung disease

hodgkin lymphoma, classical

holt-oram syndrome

hydrocephalus with stenosis of the aqueduct of sylvius

junctional epidermolysis bullosa

kabuki syndrome

kallmann syndrome

liposarcoma

locked-in syndrome

lymphangioleiomyomatosis

malignant atrophic papulosis

megacystis-microcolon-intestinal hypoperistalsis syndrome

monosomy 21

neuralgic amyotrophy

oculocutaneous albinism

oligodontia

omenn syndrome

oral submucous fibrosis

papillon-lefèvre syndrome

pendred syndrome

phenylketonuria

primary effusion lymphoma

primary hyperoxaluria type 1

severe combined immunodeficiency

sneddon syndrome

triple a syndrome

trochlear dysplasia

von hippel-lindau disease

waldenström macroglobulinemia

well-differentiated liposarcoma

werner syndrome

wiskott-aldrich syndrome

wolf-hirschhorn syndrome

x-linked adrenoleukodystrophy

zellweger syndrome

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