Mutatednup62causes autosomal recessive infantile bilateral striatal necrosis

Abstract

Objective: The objective of this study was to identify the gene causing autosomal recessive infantile bilateral striatal necrosis. Methods: We have mapped the disease gene in the candidate region to approximately 230kb on 19q13.33 in 8 interrelated families including a total of 12 patients and 39 unaffected individuals. Results: Sequencing of the nup62 gene showed a missense mutation causing a change from glutamine to proline (Q391P) in all the patients, producing a substitution from a polar, hydrophilic residue to a nonpolar, neutral residue. All the other 12 candidate genes were sequenced, and no pathogenic sequence changes were found. Comparisons of p62 protein sequences from diverse species indicate that glutamine at position 391 is highly conserved. Five prenatal diagnoses were performed in three at-risk families. Interpretation: This is the second example of a nuclear pore complex protein causing mendelian disease in humans (the first one is triple A syndrome). Our findings suggest that p62 has a cell type-specific role and is important in the degeneration of the basal ganglia in humans.

Nucleoporin 62-Like Protein Activates Canonical Wnt Signaling through Facilitating the Nuclear Import of β-Catenin in Zebrafish

“…Furthermore, inappropriate expression of Nup62 is linked to developmental defects and several human diseases, such as primary biliary cirrhosis (110) and autosomal recessive infantile bilateral striatal necrosis (30). Findings from this study have revealed a regulatory network among Nup62l, Wnt/␤-catenin, and Bmp signaling in zebrafish (Fig.…”

“…Nuclear mRNA export is disrupted in a temperature-sensitive mutant of Nsp1p, the yeast homologue of mammalian Nup62 (29). Moreover, a missense mutation of Nup62 in humans leads to infantile bilateral striatal necrosis (30). Nevertheless, physiological, pathological, and developmental roles of Nup62 in vertebrates remain to be well defined.…”

Leigh map: A novel computational diagnostic resource for mitochondrial disease

“…The outermost compartment represents the cytosol, where it is possible to find the nucleus and the mitochondrion. Three nuclear genes, nuclear envelope protein NUP62 , nuclear export protein RANBP2 , and adenosine deaminase ADAR , have been included in our network as genes causing a clinical and radiological phenotype closely resembling Leigh syndrome 14, 15, 16. The mitochondrion is visualized in its double membrane structure, and mitochondrial genes are grouped according to function and can be found in their submitochondrial location (eg, outer membrane, matrix).…”

Protein localization in disease and therapy

“…For example, in patients with familial atrial fibrillation, the homozygous mutation R391H in the nucleoporin NUP155 has been shown to reduce nuclear envelope permeability and affect the export of Hsp70 mRNA and import of HSP70 protein (Zhang et al, 2008). That study was the first to link a nucleoporin defect to cardiovascular disease.Mutations in other components of the NPC, such as the nucleoporin p62 protein and ALADIN (alacrima achalasia adrenal insufficiency neurologic disorder, officially known as AAAS) are thought to cause the neurodegenerative diseases infantile bilateral striatal necrosis and triple A syndrome, respectively (Basel-Vanagaite et al, 2006; Kiriyama et al, 2008). Mutant ALADIN prevents nuclear entry of the DNA repair proteins aprataxin and DNA ligase I and, therefore, results in increased DNA damage and subsequent cell death caused by oxidative stress (Kiriyama et al, 2008).…”